physiologic and hemodynamic considerations in blood pressure control while maintaining organ...

Physiologic and Hemodynamic Considerations in Blood Pressure Control While Maintaining Organ Perfusion

MATTHEW R. WEIR, MD, and JAMES R. SOWERS, MD

Essential hypertension remains a significant contrib- utor to mortality, despite treatments effective in decreasing blood pressure. A major reason ‘mortality remains high may be that the conventional stepped- care approach does not always reduce btood presr sure fn a physiologic manner, which may result in metabolic derangements and elicitation of undesirable reflex mechanisms. Use of the stepped-care approach does not take into account fundamental hemodynamic differences associated wfth a hypertensive uatient’s age, race and weight. A nonphys-

iokgic approach in the use of antihypertensive agents may be associated with progression of left ver@kular hypertrophy, metabolic derangements, arrhythmias, sudden death, and increased athero- sclerotic and nephroscleroti~ complications. Consid- erations of the alterations in cardiovascular structure that can occur in light of the activity of the renin-an- gfotensin system, the sympathetic nervous system and transcellular cafcium flux are discussed as to how they affect long-term survival.

(Am J Cardiol 1988;61:60H-66H)

E ssential hypertension remains a significant con- tributor to mortality from cardiovascular disease.’ Although many treatment methods are effective in reducing blood pressure, death from hypertensive se- quelae such as stroke, myocardial infarction and con- gestive heart failure, although improved, has not been prevented.2J The effects of antihypertensive medical therapy in reducing morbidity and mortality associated with coronary artery disease have been especially disappointing.2 One major reason mortality has not been satisfactorily controlled may be that many current therapeutic methods for reducing blood pressure are nonphysiologic. Nonphysiologic methods result in adverse metabolic changes and undesirable reflex mechanisms, causing increased morbidity and mortality as well as decreased compliance due to adverse effects.2s3-5’15

To develop treatment methods that control hypertension in a physiologic way, a good understanding of our current knowledge of the pathogenesis of hypertension and the body’s systemic and local blood pressure control mechanisms is required. Thus, a more physiologic approach to the control of blood pressure to maintain organ perfusion and function and yet

From the Nephrology Division, Department of Medicine, Uni- versity of Maryland Hospital, Baltimore, Maryland and the En- docrine and Hypertension Division, Wayne State University School of Medicine, Detroit, Michigan.

Address for reprints: Matthew R. Weir, MD, Renal Division, University of Maryland Hospital, 22 South Greene Street, Balti- more, Maryland 21201.

maintain quality of life is warranted in order to improve overall cardiovascular mortality related to hypertension.

Pathogenesis of Hypertension Essential hypertension is a disorder of arterial

blood pressure control. Blood pressure regulation is mediated by several physiologic mechanisms within the renal, neurohormonal, vascular and cardiac systems.16J7 The origin of essential hypertension remains elusive and it may be that the mechanisms that initiate hypertension differ from those that sustain hypertension

Breakthrough discoveries in the etiology of essential hypertension have been thwarted, in part, because early research considered essential hypertension as a single disease entity. New findings show that the pathogenesis of essential hypertension is not homoge- neous as was once thought. Factors such as genetics, age, race, sex, salt sensitivity and obesity influence the development and course of essential hypertension as well as the response to specific drug treatments.18-20

Effects of Age, Race and Obesity on the Hemodynamics of Hypertension: Physiology of Pharmacologic Intervention

Influence of age: Researchers have found that age significantly affects the hemodynamics of hypertension.21J2 Blood pressure is a product of cardiac output and peripheral resistance. Young patients (younger than age 40 years] typically display elevated cardiac output, normal peripheral resistance, salt insensitiv-

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ity, normal intravascular volume, and greater plasma renin and adrenergic activity2*,22 (Table I]. Such patients have a cardiac output approximately 10 to 20% above normal and often manifest cardiogenic hypertension.21 Thus, a variety of antihypertensive agents directed against these pathophysiologic factors have been noted to be effective (e.g., elevated cardiac output-p blockers, calcium entry blockers; higher plasma renin-angiotensin-converting enzyme (ACE] inhibitors; and higher adrenergic activity-centrally acting agents, (Y blockers and ACE inhibitors].

