Normal Circulation
Regulation of the Blood Pressure System
The maintenance of blood pressure is dependent upon intrinsic, reflex, hormonal, renal, and microvascular control systems. The complexity in the control of blood pressure is dependent upon the interaction from each control system. Each system of control will be discussed separately. Where applicable, simple interactions of systems are discussed; however, the normal range of blood pressure from short term to long term is controlled by the precise integration of all control systems.
According to Poisuille's law, [pressure is equal to flow times resistance], there are three ways to change blood pressure [P]: 1) altering flow [Q], 2) resistance[R] (i.e. total peripheral resistance [TPR]), or 3) both (73, 124). Thus, an increased blood flow and/or resistance to blood flow may alter blood pressure (35). This conclusion is based on the fact that mean arterial pressure [MAP] is the product of cardiac output; [Q] = [heart rate X stroke volume], and total peripheral resistance [TPR], thus, [MAP = CO X TPR](35). Blood pressure can increase or decrease only if the cardiac output and/or total peripheral resistance is altered. Regardless of the control systems used to adjust blood pressure, the resultant change in blood pressure is dependent on how these systems regulate [Q] or [TPR], or both.
Intrinsic Regulation
The integrity of the cardiovascular system is necessary to maintain life. Central determinants of blood pressure are stroke volume and heart rate; both of which influence cardiac output. Intrinsic mechanisms of the cardiovascular system stabilize cardiac output via stroke volume and heart rate.
The intrinsic control of stroke volume is predominantly what regulates cardiac output (125). The volume of blood that fills the ventricles of the heart determines intrinsic control of stroke volume. Thus, peak wall tension is approximated by the peak pressure or volume [stroke volume] ejected during contraction (125). This relationship is known as the Frank Starling mechanism (108). The end?diastolic filling pressure [preload] is the most important determinant of stroke volume (125).
Another intrinsic factor that determines stroke volume is the amount of resistance offered against the left ventricle during contraction. This is known as aortic pressure or afterload (125). A higher afterload will decrease stroke volume. Because the contraction velocity is decreased with a higher afterload, and because the time of contraction is regulated by the duration of depolarization, stroke volume will be lower at a higher afterload (125).
Stroke volume is well regulated by the interaction of both preload and afterload. Both can have independent effects on stroke volume, but both rarely change separately. When cardiac output increases more volume is derived from the venous pool increasing preload. Thus, arterial pressure will then increase, increasing afterload. So, preload and afterload tend to oppose a rise in cardiac output [i.e., a balanced intrinsic regulation], (125).
Heart rate is an intrinsic factor and central determinant of blood pressure. Heart rate properties that affect flow include: 1) an increase in heart rate which will increase the contractile strength and, 2) transient changes in heart rate where the contractility decreases with lower rates and increases with higher rates (125).
Of the three central intrinsic control mechanisms, heart rate will have the least influence on cardiac output during rest. If heart rate is increased cardiac output will increase but this increase is not proportional to the increase in heart rate (125). This is because with an increase in heart rate: 1) there will be a decreased preload, and 2) an increased afterload. If peripheral resistance remains constant blood pressure will increase, like cardiac output, but proportionally less than heart rate (125).
Intrinsic controls also exist in the periphery to regulate flow via changes in peripheral vascular resistance. In the arterial system, there is metabolic control of the smooth muscle cells of the arteries. An inadequate supply of oxygen or build up of other metabolites will promote vasodilation (125).
Another important intrinsic control mechanism is autoregulation. Autoregulation of organs assures a constant blood flow under changing pressures and decreases peripheral resistance when arterial pressure or oxygen content of arterial blood falls (125).
Reflex Regulation
Intrinsic regulation is an effective control mechanism for maintaining blood pressure under resting conditions. A faster response system is needed under conditions of posture change, exercise, and moderate temperature changes. The reflex regulation system of baroreceptors [pressoreceptors] is able to control sudden changes in blood pressure with these conditions. The baroreflex system is composed of: 1) baroreceptors in the aortic arch and carotid sinuses; 2) sensory nerve fibers which relay signals both to and from the receptors to the medullary region of the brain; 3) and cardiac and smooth muscle cells on which the nerve fibers act to alter cardiac contractility, heart rate, and peripheral vascular resistance (125).
The baroreceptors respond to changes in length, [stretch], of the tissue in which they lie (125). When there is an increase in blood pressure the receptors are stretched and the rate of firing or signaling to the medullary region of the brain is increased. When there is a decrease in pressure, the opposite occurs. These receptors have both a static and dynamic response: a) static responses are to maintained levels of pressure [ie. when rate of change of pressure is zero]; and, b) dynamic responses to phasic changes in pressure, [i.e. arterial pulse wave] (125). With the static response, firing rate will be minimal at a pressure of 20 to 50 mmHg, below which no firing will occur, and the frequency of the firing will increase as the pressure increases above this threshold (19, 40, 83, 133). As pressure increases, this firing rate will reach a plateau. In the dynamic response, the receptors fire with greatest frequency when the pressure is greatest during the arterial pulse wave and may cease to fire when pressure falls off. Thus, the receptor is sensitive to the mean pressure and rate of change in pressure. Because the receptor is sensitive to mean pressure and the rate of change in pressure, reflex responses are dependent upon mean arterial pressure, pulse pressure and heart rate (19, 40, 83, 133).
Sympathetic and parasympathetic nerve fibers run from the baroreceptors to the medullary centers of the brain. Different regions of the medulla are responsible for stimulation of either the parasympathetic or sympathetic nerve fibers which, in turn, innervate the heart, arteries and adrenal gland (125). Sympathetic impulses to the medulla will decrease in firing frequency as arterial pressure and baroreceptor discharge increase (43, 74). The opposite is also true. As pressure increases, the parasympathetic activity increases (71, 133). The relationship between the two systems is linear and inverse (125). The different regions of the medulla will respond to the increase in sympathetic or parasympathetic activity. Increased sympathetic activity and decreased vagal activity to the medulla will result in a increased heart rate, and cardiac contractility, via norepinephrine release from adrenal gland on the cardiac pacemaker and myocardium. Increased sympathetic activity to the medulla will also cause a widespread vasoconstriction via norepinephrine on the peripheral arterioles (125). Increased parasympathetic activity to the medulla produces the opposite motor responses.
Other Reflex Mechanisms
Other reflex mechanisms involved in the regulation of blood pressure are the cardiopulmonary receptors and chemoreceptors. The cardiopulmonary receptors are located in the walls of the cardiac chambers and the pulmonary artery. The chemoreceptors are located close to the arterial baroreceptors and within the central nervous system (125).
The firing pattern of the cardiopulmonary receptors parallels the pressure changes within the chambers or vessels where they are located. Impulses travel to the control centers in the brain through the vagus nerve (125). The most prominent cardiopulmonary receptor is located in the atria. Atrial receptors have a role in the regulation of the volume of body fluids (53, 128). The stronger reflex effects of the atrial baroreceptors mask the reflex effects of cardiopulmonary receptors of the atria. Experiments have been conducted on the canine model where the arterial baroreceptors have been denervated. Results from these experiments have shown cardiopulmonary receptors have effects on the peripheral resistance and heart rate in canine. Cardiopulmonary receptors of the atria can produce a global vasoconstriction (33), and stretching the atria may also produce tachycardia (7, 87).
The prominent chemoreceptors include the arterial, ventricular, and medullary chemoreceptors. Collectively, these receptors are sensitive to changes in pH, blood gasses, or changes in plasma composition.
The arterial chemoreceptors are composed of the aortic and carotid bodies. The carotid body is more sensitive. The carotid body is a small mass of tissue but receives a high volume of blood flow and is located close to the carotid baroreceptors (125). It is sensitive to changes in the partial pressure of oxygen and pH. The bodies in the aortic arch respond in a similar fashion as the carotid, but their response is attenuated under comparison. Both chemoreceptors have marked effects on respiration and under conditions of extreme depravation of oxygen will cause severe vasoconstriction and bradycardia (125).
The chemoreceptors of the ventricles will respond to a series of pharmacological agents including: Veratrum alkaloids, nicotine, and serotonin. Exposure to these agents will cause a marked bradycardia and vasodilation, known as the Bezold?Jarisch reflex (125). Its significance in circulatory regulation remains unknown.
The chemoreceptors of the medulla are sensitive to a decrease in pH or an increase in plasma carbon dioxide concentration. Inadequate profusion of the medullary region, increased plasma carbon dioxide, or hydrogen ion concentration, can cause a marked vasoconstriction (125).
Hormonal Regulation
Hormones also operate in maintaining the blood pressure. Two hormones of concern are the hormones included in the renin?angiotensin system, and vasopressin. Both are slower regulatory mechanisms of blood pressure.
Renin is an enzyme produced in the juxtaglomerular cells of the kidney. A decrease in the pressure at the renal artery, an activation of the sympathetic nerve fibers to the kidney, or a decrease in the amount of sodium passing through the distal tubule of the kidney, will prompt the release of renin. The release will convert renin to angiotensin I and angiotensin I is converted to angiotensin II in the lung and other organs. Angiotensin II is a potent vasoconstrictor and will also stimulate the release of aldosterone from the adrenal gland. Aldosterone will increase sodium absorption at the kidney, thus allowing for fluid retention and increasing plasma volume (125).
Vasopressin, better known as antidiuretic hormone ,[ADH], is housed in the pituitary gland. Two major stimuli promoting the release of ADH are increase in the plasma osmolarity, and decreases in plasma volume by an indirect route from pressoreceptors in the carotid sinus and aortic arch. These pressoreceptors communicate with the hypothalamus, and a decrease in the firing rate from the receptors will somehow initiate the release of ADH (125). ADH is both a potent vasoconstrictor and plasma volume regulator (107). ADH will regulate plasma volume by resorption of water at the distal tubule of the nephron (125).
Renal Regulation
The kidneys control blood pressure through the retention and excretion of extracellular fluid. The glomerular filtration rate is dependent upon the mean arterial pressure; however, a large increase in arterial pressure will only slightly increase glomerular filtration (103, 155). Filtration is not greatly increased because renal arterial pressure is autoregulated before reaching the glomerular capillary. The loss of extracellular fluid is more pronounced by a lack of resorption. As previously discussed, resorption in the kidney is controlled by aldosterone and ADH.
Extracellular volume is determined by the osmolarity of the plasma. Sodium and coanions constitute 95% of the osmotically active solute of the extracellular fluid and osmolarity is regulated by water excretion. Thus, extracellular volume is controlled by the amount of sodium retained by the body (136). Aldosterone is the most important determinant of sodium retention in the kidney.
The kidneys, under hormonal regulation, will control the extracellular volume. An increase in renal output will decrease the extracellular volume, decreasing venous return and subsequently cardiac output and arterial pressure. An increase in extracellular volume without compensation from the kidney has been shown to maintain elevated arterial pressure (136).
Atrial natriuretic factor [ANF] has also been shown to increase glomerular filtration rate and the filtered load of sodium and sodium excretion in mammals (32, 104). ANF may play an important indirect role in regulating intravascular volume and decreasing blood pressure. An increased intravascular volume (ie. extracellular fluid) will stretch the atria and stimulate the release of ANF. ANF will inhibit the release of vasopressin. Other circulating substances with natriuretic activity have also been reported (21). Agents which control the synthesis and release of ANF have not been determined (104).
Thus, renal regulation of blood pressure is by control of extracellular volume. This is accomplished through the hormonal regulation of resorption, and to a lesser extent, glomerular filtration rate. Hormonal control of resorption is through the action of ADH and aldosterone, whereas glomerular filtration rate is effected to some degree by filtration pressure, ANF, and possibly other circulating natriuretic factors.
Microvascular Circulation
Vascular fluid shifts occur with the microvascular circulation (ie. at the capillaries). The rate of fluid movement across exchange vessel walls is proportional to the difference between the hydrostatic and colloid osmotic pressures (100). In other words, high arterial pressure tends to decrease plasma volume by driving fluid into the interstitium, while high plasma proteins tend to increase plasma volume by osmotically drawing fluid from the interstitium (136).
This mechanism would allow a decrease in intravascular volume from the higher hydrostatic pressure and a concomitant decrease in cardiac output and arterial pressure (125). The opposite is also true. All things being equal, a low plasma volume would increase the concentration of positive colloid pressure drawing fluid from the interstitium to the capillary, increasing intravascular volume.
Integration
The mechanisms which regulate the blood pressure do not respond simultaneously. Some mechanisms require only a few seconds to respond whereas others may require a period of days. The mechanisms for the control of blood pressure may work somewhat independently, such as the baroreflexive control of blood pressure in posture changes. However, in the maintenance of normal pressure from changes in vascular volume, integration of the mechanisms becomes crucial.
Short term mechanisms may be activated within seconds. These include all of the reflex mechanisms and chemoreceptor control. Intermediate mechanisms are usually activated within hours. These include fluid shifts in the microvascular circulation and the renin?angiotensin system. Long term mechanisms are the hormones which direct the renal control of extracellular volume. Under normal conditions, these control mechanisms should function to keep the blood pressure within a normal range indefinitely.
Age Related Changes in Blood Pressure
The aging process, itself, is not entirely responsible for the development of hypertension, even though there is a high incidence of hypertension in the elderly (150, 152). Aging does have an effect on all of the major organ systems including the heart, kidneys, peripheral vasculature, and central nervous system (150). These systems function to regulate blood pressure and all of these systems may age at different rates. A deficiency in any one of these particular systems will cause an altered response or compromise of one or more of the others. As indicated in the previous section, a proficient functioning of the cardiovascular system is a delicate balance of these systems under intrinsic and extrinsic modulation.
The effect of age on the cardiovascular function should be addressed in the context of the population studied and the variable used to define and measure cardiac function. Probably the most consistent findings in the studies of the influence of aging is the large variation in the older population for nearly every cardiovascular variable (18).
Intrinsic Regulation
Early invasive studies in the elderly indicated that there was a reduction in cardiac output at rest as a function of aging (17, 27, 139). One study indicated that reductions in cardiac output in the elderly may be related to a reduced stroke volume (88). Conversely, the large Baltimore Longitudinal Studies have shown an age?related reduction in heart rate. However, they also reported that cardiac output was not affected because an increased stroke volume compensates for the decrease in heart rate.
It is speculated that the early invasive studies reported differences in cardiac output between the old an young based on the technique used (18). Cardiac output may have been greater in younger subjects because of an age difference in the stress response to the invasive procedure itself. The age?related decline in cardiac output and stroke volume found in the elderly may also be due to a decreased stress response to circulating catecholamines (88). Studies indicating marked differences in these intrinsic variables are probably also affected by superimposed disease or deconditioning (18, 88). Non?invasive studies have shown no age?related decrease in cardiac output, heart rate, or stroke volume at rest (41, 112, 116, 120).
Of the three intrinsic control mechanisms, there is still disagreement on heart rate. As indicated, some studies have demonstrated no age related decrease in heart rate, (41, 112, 116, 120), where others have shown an age related decrease (82). A probable cause for these conflicting findings may be due to the amount of loss of intrinsic autonomic control of the sinus rate or an increase in vagal tone, [ie. the rate of loss of autonomic control or gain of vagal tone may not be predictable], (82). Studies have reported a decrease in the intrinsic sinus rate with aging. The intrinsic sinus rate has been reported to decrease from 104 beats per minute, [bpm] at age 20 to 92 bpm in a 45?55 year old individual (82).
Two common changes seem to occur in the cardiovascular system with aging that may affect the intrinsic modulation of blood pressure. One change is an increase in peripheral vascular resistance, and the second, is a disproportionate increase in systolic blood pressure.
A common age associated variable of change is peripheral vascular resistance, [PVR] . An increase in PVR may be inherent in the aging process (69, 73, 98, 129). Even though the intrinsic control remains unaffected by aging alone, a continual increase in PVR over time may produce morphological changes to the heart, thus effecting intrinsic control.
Many studies have reported increased vascular stiffness, especially in the aorta, associated with aging. This increased arterial elasticity, or arteriosclerosis is probably indicative of frayed elastin fibers, increased content of calcium, with the effective shortening of the elastin chains that compose the arterial wall (82). An increase in vascular stiffness may be detected by an increase in the pulse wave velocity. Many elderly have a greater pulse wave velocity than younger counterparts (82).
There also seems to be some deficit with arteriolar dilation and reflex vascular impedance in the elderly perhaps due to some deficit in the "relaxant effects" of the vessels themselves. The failure of arteriolar dilation may be due to a lack of response by the arteriolar smooth muscle cells to b?adrenergic stimulation (82). This may be a condition which assists in elevating the PVR (82).