The hemodynamic profile of the young patient con- trasts significantly with that of patients older than age 40 who, as they age progressively, display reduced cardiac output with increased peripheral resistance, decreased intravascular volume, increased salt sensitivity, reduced plasma renin and decreased baroreceptor sensitivity.21-27

With increasing age, the left ventricle becomes overworked by prolonged high afterload, and com- pensatory left ventricular hypertrophy ensues.28p2g This hypertrophy can lead to increased ventricular ectopy, impaired coronary reserve and sudden death.3OJl Thus, an important property of an antihypertensive agent in this age group would be that of causing regression of left ventricular hypertrophy. An- tihypertensive agents can have significantly different effects on the regression of left ventricular hypertrophy. Beta blockers, (Y blockers, ACE inhibitors and calcium antagonists appear to promote regression of left ventricular hypertrophy, whereas diuretics and vasodilators have no beneficial effects or may even promote hypertrophy. 15~32 The development and progression of hypertension is also associated with altered structure of the vasculature, resulting in effective narrowing of vessel lumen .33*34 The morbid consequences of hypertension, such as myocardial infarction and cerebral hemorrhage, are closely associated with the vascular structural changes.35

As the hypertensive process progresses, elevation of intraglomerular pressures may occur, ultimately leading to nephrosclerosis and a decline in renal func- tionn36 Until recently, it has not been appreciated that reduction in systemic blood pressure does not invari- ably result in glomerular capillary pressure reduction and that physiologic reduction of intraglomerular capillary pressures is necessary to protect renal tissue from the glomerulosclerotic effects of intrarenal hypertension.13 Recent experimental studies have demonstrated that ACE inhibitors and calcium entry blockers have the ability to control both systemic and glomerular capillary pressures and can potentially reduce the acceleration of glomerulosclerotic disease seen in hypertensive patients.37-44

Thus, the hemodynamics of hypertension in the elderly patient would predict that antihypertensive agents targeted at poor cardiac output, high peripheral vascular resistance and reduced tissue perfusion would be most effective (Table II). Specific afterload reduction with agents that can reduce systemic blood pressure and still improve cardiac output and improve organ perfusion make the most sense both from a phys-

TABLE I Physiologic Consldereilons for Blood Pressure Reduction in the Young Hypertensive

Pathophysiologic Findings

Desired Pharmacologic

Effects

High cardiac output Negative inotropic and

and heart rate chronotropic effect

Normal TPR No effect on TPR

Activated renin- Supression of renin

angiotensin system secretion

Normal to contracted No effect on plasma

plasma volume volume

TPR = total peripheral resistance.

TABLE II Physlologlc Considerations for Blood Pressure Reduction In the Elderly Hypertensive



Findings

Low cardiac output and heart rate

High peripheral vascular resistance

Contracted total blood volume

Decreased adrenergic activity, salt sensitivity

LVH Nephrosclerosis and impaired

renal function/renal blood flow

Afterload reduction

Restore appropriate vascular volume and improve tissue perfusion

Natriuretic effect

Regression of LVH Improve renal blood flow

LVH = left ventricular hypertrophy.

iologic as well as side-effect standpoint. Thus, it is understandable why a diuretic [an elderly patient has volume contraction) or a p blocker (an elderly patient has a low cardiac output) may not be as effective from a physiologic or side-effect standpoint in a patient older than age 40 compared with specific afterload reduction with an (Y blocker, ACE inhibitor or a calcium antagonist. Agents such as calcium antagonists, which are effective in low-renin, salt-sensitive, elderly patients, can provide a successful monotherapeutic approach, whereas ACE inhibitors and CY blockers are more effective when combined with low doses of a thiazide diuretic.