The increase in systolic blood pressure associated with aging is probably secondary to the age?associated changes in arterial stiffening because the rise in blood pressure varies directly with vascular stiffness in different populations (6). The prevalence of an isolated increase in systolic blood pressure is significantly greater in the elderly as compared to younger populations (3, 69). Hypertensive disease and its progression in the elderly will be discussed in a later section.
Reflex Regulation
The baroreceptor set point and central control mechanisms regulate mean arterial pressure [MAP], must also be considered. Faulty autoregulation in blood pressure may occur because of alterations in the baroreceptor reflex mechanisms. These alterations may be the result of an aging autonomic nervous system (88, 115, 150, 154). The precision of the autonomic nervous system declines as a function of aging (60). Both age and hypertension reduce baroreflex sensitivity independently of each other (60). Sustained elevations or reductions in blood pressure associated with aging result in resetting baroreflex sensitivity. The baroreceptors may lose their original sensitivity if the vascular changes associated with aging and/or blood pressure elevation reset the sensitivity (115, 154).
Renal Regulation
Renal blood flow has also been shown to decrease with increasing age. However, there is no evidence to support that renal ischemia is the result of age associated changes that are linked with increased peripheral vascular resistance (82). If renal blood flow is compromised, the renin?angiotensin response may be elicited.
ETIOLOGY OF HYPERTENSION
Etiology
Many conditions have been associated, some more strongly than others, with the presence of hypertension. These conditions are also believed to be implicated in the development of hypertension. Some of the etiologic risk factors that cannot be controlled include: a positive family history of hypertension, sex, and race. Other risk factors that may be controlled through behavioral modification or medications include body composition, diet, stress, and neural?humoral and renal regulation.
Genetic Factors
Familial Hypertension
There is familial aggregation of hypertension among parents, siblings, and children at all ages (154). The tendency for relatives of hypertensive patients to resemble each other's arterial pressures is similar at all levels of pressure. In addition, higher correlations are found among close relatives than among distant ones (154). A stronger argument for the genetic influence on hypertension may be found in twin studies. There is similarity between both systolic and diastolic blood pressures in monozygotic twins and is significantly closer than those pressures of dizygotic twins (154). There has been no significant correlation in pairs of adopted children living together or between adopted children and their adopted parents or siblings (154).
Molecular biological markers as predictors of hypertension are increasingly being recognized (56). The precise mode of genetic inheritance of hypertension has not been demonstrated; however, it appears to be polygenetic (154). The major stumbling block is in the identification of which particular phenotype is precisely related to hypertension (56). Hypertension is unimodally distributed and not bimodally, as molecular biology approaches have been so defined, so it cannot be used as a phenotype. There are examples of bimodally distributed hypertension such as modulating and nonmodulating sodium sensitivity (56). Discoveries in the area of genetic based relationships and research in hypertension seems to be an area where future advancements may be readily made in determining those individuals at greater, or perhaps somewhat inevitable risk.
Sex
Men and women are equally represented in number of the forty million Americans who have hypertension (49); however, the prevalence within age cohorts is different between the sexes (56, 102, 154). Younger men have higher blood pressures than younger women (56, 154). Middle?age men have higher blood pressures than middle?aged women, but during this time the rate in increase of systolic blood pressure is greater in women than in men (29). By old age, women have higher blood pressures than older men (56, 154). Because a greater proportion of women develop hypertension as they age, there is a stronger association with hypertension in women with increasing age than in men (102).
One reason for the increased prevalence of hypertension in older women may be due to the greater prevalence of mortality associated with hypertensive disease in younger men (49, 153). Even though women over the age of 65 have a higher incidence of stroke than their younger counterparts (115), women still have a lower incidence of mortality associated with hypertension across all age groups (49).
Race
Race is also an attributing factor of hypertension (124). Hypertension affects 18% of the adult Caucasian population compared to 35% of the adult African?American population (13). These figures indicate a significantly higher prevalence in hypertension among African?Americans compared to their Caucasian counterparts (154). In African?Americans, the prognosis is less favorable with excess mortality (154) and morbidity from hypertension related diseases than in Caucasians at similar baseline blood pressures (37).
The etiology of the hypertensive disease may be traced into the childhood years of the African?American population to a greater extent than their Caucasian cohort (56). Perhaps what is most intriguing is the difference in the magnitude of response between the two races when other factors associated with hypertension are combined with race. Data suggests that African?American children seem to have an interactive hypertensive response between stress and sodium sensitivity, such that the combination of being African?American, on a high salt diet, and being exposed to stress produces a higher than expected increase in blood pressure (56). These data are interesting not only because of the impact of diet and stress on the development of hypertension in the African?American adult population but may also explain why hypertension is much more prevalent and lethal in the African?American population in the United States as compared with the Caucasian (56).
Body Mass/Composition
In adults, body mass is directly related to the blood pressure (154). An increase in body mass is associated with an increased risk of high blood pressure (21, 37, 65, 79, 149) and longitudinal studies have shown those who gain more weight demonstrate a larger increase in blood pressure (154).
The opposite is also true. A reduction in body mass achieves a proportionate decrease of arterial pressure (154). Controlled three year trials have demonstrated a loss in body mass will even decrease blood pressure in normotensive populations (23). Blood pressure was lowered in 15 out of 16 controlled studies treating high blood pressure through reducing body mass (140).
Because this reduction has been shown to decrease the risk of high blood pressure, adults should attempt to have a body mass index (BMI) no greater than 27 (23). The body mass index succinctly relates body mass to body composition because it is an estimate of body fatness and is equal to the mass in kilograms divided by height in meters squared (23). Thus, overweight individuals with hypertension should be no greater than 15% above their desirable body mass index (23, 29, 39).
Not all hypertensives adults are obese or all obese hypertensive; however, within 10?15 years at least 60% of overweight individuals will develop hypertension (140). Obese adults have a three?fold risk for the development of hypertension compared to non?obese counterparts (35).
One of the mechanisms for the development of hypertension associated with obesity may involve an increase in vascular tone. The increase in vascular tone or total peripheral resistance in the obese may be caused by an increase in the alpha?adrenergic response (35), and increased noradrenergic activities (84) or opiate suppression (36). Obese hypertensives have been shown to have a greater alpha?adrenergic response than their non?obese counterparts (35). Thus, the higher preload and afterload placed on the heart from an increased vascular tone may explain why the obese are at a threefold greater risk of developing subsequent hypertension (35) Other suggested mechanisms linking obesity with hypertension include an increased cardiac output (2), possibly due to an increased blood volume or sodium stores because of hyperinsulinemia or aldosterone -renin alterations (54).
Obesity in of itself is a moderate predictor of hypertension; however, centrally distributed obesity, tends to be a potent predictor of hypertension (56). There is a positive relationship between centrally distributed obesity and hyperinsulinemia. Hyperinsulinemia is also a suggested mechanism linking obesity with hypertension (54). Insulin is a potent trophic hormone, and the insulin receptors are present in the endothelial and arterial smooth muscle cells (8). Insulin may also elevate blood pressure by two other mechanisms. These include the action of insulin to increase circulating catecholamines (122), and the stimulation of renal sodium resorption (10).
Older individuals have a higher percentage of centrally distributed body fat than their younger counterparts. The decrease in lean body mass with an increase in total body fat, especially in central distributions, in older patients may contribute to the development of hypertension (150).
Diet
Sodium Intake
Increased sodium consumption can elevate blood pressure in some individuals. These sodium sensitive individuals likely have high membrane permeability to sodium that may be genetic (18). This increased membrane permeability has been demonstrated in normotensive children of hypertensive parents. These children have higher concentrations of intracellular sodium compared to children of normotensive parents (110). The increase in intracellular sodium has been linked to an increase in intracellular calcium in cells from hypertensives (12). It is postulated that sodium sensitive individuals have an increased vascular tone because of the increase in intracellular calcium (59, 80). This influence of increased levels of intracellular calcium on blood pressure is discussed in the subsequent section.
Sodium also increases intravascular volume. It has been proposed that an increased intravascular volume stimulates the secretion of a digitalis?like natriuretic hormone that inhibits the sodium, potassium ? ATPase pump. Inhibition of this pump would increase renal sodium excretion to restore vascular volume; however, it would, at the same time, increase intracellular sodium content (32).
The transport of sodium may be altered by an inherited defect in the structure of the cell membrane (127). Increased activity of the NA+/H+ antiporter could be involved in various local stimuli that increase vascular tone and vascular smooth muscle cell hypertrophy (127). The activity of the NA+/H+ antiporter was found to be increased in African?Americans (52). The erythrocyte sodium?potassium exchange is also decreased in African?Americans as compared to their Caucasian counterparts (37). The decrease in this exchange mechanism results in an increased intracellular sodium content promoting an increase in vascular resistance (37). The deficiency in these exchange mechanisms may be part of the reason African?Americans demonstrate an increased sodium sensitivity (37, 38).
Calcium
There may not be a strong association of blood pressure with the amount of calcium in the diet, although epidemiologic studies have suggested that reduced dietary calcium intake may be a predictor of the development of hypertension (85, 92, 138). Disturbances in calcium metabolism have been reported in hypertensive adults (92). Abnormal activities in the intracellular calmodulin have been reported to parallel the increase in the intracellular calcium concentration (91). This increase of intracellular calcium and concurrent decrease in extracellular calcium has been associated with increased vascular tone (12, 92). A defect by the calcium binding to the inside of the cell membrane could possibly increase the free cytosolic calcium concentration, thus increasing the intracellular calcium (113). Although the poor regulation of calcium channels does increase the intracellular calcium concentration (91), the causal mechanism for the binding of calcium on the inner aspect of the cell membrane is still unknown (59). In vitro studies have demonstrated membrane stabilization, relaxation of vascular smooth muscle, and improvements in calmodulin activity by increasing the extracellular concentration of ionized calcium (14, 55, 66, 91, 146).
Potassium
Total body potassium was found to be significantly decreased in patients with essential hypertension (101), and those hypertensives that have supplemented the diet with potassium demonstrate decreases in systemic pressure (145). Decreased levels of intracellular potassium with concomitant elevations in intracellular sodium and calcium have been found in hypertensive vascular tissue (61, 145). These findings of an increased loss of intracellular potassium may be due to the calcium activated potassium channels passively leaking potassium (61). The higher intracellular concentrations of calcium will cause a passive leaking of intracellular potassium while promoting an increase in intracellular sodium (61). Both increases in intracellular sodium and calcium have been previously reported to parallel an increase in blood pressure.
Autonomic Nervous System
The sympathetic nervous system has a major role in the regulation of cardiovascular homeostasis (63, 156). Even though cause and effect relationships cannot be implied, it is possible that aberrations in the sympathetic nervous system function could be another important primary alteration that leads to the hypertensive state (28). However, its role in the regulation and maintenance of hypertension is subject of continuing debate (63, 156).
Stress is a probable cause for increased sympathetic outflow (18, 156). Increased sympathetic outflow is probably responsible for the initial state of high cardiac output and high heart rate found in the initial stage of hypertensive disease (88, 154).
At some point, stress causes functional changes in blood pressure, especially when stress is repeated intermittently over time (57). When this occurs at the vascular level there is an increased resistance, causing an increased presser effect (18, 156). Long?term stress probably involves other neurohumoral factors such as the renin?angiotensin system in the maintenance and progression of hypertension (156). Thus, catecholamines may act alone, or in concert with the stimulation of the renal sympathetic drive promoting renin release (18).
Two populations of hypertensives which have demonstrated higher catecholamines are the obese (73), and the elderly (96). In a group of hypertensive elderly, noradrenaline concentrations were more likely to be elevated. However, elevated levels of adrenaline and dopamine were not found (96).
Along with the increased circulating catecholamines is a decreased b?adrenergic sensitivity (115). Thus, creating a decreased affinity for the agonist. It is uncertain whether this down regulation is responsible for the increased circulating catecholamines. Related research seems to support this phenomenon. It has also been reported that normal aging is associated with a decrease in cardiovascular response to b?adrenergic stimulation, or a down regulation phenomenon (42). Also, the a and b? adrenergic receptor numbers and the alpha adrenergic sensitivity are unchanged with increasing age (115).
Increased noradrenergic activities have been found in obese individuals (73). This increased sympathetic outflow of neurotransmitters may be a possible link between obesity and hypertension (56).
Kidney
Renin/angiotensin
The renin?angiotensin system may also be involved in the pathogenesis of hypertension (18). As previously indicated, an increase in renal sympathetic drive will cause the release of renin from the juxtaglomerular cells of the kidneys (125). Other factors which prompt the release of renin is a fall in pressure at the renal artery and a decrease in the amount of sodium chloride passing through the distal tubule (18, 125).
The increased production of renin leads to the formation of angiotensin I, which is converted to angiotensin II in the lungs and other organs (125). Angiotensin serves a dual function to increase sodium retention through its action on the adrenal secretion of aldosterone, and solely acts a potent vasoconstrictor (125).
Renal blood flow is autoregulated to maintain a constant pressure and glomerular filtration rate is increased disposing of sodium and water following volume expansion. These are the characteristics of a normal negative feedback loop following the actions of the renin?angiotensin system (18, 125).
Theoretical models have demonstrated in early pathogenesis an increased sympathetic drive might increase renin secretion owing for the volume expansion via renin (110). However, hypertension may be developed with concomitant high or low renin (18). Renin may be suppressed by mineral corticoid excess, or elevated by renal vascular sclerosis (18). Thus, in the latter stages of hypertension, renin may again be varied. A decreased filtration surface area, by a decrease in the number of functioning nephrons, contributes to renal sodium retention and reduced renin production. Or, with kidney damage (ischemic nephrons), renin production may be elevated (18).
Elderly hypertensives are more likely to have low or normal renin than are their younger counterparts (42, 96). Supporting data have also shown that peripheral plasma renin and angiotensin II are related inversely to age in essential hypertension (154). Why this seems to occur in the elderly as compared to their younger counterparts is unknown. These findings are the opposite of expected. The higher renin is probably due to a decrease in renal blood flow and increased renal vascular resistance (98), and renal blood flow may be 40% lower in elderly patients with the concomitant fall in cardiac output of 24%. This is probably the result of excessive nephrosclerosis and increased renal vascular resistance (99).
Other Mechanisms
Other mechanisms have been suggested for playing a role in the development of hypertension. These include antidiuretic hormone[ADH] and baroreceptor resetting. ADH regulates blood pressure through vasoconstriction and resorption of water (110). ADH is produced in the pituitary gland. Neural connections allow the pituitary to communicate with the hypothalamus. The hypothalamus is an important link between the psychological events in emotion (131). Thus, the release of ADH is under control of hypothalamic function. However, a clear connection between emotional stressors and hypothalamic control, either directly through the sympathetic nervous system, or indirectly with ADH release has not been established (110).
It is possible that the baroreceptor reflexes could be reset to maintain an elevated blood pressure indefinitely. There are two reasons suggestive that there is no long term baroreceptive control and that resetting may occur. First, if baroreceptors are subjected to a maintained high pressure, their mean firing rate returns to normal over a period of time (76, 93). Recent evidence suggests that there may be a substantial resetting within 20 minutes (25, 79). Secondly, there is supporting evidence that experimental denervation of baroreceptors in animals produces severe short term hypertension followed by a return to normal pressure (28, 58). This phenomenon is probably resultant of central neural control adaptation (28, 58), however the mechanisms that maintain pressure if baroreceptors are absent are still a subject of speculation (18).
PATHOLOGY OF HYPERTENSION
Natural History
Hypertension is a progressive and deleterious disease. The progression of arterial hypertension may be classified by blood pressure and by the pathophysiology (154). The rate of progression of hypertension may vary from one individual to another; however, the extent of organ damage most closely parallels the pressure (154). Organic changes of the heart, blood vessels, brain, kidney, and eye, are associated with the progression of hypertension. Thus, the greater the pressure sustained over time, the greater the chance of organ damage (154).
Elevation in blood pressure and resultant organ changes has been classified into stages (154). Not only is there progression of organ changes associated with each stage of hypertension, but also hemodynamic changes which accompany each stage (154). There is a continuum of hemodynamic alterations that occur in the development of essential hypertension.
Stages of Hypertension
Stage I of hypertension is described as a hyperkinetic state. There is an increased heart rate, stroke volume, plasma volume, and normal or slightly elevated PVR. This seems to be attributable to peripheral venoconstriction, but as vascular resistance progressively increases over time intravascular volume contracts (96). Thus, a hyperkinetic hypertensive will present with an elevated cardiac index [cardiac output/body surface area].
Stage II of hypertension is described as a normokinetic state. PVR continually increases while central hemodynamics shift within normal ranges (154). As the constrictor influence on the capacitance and resistance vessels persist and progress, arterial resistance and vascular resistance increase further (154). A normokinetic hypertensive will present with a normal cardiac index.