Influence of race: Hypertension in the black population is characterized by earlier onset, increased se- verity and different hemodynamic and biochemical factors compared with the nonblack population.45-52 The hemodynamic profile of the black hypertensive is similar to the elderly hypertensive with salt sensitivity, low-renin production, low cardiac output and increased peripheral and renal vascular resistance (Ta- ble III]. However, the black patient tends to be euvo- lemic, or volume-expanded, while the elderly patient is usually volume-depleted.13.53

Antihypertensive agents in the black patient should be targeted either to their expanded plasma volume, if evident, or reduced cardiac output/increased pe-

62H A SYMPOSIUM: THE SALT-SENSITIVE HYPERTENSIVE PATIENT

TABLE III Physiologic Conslderatlons for Blood Pressure Reduction In the Black Hypertensive



Effects

Low cardiac output Tendency toward expanded

plasma volume High peripheral vascular resistance Decreased renin activity.

salt sensitivity Decreased renal blood flow Increased risk for LVH

Afterload reduction Natriuretic effect

Physiologic vasodilatation Natriuretic effect

Increased renal blood flow Regression of LVH

LVH = left ventricular hypertrophy.

TABLE IV Physiologic Considerations for Blood Pressure Reduction in the Obese Hypertensive



Effects

High cardiac output Expanded plasma volume Low-renin levels, salt sensitivity Variable total peripheral

resistance Elevated sympathetic nervous

system

Negative inotropic effect Natriuretic effect Natriuretic effect No effect on TPR

Normalization of sympathetic nervous system activity

TPFf = total peripheral resistance.

ripheral vascular resistance. Although diuretic drugs have long been known to be effective, metabolic factors, concerns for maintaining tissue perfusion and ability to cause regression of left ventricular hypertrophy are not fully met by these agents.6,7,g-*2J5v32 Conse- quently, more consideration should be given to specific afterload reduction with agents that can reduce systemic blood pressure, yet maintain organ perfusion and cause regression of cardiovascular structure. This is especially important in the black hypertensive who tends to have accelerated cardiovascular disease and manifests earlier end-organ damage than nonblack hypertensives.47-51 Specific examples of afterload reduction include combination therapy with an (Y blocker or ACE inhibitor with low doses of thiazide diuretics or monotherapy with a calcium antagonist.

Influence of obesity: The obese hypertensive patient is characterized hemodynamically (Table IV) like black hypertensives, by an expanded total blood volume.54 The increase in body mass of the obese patient requires both this increase in intravascular volume and an increase in cardiac output to meet metabolic requirements. Increased cardiac output results pri- marily from a higher stroke volume in obese persons.54 Because of the heightened cardiac output, peripheral vascular resistance tends to be lower for any given blood pressure level compared with nonobese hypertensives.55*56 Heightened sympathetic nervous system

activity appears to be an extremely important factor in the development and maintenance of hypertension associated with obesity.57

Antihypertensive therapy in the obese hypertensive subject can focus on either their cardiogenic, volume-dependent or adrenergic aspects of their systemic blood pressure elevation, or all of them. Agents such as low-dose thiazide diuretics or calcium antagonists (mild volume expansion), centrally acting agents or /I blockers [elevated sympathetic nervous system activity and cardiac output) may be effective. Obesity adds a compounding factor to that of hypertension in the development of left ventricular hypertrophy. Thus, antihypertensive agents that can cause regression of left ventricular hypertrophy would be important to use, rather than relying only on diuretics. The /3 blockers or calcium antagonists alone, or ACE inhibitors or (Y blockers in conjunction with a low dose of a thiazide diuretic, would be most appropriate.

Physiologic Theories of Hypertension Development and Drug Management

Some of the key mechanisms that are thought to contribute to the development of essential hypertension include vascular structural alterations, the renin- angiotensin system, the sympathetic nervous system and intracellular accumulation of calcium. Drug classes have been developed to regulate these systems, including diuretics, vasodilators, (Y and ,8 blockers, centrally acting agents, ACE inhibitors and the newly developed calcium antagonists. The physiology of blood pressure regulation and how this regulation is affected by various drug classes will be reviewed in the ensuing sections.

Vascular alterations: Although hypertension may have many causes, in all cases the development of hypertension is eventually associated with altered structure of the vasculature.35

In essential hypertension, peripheral resistance is elevated by a generalized effective narrowing of the vasculature.34 A major reason changes in the vasculature are critical in the development of hypertension is that very small changes in arteriole vessel radius can cause major changes in resistance. This physical ob- servation is elucidated in Poiseuille’s Law that relates vascular resistance to the fourth power of the vessel radius.s8 This physical law has prompted scientists to investigate the various mechanisms that control vessel radius.

The narrowing of the lumen is caused in part by enhanced vascular smooth muscle constriction. This, in turn, may be related to increased sympathetic ac- tivity5g-61 and raised levels of hormonal pressor agents.62-65 However, histologic studies have shown that narrowing is also associated with structural alterations within the vasculature.66s67 In animal models, increased arterial wall thickness is accompanied by increased quantity of smooth muscle.66.69 It is not clear, however, whether this increased quantity of smooth muscle is due to hyperplasia or hypertrophy of the smooth muscle cells.34 These changes may be initiated by increased blood pressure, and therefore are consid-

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ered to be an adaptation .34 The role of putative mito- genie factors in vascular smooth muscle such as the local renin-angiotensin system, platelet-derived growth factors and other factors, is a considerable current investigative intent.

Folkow5s suggests that in some variants of primary hypertension, as in spontaneously hypertensive rats, and perhaps often in humans as well, the normal process of structural adaption seems to be genetically re- inforced via both protein synthesis links within the muscle cells and via extrinsic-trophic influences ex- erted by catecholamines. In spontaneously hypertensive rats, it appears as if the structural factors even precede the pressure increase.70x71 This suggests that the structural changes may be due, in part, to other factors independent of pressure such as growth factors in the serum.

It appears that plasma may contain a factor or factors that stimulate growth of the arterial smooth muscle cells.34 Vasoactive agents such as angiotension II, va- sopressin and norepinephrine can stimulate prolifera- tion of the smooth muscle cells.34 Thus, these sub- stances are not only vasoconstrictors but are also trophic or mitogenic agents for encouraging vascular hypertrophy [Fig. 1). OverbeckGo demonstrated in rats made hypertensive by coarction of the aorta that the vasculature distal to the coarctation and thus not ex- posed to high pressures still developed higher resistance and greater wall-to-lumen ratios than that in sham-operated rats, suggesting that nonpressure-dependent factors may be involved.

The treatment of hypertension is not only con- cerned with the control of blood pressure but also with controlling the factors that are responsible for the disease. As one of these factors is likely to be vascular structure abnormalities, therapies that can control vascular structure are likely to be more beneficial than those that do not.35 Evidence that this might be the case was recently provided by Freslon and Giudicelli72 who treated spontaneously hypertensive rats from age 1 to 5 months with either dihydralazine or captopril. Both treatments prevented the development of hypertension, but 7 weeks after discontinuing treatment, blood pressure was still reduced in the rats that had been treated with captopril, while those that had been treated with hydralazine did not experience a reduction. The investigators also measured the structure of mes- enteric resistance vessels and found that captopril treatment was more effective in preventing the development of abnormal vascular structure. Thus, there seemed to be a correlation between the ability to control vascular structure and the rate at which blood pressure redeveloped, suggesting that vascular structure can indeed have a direct effect on blood pressure.35 In addition, studies assessing the different capabilities of antihypertensive agents to cause regression of left ventricular hypertrophy have demonstrated that agents capable of depressing angiotensin II or norepinephrine effects at a tissue level appear most effective.15s73

These results suggest that in the treatment of hypertension, the actual long-term goal must be to achieve a

Hypertensive Activation Signal

Peripheral Vascular Resistance

FIGURE 1. Theoretical relations between blood pressure, vascular

structure and neurohormonal factors demonstrating pressure-de-

pendent and pressure-independent effects on vascular structure

and resistance.

substantial pressure decrease with minimal adverse effects and at the same time protect the cardiovascular system from the trophic effects of smooth muscle vascular mitogens such as angiotensin II and norepinephrine, etc.