Stage III of hypertension is described as a hypokinetic state. There is a severely elevated PVR and hypofunction of central hemodynamics. Further progression in this stage will result in hypofunction of the heart and cardiac failure will supervene (154). Even though renal function may be impaired causing intravascular volume to expand, a hypokinetic hypertensive will present a low cardiac index.
In terms of mortality associated with the various pathologic states, there appear to be significant differences between a "volume load " hypertensive (Stage I) and a "constrictor" hypertensive (Stages II,III, respectively). The treatment is much more effective for a volume load hypertensive than a constrictor hypertensive (73).
Progression in Kinetic States
As indicated in the previous section, blood pressure is usually associated with different kinetic states, and the different kinetic states are associated with specific hemodynamic changes.
A borderline hypertensive adult will present a resting blood pressure between 140/90 ?160/95 mmHg and often demonstrates hemodynamics of Stage I (154). However, not all borderline hypertensives demonstrate these hemodynamic characteristics (95, 97). The same is true of essential hypertensives. An essential hypertensive will present a resting blood pressure greater than or equal to 160/95 mmHg (95, 97, 154). Thus, blood pressure does not always indicate the kinetic state, nor the determinants involved.
The progression of hypertensive disease is dependent on the rate of progression of organ damage. Blood pressure and the extent of organ damage are related and each serve as a physiological positive feedback for the other. Thus, higher pressures produce greater organ damage, and the greater the organ damage, the higher the pressure.
Early in the course of hypertension hyperkinetic hemodynamics are present [Stage I]. The determinants of heart rate, stroke volume, and cardiac output are all elevated while peripheral vascular resistance is within a normal range (154). There may be arteriolar constriction and mild venoconstriction which serves to redistribute the circulating blood from the periphery to the cardiopulmonary area (154).
As hypertension progresses, [Stage II] the total peripheral resistance and aortic impedance increase. Heart rate may remain elevated or within a normal range, stroke volume and cardiac output are also normal (154). As arteriolar resistance and venoconstriction continue to increase, the heart begins to show signs of left ventricular hypertrophy (154). With the increased resistance, renal blood flow is impeded and glomerular filtration rate may decrease. This impaired renal function may assist in further elevating peripheral vascular resistance (99). Organ damage, which is associated with Stage II and III, is often associated with a lower cardiac index than in stage I (88).
Plasma volume tends to decline slowly with the progression of hypertension as peripheral resistance increases (154). In the final stages of hypertension, [Stage III] there is a further increase in peripheral vascular resistance that causes stroke volume and cardiac output to fall until cardiac failure supervenes (154). The large resistance to the left ventricle [aortic impedance] and the decreased contractility of the hypertrophied heart may be the mechanisms that contribute to cardiac failure in end stage hypertension (99).
Hypertension in Young and Old Populations
Prevalence of Hypertension
General
The prevalence of hypertension in North America has been reported to account for approximately 20% of the adult population (39, 49). The prevalence of hypertension is greater in African?Americans across all age groups (73). Between the sexes, men have a higher prevalence of hypertension through the fifth decade of life. After the fifth decade the prevalence of hypertension in women exceeds that in men (15). The prevalence of hypertension reported for the general population is dependent upon the age ranges considered. If the older population is calculated in the general prevalence, higher figures will be reported.
In Old
Reports on the prevalence of hypertension in older adults show that 30?50% of the adults over the age of 65 years may have chronic hypertension (3). There is very limited data available to estimate the rate of onset of new incidence cases of hypertension in the elderly (3). Even though the apparent prevalence of hypertensive disease is high among the old, it should be noted that as the number of measurements taken increases, the prevalence decreases (152). Studies which have used more than one occasion to determine the total prevalence indicate that the figures may not be as high as the 50% previously reported (152). Because many of the hypertensive studies have failed to be consistent in the number of measures utilized, it is difficult to determine the true prevalence in the elderly population.
Health Considerations in Both the Young and Old Populations
The presence of hypertensive disease compounds the general health risk in the development of cardiovascular disease. In both the young and old populations, risk factors seldom occur in isolation. When these factors aggregate, they greatly augment the risk associated with any particular risk factor (69). It is clear that hypertension does interact with the other risk factors to compound the risk of cardiovascular morbidity and mortality (3). Even though the prevalence of hypertension is greater in the old, the attenuation of hypertensive disease will reduce the overall risk for cardiovascular morbidity and mortality in both the young and old populations. On this premise, assessing the morbidity and mortality from hypertensive disease, it should be noted that less than 10% of the old hypertensive adults are free of other major cardiovascular risk factors (69). In the older hypertensive, both systolic and diastolic blood pressure are independent risk factors for cardiovascular disease (4, 15, 141). The higher the systolic and diastolic pressure the greater the incidence of disease in the old (4, 15, 141). Systolic and diastolic hypertension are the most important factors for predisposition to atherothrombotic brain infarction and thromboembolic stroke (4). Those old who demonstrate lower blood pressure values have better survival rates (141). Forty?two percent of strokes in elderly men and 70% of strokes in elderly women are directly attributable to hypertension (3).
Aging may alter the relationships between the incidence of cardiovascular complications, such as hypertension, and certain indicators of cardiovascular risk, such as body weight or serum total cholesterol (99). If this is the case, then the current recommendation for modification of lifestyle should not be necessarily similar between the middle?aged and the elderly (99).
Comparative Hemodynamic Pathologies in Young and Old
The pathologies associated with hypertension in both the young and old adult are multifactorial and complex (152). A high cardiac output and normal resistance has been found in the groups of individuals below the age of 40 years (96). Conversely, a low cardiac output and higher peripheral resistance have been found in older hypertensives (88).
A study of young hypertensives [age<45 yrs.] demonstrated those hypertensive patients with lower cardiac outputs were older and had slightly higher arterial pressures (96). Higher intravascular volume is associated with a higher cardiac output. Thus, total intravascular volume was lowest in the low cardiac output and highest in the high cardiac output groups (96). An inverse correlation between total peripheral resistance and intravascular volume was found. Also: 1) the magnitude of cardiac output correlated well with the total circulating and central blood volume, and 2) the renal and hepatic blood flows varied in parallel to cardiac output with no evidence of redistribution between those two major circulations (96). Thus, in young hypertensive patients, plasma volume seems to be more closely related to total peripheral resistance (96). Younger hypertensives also have higher heart rates than older hypertensives. This is perhaps due to enhanced myocardial contractility associated by a translocation of intravascular volume from the periphery to the cardiopulmonary circulation (96).
In summation, younger hypertensives demonstrate an elevated cardiac output, plasma volume, and heart rate (96). Also, as the level of peripheral resistance increases, the plasma volume and cardiac output decrease (96). The older young hypertensives demonstrated lower cardiac output and higher peripheral resistance as indicated by higher arterial pressure [ie. higher afterload]. (96). Evidence of a decreased renal blood flow associated with decreased cardiac output and with increased peripheral resistance, may serve as some indication of possible renal involvement in the later stages of hypertension (96).
With advancing age, there is a pattern toward a low cardiac output and high peripheral resistance in persons over 50 years of age (88). The resting cardiac output decreases by about 10 percent, so there is a substantial increase in systemic vascular resistance (153).
These changes in the intrinsic regulation of blood pressure seem to disproportionately affect the systolic blood pressure in many older [age > 55yrs.] hypertensives. Systolic blood pressure increases progressively with age while diastolic pressure rises to 60 years of age, then levels off (153). Systolic pressure was 19% higher and diastolic pressure was 14% lower in the elderly than in the younger patients which may indicate a higher prevalence of isolated systolic hypertension in the older adult (99). Mean arterial pressure also increases from 85 mmHg at age 25 to about 104 mmHg at age 75; an increase of 22 percent (99).
The exact causal mechanisms for the pathophysiology of hypertension in the older adults and whether they differ from the mechanisms involved in younger adults remains to be determined (3). Still, it is important to note hypertension in older adults has been characterized by a hypertrophied heart, low cardiac output possibly resulting from a smaller stroke volume, low plasma volume, slower heart rate, and high peripheral resistance (73, 98, 99, 129). In younger adults with severe hypertension and end stage renal disease, disturbances in left ventricular performance due to myocardial failure have been reported (88). Young hypertensives with end stage renal disease tend to have a hemodynamic pathology that resembles elderly hypertensive subjects with less severe hypertension (88). The etiology for the development of hypertension in older adults as compared to young hypertensives has not been determined, (3), and the pathology demonstrated in the presence of hypertension in both the young and old appear dissimilar (3, 73, 88, 99, 129).