Renin-angiotensin-aldosterone system: The hormone angiotensin II is one of the most potent known vasoconstrictors. The production of angiotensin II sys- tematically results from the kidney’s release of renin into the blood stream. Renin converts renin substrate into angiotensin I, which in turn is converted in the lungs to angiotensin II .74 Angiotensin II causes vasoconstriction of the arterioles, thereby increasing peripheral resistance as well as elevating blood volume through stimulation of aldosterone and through direct effects on the kidney to decrease excretion of both salt and water.74

Recent studies have greatly expanded our knowledge of the renin-angiotensin system. It has now been demonstrated that there is also localized production of angiotensin II at tissue sites.72z75 This phenomenon is an important aspect of local vascular control, because this allows marked heterogeneity in terms of vascular supply and pressure. Blood pressure that is measured at the level of the brachial artery with a blood pressure cuff may not reflect the blood pressure of the glomeru- lus, liver or brain. Angiotensin II has been demonstrated to act directly within the kidney on vascular endothelium, tubular epithelium, and mesangial, in- terstitial and juxtaglomerular cells, which may explain its effects on salt and water handling.36

Traditional therapy has used drugs such as diuretics and vasodilators to control blood pressure. Recent experimental findings, however, have raised ques- tions concerning the use of diuretics and vasodilators as sole or combined therapies for the treatment of hypertension.13 Both diuretics and vasodilators stimulate the renin-angiotensin system through nonphysiologic reductions in blood pressure.36 Elevation of intrarenal angiotensin II has the potential to vasoconstrict the efferent arteriole, maintaining higher glomerular capillary pressures despite a reduction in systemic blood pressure.13,36*76 It has been demonstrated in rats that the combination of a diuretic, reserpine and hydralazine does not reduce glomerular capillary hydraulic

64H A SYMPOSIUM: THE SALT-SENSITIVE HYPERTENSIVE PATIENT

pressure despite a significant decrease in systemic blood pressure. The result in these rats was that glomerular injury and proteinuria was not abated by therapy with these agents.13

Only 2 classes of medications have been demonstrated to lower peripheral resistance in a physiologic way and to interrupt the effects of angiotensin II at the intrarenal level: ACE inhibitors and calcium antagonists.37-44 These drugs decrease the sensitivity of renal vasculature and mesangium to angiotensin II.36 ACE inhibitors mediate their effect by preventing the con- version of angiotensin I into angiotensin II at a vascular leve1,7sT75 whereas calcium antagonists decrease calcium transport into vascular smooth muscle cells, thereby reducing the sensitivity of the vasculature to angiotensin II as well as norepinephrine.36

Sympathetic Nervous System Stimulation of the sympathetic nervous system not

only causes direct nervous excitation of the blood vessels and heart but also causes the release by the adre- nal medulla of epinephrine and norepinephrine into the circulating blood.74 Norepinephrine and epinephrine excite the heart and constrict most of the blood vessels and veins.74

For patients with essential hypertension, drugs such as p and (Y blockers have been developed to dis- rupt the effects of the sympathetic nervous system at the receptor sites on target tissues, while centrally acting agents have been targeted to decrease central sympathetic nervous system efferent function.77-81 The calcium channel antagonists on the other hand, have a direct inhibitory effect on norepinephrine effect at a vascular level through a reduction in antagonist-induced cellular uptake of calcium.82 Because norepinephrine is not only a potent vasoconstrictor but also a potential smooth muscle vascular mitogen,34 it is important to be able to treat hypertension and at the same time decrease the tissue effects of the sympathetic nervous system. Agents such as diuretics or nonspecific vasodilators that can cause reflex increases in sympathetic outflow through volume contraction and blood pressure reduction, respectively, may be counterpro- ductive in the long term despite their blood pressure- lowering effects, by increasing the vascular effect of norepinephrine.

Calcium Ion Calcium may be one of the most important ions

involved in the maintenance of arteriolar tone.74 Cal- cium activates the contractile process of smooth muscle, and increased intracellular calcium results in increased vascular reactivity to vasoconstrictor sub- stances.74 Thus, relaxation of smooth muscle in the arteriolar wall may be accompanied by decreasing smooth muscle-free cytoplasmic calcium levels.74 Ab- normal cellular transmembrane calcium fluxes could explain the increase in peripheral resistance observed in patients with essential hypertension.82v83

There are several hypotheses that attempt to explain how abnormal calcium accumulation in the cell

could contribute to the development of essential hypertension. One theory postulates that in salt-sensitive patients (such as the elderly or the black hypertensive), the effect of salt loading and a defect in the kidney’s ability to excrete salt may lead to a secondary increase in circulating natriuretic factors.84*85 These natriuretic factors lead to intracellular calcium accumulation and hyperreactive vascular smooth muscle. Other stud- iese6se7 have documented a membrane defect resulting in abnormal accumulation of calcium within vascular smooth muscle. The membrane defect is postulated to be an abnormal sodium-calcium exchange system. Finally, salt-induced changes in calcium-regulating hormone, such as parathyroid hormones, could increase vascular constriction indirectly by mediat- ing increased vascular smooth muscle-free calcium levels.88~8g