Possible interactions of the aging cardiovascular system and the development of hypertension in older adults will be discussed in the following section. Again, it should be emphasized that hypertensive disease evolves through hemodynamic changes associated with each disease state (154). Of equal emphasis, the cardiovascular system also undergoes morphological changes associated with aging. These changes also effect blood pressure. The synergistic effects of disease and aging are difficult to separate.
Pathology in Older Adults
Increased arterial resistance [PVR] is common in the aging cardiovascular system (69, 73, 150). Arterial distensibility is not reduced in asymptomatic healthy humans, but there is a age related reduction in arterial luminal diameter associated with aging (88). The aortic wall thickness also increases with age, and elasticity increases (88, 150). The increase in aortic cross?sectional thickness results in an increased vascular stiffness (150). Thus, the increase in PVR associated with aging can be attributed to the morphological changes occurring in the arterial system (88). This age related change is commonly referred to as arteriosclerosis.
An elevation of PVR results in the left ventricle having to pump harder against a stiff aorta. This will create a higher afterload. A higher afterload will consequently elevate the left end diastolic volume. The larger left end diastolic volume results in initiating a fall of stroke volume and cardiac output, as previously indicated. This may be why the hemodynamic profile accompanying the onset of hypertension in older individuals is often associated with and increase in systemic vascular resistance rather than an increase in cardiac output (42).
With the establishment of increased PVR the heart will begin to show signs of adaptive hyperfunction and left ventricular hypertrophy. These changes also coincide with a prolonged left ventricular ejection time (103). With further progression of PVR both stroke volume and cardiac output continue to decline until cardiac failure supervenes (154). Plasma volume tends to decline slowly with the progression of PVR (154).
Thus, several determinants may contribute to the fall in cardiac output in older hypertensives: 1) the resistance to left ventricular emptying (aortic impedance) increases with age, and 2) myocardial contractility and left ventricular filling could become impaired because the left ventricular wall thickens and its compliance decreases with age (99).
Profusion of vital organs is often compromised as PVR increases and volume declines, especially renal blood flow, and these small changes in blood flow can endanger organ function which is already reduced in the older persons (98, 99). As total PVR increases more steeply, there is a continued rise in renal vascular resistance accompanied by a fall in glomerular filtration rate and deterioration in overall renal function (154). Renal blood flow was found to be 40% lower in older adults, whereas the fall in cardiac output was only 24%, indicating a redistribution of cardiac output in the old (99). It is believed that these findings resulted from excessive nephrosclerosis, suggested by and increase in renal vascular resistance (99).
One method of determining an elevated PVR is measuring the pulse wave velocity through the aorta. Thus, an increased afterload [PVR] will increase the pulse wave velocity. Atherosclerotic disease may also disproportionately increase systolic blood pressure over a diastolic rise. Pulse wave velocity is also significantly correlated with systolic blood pressure (81). These findings may help explain the higher incidence of isolated systolic hypertension [ISH] in older adults.
The hemodynamic findings associated with a normokinetic circulation and essential hypertension are also found in older adults exhibiting arteriosclerosis (42). In older patients with severe hypertension , [ie. high PVR], the hemodynamic pathology similar regardless of the patient's age (88).
TREATMENT OF HYPERTENSION
The major treatment regimens for hypertensive disease include the use of dietary modifications, antihypertensive medications, and exercise intervention. Dietary modifications for the treatment of hypertension typically include the reduction of sodium chloride, while increasing calcium and potassium in daily food choices.
Diet
Sodium Chloride Intake
Epidemiologists have observed communities with reduced blood pressures and communities with high blood pressures. Communities that have a reduced salt intake also have reduced blood pressures compared to those communities where salt consumption and blood pressures are higher (154). Individuals who are sodium sensitive will have an increase in blood pressure, regardless of their hypertensive status, when additional sodium is added to the diet (56). It appears that approximately one fourth of normotensive subjects and approximately one half of hypertensive subjects have sodium sensitivity (56). More pronounced sodium sensitivity may occur in the older adults and in African?Americans (37, 38).
Once hypertension is present, modest salt reduction may be effective in reducing the blood pressure (18). A review of 24 intervention studies that used moderate sodium restrictions, (approximately 2 grams per day), produced a decrease of 5.4 mmHg systolic and 6.5 mmHg diastolic blood pressure (134). It has also been suggested that not only dietary sodium but the proportions of sodium to potassium, sodium to calcium, and sodium to magnesium may be important in determining the disease process (154).
Calcium Intake
Studies have shown that hypertensives consume less calcium when compared to their normotensive counterpart (80, 91, 92). Thus, calcium supplementation to the diet has been recommended as an adjunct to hypertensive therapy. In a review of 22 short term studies, hypertensives were given between one and two grams of supplemental calcium daily. Approximately one?third of those receiving the supplementation decreased their blood pressure (45). These results also indicate that some hypertensive individuals do not respond in a positive manner following calcium supplementation (45); however, recent research has shown the diets high in calcium can reduce blood pressure by promoting high resorption of calcium with improvements in calcium transport, decreased intracellular calcium concentrations, and improved calmodulin activities (91).
Potassium Intake
Extra dietary potassium intake may protect against vascular damage in strokes (75). A deficiency of dietary potassium may exert multiple effects that may increase blood pressure (77). However, the evidence that: 1) the supplementation of potassium for the correction of hypokalemia (70), or; 2) that the addition of dietary potassium in normokalemia, will lower blood pressure (44) is sparse. Some advantages of a lower sodium intake is an increase in body potassium content (18). Thus, potassium supplementation may be more effective in the reduction of blood pressure for those hypertensives whose diet is high in sodium.
Medication
As previously stated, there are three ways to change blood pressure. Either by altering flow, total peripheral resistance, or both (73, 124). Thus, an increased blood flow and/or resistance to blood flow will raise blood pressure (35). Antihypertensive medications will alter the mechanisms that control blood flow, total peripheral resistance, or both, and thereby reduce blood pressure. This section will review the different types and actions of antihypertensive drugs.
Types and Actions
There are three basic types of antihypertensive drugs: a) diuretics,
b) sympatholytic agents, and c) vasodilators (18). Each type of drug is addressed in the following sections.
Diuretics
There are four groups of diuretics which are used in antihypertensive therapy: 1) Thiazides; 2) Thiazide-like (related sulfonamide compounds); 3) Loop acting; and 4) Potassium-sparing agents, which are usually used in combination with a thiazide.
Commonly used agents within each group are listed in Table 1.
Initially all diuretics lower blood pressure by increasing urinary sodium excretion, and reducing plasma and extracellular fluid volume to decrease cardiac output (18). Long term diuretic therapy (greater than six weeks), demonstrates a lowered blood pressure by a decrease in peripheral vascular resistance (18, 65). The mechanism responsible for the decrease in peripheral vascular resistance is unknown. Possible side effects of diuretic therapy are hypokalemia, hypomagnesemia, and increases in glucose, insulin, and cholesterol (18).
The thiazides and thiazide like agents inhibit sodium resorption in the distal tubules of the kidney. Thiazides are prescribed for mild to moderate hypertension and most have their maximum effect on blood pressure at relatively low doses (149). Increasing the dosage of thiazide agents will have some additional hypotensive effect; however, it is usually at the expense of increasing the side effects of diuretic therapy (18, 94). Thus, thiazides are often used in combination with other agents to counterbalance these side effects (65).
Loop diuretics inhibit sodium resorption in the ascending tubule (18). Loop diuretics are usually prescribed for severe hypertension that is often associated with renal failure (18).
Potassium-sparing agents are often used in combination with thiazide diuretics to slow potassium depletion. Of the three agents listed in Table 1, spironolactone is an aldosterone antagonist, while both amiloride and triamterene directly inhibit potassium secretion (18).
Sympatholytic Agents
There are four types of sympatholytic agents which are used in antihypertensive therapy: 1) centrally acting; 2) peripherally on neuronal catecholamine discharge; 3) peripherally by blocking alpha-adrenergic receptors; and/or 4) peripherally by blocking beta-adrenergic receptors. The alpha- and beta-blocking receptor agents are categorized by their site selectivity. Beta-blocking agents are also classified by whether they possess intrinsic sympathomimetic activity (ISA).
Commonly used agents within each type are listed in Table 2a and 2b, by product and generic name. Sympatholytic drugs are often prescribed in conjunction with diuretic therapy. These are indicated with their addition (+ diuretic = ) in both tables. Also, indicated in Table 2b are the ISA [+] and non-ISA [-] agents.
Centrally acting sympatholytic agents lower blood pressure by decreasing the sympathetic outflow from the central nervous system (18). Methyldopa decreases blood pressure by reducing peripheral vascular resistance with little effect on cardiac output. Clonidine has many of the same properties as methyldopa but also decreases heart rate and preload (18). Guanabenz and Guanfacine are similar to Clonidine. All centrally acting drugs may have typical side effects of sedation, dry mouth, orthostatic hypotension, impotence, and galactorrhea (18).
Peripheral neuron inhibitors reduce blood pressure by inhibiting the release of norepinephrine from peripheral adrenergic neurons [postganglionic sympathetic neurons] (18). Guanethine lowers blood pressure via reducing cardiac output and preload. With prolonged usage, cardiac output may return to pretreatment values while peripheral vascular resistance decreases (149). Guanadrel, Bethanidine, and Deserpine are similar to Guanethine (18). Reserpine depletes the postganglionic adrenergic neurons of norepinephrine by inhibiting its uptake into storage vesicles (18). Reserpine lowers blood pressure in a combination of decreased cardiac output and peripheral vascular resistance. Peripheral neuron inhibitors are often combined with diuretics, and may share common side effects of orthostatic hypotension (18).
Adrenergic receptor blocking agents block the effects of norepinephrine at the a- and/or b- adrenergic receptors. Prazosin is the most commonly prescribed a-blocker, and is often prescribed with a diuretic combination. As with Prazosin, other a-blocking agents lower blood pressure by decreasing peripheral vascular resistance in both arterial and venous vessels while maintaining cardiac output(18). Alpha blockers are recommended for those hypertensives with peripheral vascular disease and/or who have complications with b-blockade therapy (18). Side effects, after first-dose postural hypotension, include dizziness, weakness, fatigue, and headaches (18).
Beta blockers have become one of the most widely used classes of drugs to treat hypertension (149). Beta blockers act by competing or blocking the catecholamine neurotransmitters which stimulate the b-receptors of the heart, lung, and arterial vascular system (18,149). Beta blockers be classified by their degree of cardioselectivity relative to their blocking effect on the b1 adrenergic receptors in the heart compared to that on the b2 receptor in the bronchi, peripheral blood vessels, and elsewhere (114). These agents may also be classified by whether they possess intrinsic sympathomimetic activity (ISA). The b-blocking drugs which possess ISA are actually "weaker" b-blockers and effect the blockade by competing with the catecholamines for the receptor site. Thus b-blocking drugs with ISA produce an agonist response at the same time blocking the greater agonist response of the endogenous catecholamines (18). Initially, b-blockers lower blood pressure by reducing cardiac output. Cardiac output is reduced via a decreased heart rate and myocardial contractility (149). With long-term therapy, cardiac output falls back within normal limits and the lowered blood pressure may be attributed to a decreased peripheral vascular resistance (18,149). Beta blocking agents with ISA tend to lower blood pressure by decreasing peripheral vascular resistance without decreasing resting cardiac output (18). Atenolol and Nadolol are among the least lipid soluble of the b-blockers (18). A decreased lipid solubility leads to the clinical advantage of less drug dosage, allowing once-a-day dosage (18). The blocking drugs which resist lipid solubility escape hepatic inactivation and do not enter the central nervous system (CNS) as readily, thus producing less associated CNS side effects of the b-blocking agents. Side effects of the b-blocking drugs include the CNS dysfunctions of fatigue, bronchospasm, peripheral vasospasm, and depression.
Vasodialators
There are three groups of vasodialating drugs. These are: 1) Direct vasodialators; 2) Calcium antagonists; and 3) Converting enzyme inhibitors. Both the calcium antagonists and the converting enzyme inhibitors produce vasodilation through indirect means. Commonly used agents within each group are listed in Table 3.
The primary hypotensive effect of direct vasodialators is via their relaxation of the arterial vascular smooth muscle which results in a decreased peripheral vascular resistance (18). Hydralazine and Monoxidil are both very potent vasodilators. Because both drugs have very profound side effects of compensatory cardiovascular responses if used as a monotherapy, both are commonly prescribed in conjunction with diuretics and sympatholytic agents (18).
New generation vasodilation drugs such as the calcium antagonists and converting enzyme inhibitors may be used as monotherapy because they have fewer side effects with both short and long term use (18). The primary hypotensive effect of nefedipine is through direct vasodilation of the peripheral arteries. Other calcium channel blockers such as verapamil and diltiazem affect the central response by decreasing cardiac conduction time (decreased heart rate) and contractility (18). Thus, nefedipine is thought to be selective to the smooth muscle cells, whereas verapamil and diltiazem act both on smooth muscle and cardiac tissue (18). All calcium channel blockers inhibit the uptake of calcium into the smooth muscle cells that interferes with the contractile process (149) regardless of the site of action.
Converting enzyme inhibitors may decrease blood pressure by two basic modes. First, by antagonizing the vasoconstrictive effects of angiotensin by competing for the receptor cite in vascular smooth muscle. Secondly, some inhibitors will block the conversion of angiotensin I to angiotensin II. Drugs of both modes will decrease peripheral vascular resistance (149), with little, if any, effect on heart rate, cardiac output or body fluid volumes (18).
Exercise Intervention
Review of hypertension and exercise research has indicated that both chronic and acute exercise is effective in the reduction of blood pressure (143). Thirty-five longitudinal studies and the collective review of 12 epidemiological studies show that chronic exercise is beneficial for improving functional capacity that is associated with lower resting blood pressures in young and older populations (143). Less information is available on the post-exercise (acute) effects of exercise on hypertension; however, it is generally accepted that post-exercise hypotensive response is an expected physiological effect of the exercise stimulus (143).
A related review of 33 chronic (5, 9, 13, 16, 20, 22, 24, 26, 30, 31, 34, 46, 48, 51, 62, 64, 67, 78, 90, 105, 106, 117-119, 121, 123, 135, 137, 142, 144, 147, 148) and 9 acute (11, 47, 50, 57, 72, 109, 111, 132, 151) exercise studies follows which will partition the chronic and acute blood pressure response to exercise by age and hemodynamic state.
Exercise Studies
Forty-two exercise studies beginning with 1966 were included in the literature review. Studies selected must have included: 1) subjects that were hypertensive and participated in the exercise stimulus, 2) blood pressure data from the results of the chronic exercise stimulus, and 3) post?exercise data from the blood pressure response to the acute exercise stimulus. Results of the hypertensives in all studies reviewed were classified by blood pressure according to the WHO criteria. WHO has defined borderline hypertension as a blood pressure > 140/90 mmHg, and essential hypertension as >160/95 mmHg. Thus, 19 (5, 9, 20, 24, 26, 30, 31, 46, 50, 57, 78, 90, 111, 118, 132, 135, 137, 147) of the 42 [45%] studies involved borderline hypertensives, 17 [41%] (11, 16, 22, 34, 47, 48, 62, 64, 105, 106, 109, 119, 121, 142, 144, 148, 151) studies were essential hypertensives, and 6 [14%] (13, 51, 67, 72, 117, 123) studies contained both.
A total of 1358 men and women [M=753,W=225, undetermined= 380] participated in the studies. The mean age of both men and women was 48.5 + 14.4 years and ages ranged from 18 to 79 years.
Modes of exercise included cycling, interval training, jogging, rowing, swimming, walking, and various combinations of each. Exercise intensity was described as either a percent of maximal oxygen consumption [VO2], maximal heart rate reserve [HRR], heart rate threshold [HRT], blood lactate threshold [BLT], or percent maximal heart rate [MHR]. Exercise duration was described in minutes per session and used a set duration, or a progressive duration from the start to end of the study,[ie., began at 9 min. and exercised for 20 min. by the end of the study].
Exercise frequency was described in sessions per week, whereas total time of the studies was described in weeks. Frequency and total time statistics were applicable to the chronic exercise studies. Descriptive statistics for the mode, intensity, duration, frequency, and total time of the forty-two studies are listed in Table 4.
Results of the exercise stimulus on blood pressure were expressed as changes in either systolic [SBP], diastolic [DBP], or mean [MAP], arterial pressure. These results were determined by comparing pre?post exercise blood pressures.
Results of the exercise studies that demonstrated significant blood pressure reductions for SBP, DBP, and MAP are listed in Table 4. Percent reporting is defined as the number of studies with significant reductions in blood pressure divided by the total number reporting blood pressure. Thus, approximately 70% of the studies that investigated SBP, DBP, and MAP reported significant reductions in blood pressure following the exercise intervention.