Calcium channel blocking agents have been developed to inhibit intracellular calcium influx.g0 Periph- eral resistance is reduced through a physiologic relaxation of resistance vessels due to inhibition of intracellular calcium accumulation.40 Calcium antagonists appear to lower peripheral resistance without activat- ing the reflex neurohormonal systems of angiotensin II and norepinephrine seen with with nonspecific vasodilators and diuretics40 Although the calcium blockers do have mild negative inotropic effects on the heart, the predominant effect is reduction in peripheral vascular resistance, which ultimately improves left ventricular function and ejection fraction,44*g1 with a net increase in tissue perfusion. Calcium channel blocking agents effectively reduce blood pressure in hypertensive patients who are salt sensitive with low-renin levels, and in medium-high-renin hypertensives who tend to be salt sensitive.g1sg2 Calcium channel blockers have been documented to reduce left ventricular mass concomitantly with the decrease in arterial pressure, and recent studies have noted a dramatic reduction of premature ventricular contractions achieved by calcium antagonist therapy together with reduction in left ventricular hypertrophy.g3

Investigators have also demonstrated that calcium antagonists attenuate the intrarenal effects of exoge- nously administered angiotensin II and norepinephrine.g4-gs Calcium blockers have the ability to maintain glomerular filtration rate, filtration fraction and renal blood flow, and decrease renal vascular resistance, all in the setting of reducing peripheral blood pressure 3640-44

In addition to the previous implications of the calcium ion in hypertension is the theory that elevation of cytosolic free calcium may be the final common pathway in ischemic cell death. Thus, calcium antagonists may exert, by inhibiting calcium entry into cells, a protective effect to the brain, kidney and heart under ischemic circumstances.g7*g8 However, clinical trials testing this hypothesis remain to be done.

In summary, the transcellular distribution of calcium may be important not only as a potential cause for hypertension but also critically involved in increasing the trophic influences of angiotensin II and norepi-

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nephrine on cardiovascular structure, ultimately leading to progressive senescence of the heart, various or- gans and the vascular tree.

Conclusion Recent experimental evidence and an improved

understanding of the hemodynamics of hypertension has demonstrated that the traditional stepped-care approach does not necessarily ensure that blood pressure will be normalized at vital organ sites. Reflex mechanisms associated with an unphysiologic reduction in systemic and local blood pressure can potentially lead to activation of the renin-angiotensin and sympathetic nervous systems with their trophic/mitogenic effects at the vascular level leading to progressive hypertrophy and aging of the cardiovascular tree. Thus, tissue perfusion needs to be maintained not only to ensure adequate organ function but also to be sure that local neurohormonal activation will not accelerate the risk for vascular damage. In addition, consideration of potential long-term metabolic complications of some of the antihypertensive medications need to be considered in light of potential vascular alterations related to the hypertensive process itself. A more rational approach to the treatment of essential hypertension would include assessment of underlying hemodynamic and physiologic factors that would then lead to the appropriate selection of an antihypertensive agent for a given patient. The calcium entry blockers and ACE inhibitors, because of their unique ability to antagonize the effects of the renin-angiotensin system at a vascular level, appear to have significant potential for causing regression of cardiovascular structure, and thus retard the accelerating aging effects of hypertension on the vascular tree. In addition, the calcium entry blockers, through their ability to decrease cellular uptake of calcium, may also have a theoretical cytopro- tective benefit for ischemic cells and antagonize the mitogenic effects of norepinephrine on the vasculature tree. More appropriate selections of antihypertensive agents based on underlying hemodynamics will allow a more physiologic reduction in blood pressure with fewer associated adverse effects and encourage compliance and maintenance of quality of life.

Acknowledgment: We are grateful to Vivian Dul- lien, PhD, for editorial assistance and to Teresa Chiap- parelli for secretarial assistance.

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