Chronic Exercise in Young and Old
Further analysis of the exercise studies was performed to determine if chronic exercise significantly reduced blood pressure in both young [18?45 yrs], and old [age > 55 yrs] hypertensives. Previous researchers have defined the age categorizations for both the young, < 45 years, (1, 86) and old, > 55 years, (48, 81, 118, 126, 137) hypertensive adults. Also, Abrams (1) has reported young and old hypertensive adults by these ages in epidemiological research. Diastolic pressure in both men and women hypertensives tends to increase until age 55 then begins to decline (15). Also, data from the Framingham study show that women have a greater rate of increase in systolic blood pressure than men after age 45 (68), and hypertension is more prevalent in post menopausal women and most women have experienced menopause by age 55 (130). Thus, these age categorizations were chosen to define young and old hypertensive adults.
Results are reported for both the young [y] and old [o] hypertensives to allow for simple comparisons. Although there were 33 chronic exercise studies, 18 (5, 9, 20, 24, 26, 31, 34, 48, 51, 90, 106, 117, 118, 135, 137, 147, 148) met the age limitation criteria of either young [18-45 yrs] or old [ > 55 yrs]. Twelve (5, ,46, 48, 49, 50, 51, 125, 143, 146, 167, 169) studies of 18 involved borderline hypertensives [y=4(33%), o=8(67%)], four studies (34, 48, 106, 148) were essential hypertensives [y=3(75%), o=1(25%)], and two studies (106, 117) contained both [y=1(50%), o=1(50%)]. Thus, of the studies included in the review, results were determined on mostly borderline older hypertensives with an equal distribution of hypertensive state among the younger hypertensives.
A total of 633 men and women [My=342, Mo=171, Wy=7, Wo=69, undetermined = 64 [either age or sex could not be determined], participated in the studies. Thus, the chronic exercise studies examined a larger proportion of men [87%] than women [13%]. The mean age and standard deviation of both men and women was: [M&Wy=38.7 + 4.5 yrs. ; M&Wo= 67.7 + 5.4 yrs.].
Modes of exercise, exercise intensity, duration, frequency and total time are listed in Table 5. The results are listed for both young and old hypertensives.
Results of the exercise studies that demonstrated significant blood pressure reductions for SBP, DBP, and MAP for both the young and old are listed in Table 5. Again, percent reporting is defined as the number of studies with significant reductions in blood pressure divided by the total number of studies reporting blood pressure. Thus, approximately 83% of the studies in the young and 88% in the old that investigated SBP, DBP, and MAP reported significant reductions in blood pressure following exercise intervention.
Those chronic exercise studies which demonstrated significant reductions in blood pressure in both the young and old were examined to reveal which hemodynamic determinants were responsible for the reductions. The hemodynamic determinants considered were stroke volume [SV] in milliliters, heart rate [HR] in beats per minute, cardiac output [Q] in liters per minute, and peripheral vascular resistance [PVR] in units. Most studies which reported, reported changes in the central determinants (34, 48, 106, 117, 148); however, Hagberg reported changes in both central and peripheral determinants in the same study with two different exercise intensities (48). Studies reporting the determinants for both the young and old are listed in Table 6.
The review of literature on exercise studies which evaluated the response of young and old hypertensive adults to chronic exercise produced the following findings: 1) chronic exercise significantly reduced SBP, DBP, and MAP in both the young and old hypertensives, and 2) those studies which produced significant change in the blood pressure of SBP and DBP demonstrated little change in the blood pressure determinants with the exception of a reduction in heart rate.
Further analysis of the chronic exercise studies was performed to determine if the hemodynamic determinants responded in a dissimilar fashion between essential and borderline hypertensives, regardless of age. Those studies that demonstrated significant reductions in SBP and/or DBP were examined to reveal which hemodynamic determinants were responsible for the reductions. Of the studies which showed significant reductions in blood pressure following chronic exercise, 11 studies (5, 9, 20, 24, 26, 31, 78, 90, 118, 135) demonstrated these reductions were in borderline [B] and 8 in essential [E] hypertensives (16, 22, 34, 48, 106, 142, 144, 148). Those studies reporting changes in blood pressure that also reported the determinants are listed in Table 7. None of the studies that reported significant changes in blood pressure in borderline and essential hypertensives reported changes in the determinants, however, less than one-third of the studies in borderline hypertension even investigated the determinants.
The review of literature on exercise studies which evaluated the response of borderline and essential hypertensive adults to chronic exercise produced the following findings: 1) chronic exercise significantly reduced SBP, DBP, and MAP in both the borderline and essential hypertensives, and 2) those studies which produced significant change in the blood pressure of SBP and DBP demonstrated little change in the blood pressure determinants with the exception of a reduction in heart rate in the essential hypertensives. Again, these results should be considered in light of the few studies which actually investigated the determinants.
Acute Exercise in Young and Old
Nine studies (11, 47, 50, 57, 72, 109, 111, 132, 151) reviewed on the blood pressure response to acute exercise ranged from 1981 to 1996. If these nine studies were sorted for young and old hypertensives, only one study met the age criteria for the old, three for the young, and the remaining five studies had age ranges between 45 and 55 years. Thus, results from these studies have been collapsed for age to determine the effects of acute exercise on the pressure level of hypertensive adults.
Four studies(11, 47, 109, 151) of nine involved essential hypertensives (44%), four studies (44%) involved borderline hypertensives(50, 57, 111, 132), and one study (72) involved both borderline and essential hypertensives (12%). The average age of subjects was 45.5 + 11.2 yrs. [R=19?69]. Thus, of the studies included in the review, results were determined on equally on borderline and essential hypertensives with an equal distribution across age.
A total of 170 men and women [M=117,W=53] participated in the studies. Thus, the acute exercise studies examined a larger proportion of men [69%] than women [31%].
Modes of exercise, exercise intensity, duration, frequency, and average post-exercise time are listed in Table 8. Significant results of the exercise stimulus on blood pressure were expressed as changes in either systolic [SBP], diastolic [DBP], or mean [MAP], arterial pressure are also reported. Although five studies reported significant changes in SBP(47, 50, 57, 111, 151), only three reported values (47, 57, 111); three studies reported significance in DBP (47, 111, 151), two reported values(47, 111); and, two (109, 111) reported significant changes in MAP, with only one study reporting values(111).
Those studies that demonstrated significant reductions in SBP and/or DBP were examined to reveal which hemodynamic determinants were responsible for the reductions. Of the studies that demonstrated significant reductions in SBP following chronic exercise, one study reported a significant reduction in SV in low [50% V02max] and in high [70% V02 max] intensity groups (47). The same study reported a significant a significant reduction in HR to 17 minutes post exercise in low and to 120 minutes in high intensity groups. And, a significant increase in PVR occurred in both the high intensity groups (47). Inbar reported a reduction in PVR following acute exercise with significant reductions in systolic blood pressure (57). Of the studies that demonstrated significant reductions in DBP, only Hagberg (47) reported hemodynamic determinants. Significant reductions in DBP only occurred in the high intensity group. Only one study demonstrated a significant reduction in MAP (109). Changes in the hemodynamic determinants of SV, HR, and Q are unknown; however, a significant reduction in PVR was indicated. Hagberg's (47) study involved only essential hypertensives where and increase in PVR occurred postexercise. Thus, due to the inconsistency and lack of data, information on the hemodynamic determinants following acute exercise in hypertensive adults could not be obtained from these studies.
However, a most recent acute exercise study poses a new consideration for examining the determinants of postexercise blood pressure reduction (57). The results of the study showed a negative correlation between the change in cardiac index pre to post exercise at various intensities and durations of work. Thus, those subjects who presented a high cardiac index prior to the exercise stimulus demonstrated the greatest reduction in cardiac index postexercise. From the results, the author concluded that the hemodynamic state of the patient appeared to show the hemodynamic determinant of blood pressure reduction rather than the characteristics of the exercise stimulus itself. Prior chronic exercise studies have focused more on the characteristics of the exercise stimulus, showed reductions in postexercise blood pressure, but also had mixed results on the hemodynamic determinants responsible for the blood pressure reduction (48, 64, 117). No study has compared the subject's hemodynamic state with the resultant determinant responsible for the postexercise blood pressure reduction even though Kenny and Zambraski have recommended the cardiovascular hemodynamics as a focus of blood pressure categorization (73). Inbar's study is the only acute study to date that has examined the determinants and related the hemodynamic state of the subjects to the determinant of blood pressure change (57).
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