CURRENT CLINICAL PATHOPHYSIOLOGIC CONSIDERATIONS IN ESSENTIAL HYPERTENSION

ESSENTIAL HYPERTENSION, PART I

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CURRENT CLINICAL PATHOPHYSIOLOGIC CONSIDERATIONS IN ESSENTIAL HYPERTENSION Edward D. Frohlich, MD

Over the years, much has been learned from unraveling the pathophysiologic alterations associated with hypertensive diseases. Not only have they related to the overall problem of hypertension, but also they have come to pertain to a myriad of other clinical problems pathophysiologically, diagnostically, and therapeutically. Consider the use of tilt testing for determination of neural mechanisms in hyperten~ion,4~ now employed in cardiovascular medicine and in gastroenterology for other reasons; the role of the renin-angiotensin-aldosteronesystem in renal, endocrine, hepatic, and cardiac diseases; and the role of fluid and electrolyte alterations in renal and endocrine diseases. The roles of vascular and myocardial biologic alterations and the genetic aspects of hypertension no doubt will have an impact on other areas. Similar considerations also obtain with respect to the value of the extensive variety of antihypertensive drugs and their impact on other diseases. Perhaps one of the exciting and important conceptual contributions related to the pathophysiology of hypertension is the multifactorial nature of the disease. This concept also has particular relevance to the mosaic of mechanisms that participate in other diseases (as well as other problems of humankind-sociologic, economic, and political) that can be explained on the basis of their multifactorial causation and r e s o l ~ t i o n . ~ ~ In a previous review of this problem in the Medical Clinics of North America, each of the various participating mechanisms in the hyperten-

From the Alton Ochsner Medical Foundation, New Orleans, Louisiana

MEDICAL CLINICS OF NORTH AMERICA VOLUME 81 NUMBER 5 . SEPTEMBER 1997

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sive diseases and their implications on diagnosis and treatment were c ~ n s i d e r e dThe . ~ ~ author’s review concerned various hemodynamic aspects of hypertension wherein some of the factors believed by the author to be critical in the vascular and cardiac participation in the elevation of arterial pressure and in target organ involvement by the disease were d i s c ~ s s e d .More ~ ~ recently, these concepts were updated for another issue of the Medical BLOOD PRESSURE MEASUREMENT Definition One area of ongoing concern is the interpretation of arterial pressure measurement as it relates to the definition of hypertension. Until recently, hypertension was defined solely in terms of the height of diastolic pressure, with 90 mm Hg being the breakpoint between what is termed hypertension and normal blood pressures. This concept was amended slightly with publication of the Joint National Committee’s (JNC) third report, in 1988, wherein a high-normal category (85 through 89 mm Hg) of diastolic pressure was introduced.60Systolic elevation of pressure (i.e., above 160 mm Hg) was considered important, but it was not until the publication of JNC-5 that systolic as well as diastolic pressure elevation was incorporated into a single classification of severity stages of blood Another innovation in that report was the pressure elevation (Table 1).61 recommendation that the term mild be eliminated from a descriptive Table 1. CLASSIFICATION OF BLOOD PRESSURE FOR ADULTS AGE 18 YEARS AND OLDER* Category

Systolic (mm Hg)

Diastolic (mm Hg)

Normalt High normal Hypertension* Stage 1 Stage 2 Stage 3 Stage 4

<130 130-1 39

<85 85-89

140-1 59 160-1 79 180-209 221 0

90-99 100-1 09 110-1 19 2120

‘Not taking antihypertensive drugs and not acutely ill. When systolic and diastolic pressure fall into different categories, the higher category should be selected to classify the individual’s blood pressure status. For instance, 160/92 should be classified as stage 2, and 180/120 should be classified as stage 4. Isolated systolic hypertension is defined as systolic blood pressure 2140 mm Hg and diastolic blood pressure <90 mm Hg and staged appropriately (e.g., 170/85mm Hg is defined as stage 2 isolated systolic hypertension). tOptimal blood pressure with respect to cardiovascular risk is
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terminology of the stages of hypertension. In reality, no form of hypertensive diseases should be considered to be mild because the evidence at this time is abundant in demonstrating that any stage of hypertension is potentially lethal, carrying its own risk of premature morbidity and mortality. Inherent in this concept is the belief by some authorities that other discriminators of hypertensive disease are important, and these indices of disease severity may not be solely reflected in the blood pressure reading.3l.37 Included among these important factors are clinical and physiologic evidence of vascular and target organ involvement. Ambulatory Blood Pressures

In recent years, an innovation in blood pressure measurement was introduced with ambulatory blood pressure measurements. This methodologic innovation was a simple extension of other means for understanding blood pressure variability when it was not measured in the proscribed fashion in the physician’s office. For years, physicians had employed the use of home blood pressure records to obtain a more realistic concept of the degree of blood pressure control when away from the physician’s office and thereby obviate inordinate overdosing of prescribed medications, producing symptoms related to inordinately low pressures (e.g., postural hypotension), and evaluate other responses to antihypertensive therapy. With the advent of newer electronic means for obtaining blood pressures during daily activity and while sleeping at night, ambulatory blood pressure measurement was introduced?O Indeed, this new technology has been of great value for the management of a number of clinical problems related to hypertension, as followsg7: 1. To confirm office blood pressure readings (e.g., office or white coat hypertension). 2. To determine variability of blood pressures during 24-hour period. 3. To evaluate patients with symptoms and spells with suspected pheochromocytoma, orthostatic hypotension, or similar conditions. 4. To relate blood pressure elevation with episodes of angina pectoris or cardiac arrhythmias. 5. To determine whether nocturnal angina is related to blood pressure elevation. 6 . To provide confirmation that blood pressure is well controlled and that antihypertensive treatment is efficacious. 7. To determine whether blood pressures may be elevated when office blood pressures and when target organ involvement (e.g., of heart, kidneys, and brain) are abnormal. 8. To support insurance or other third-party needs demonstrating control (or lack of control) of blood pressure levels. 9. To conduct research.

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This technique was extended by some authorities for the diagnosis of certain difficult clinical problems, including so-called office or white coat hypertension.syDiagnosis of hypertension, however, usually has relied on at least three blood pressure measurements taken on at least three separate office visits before the diagnosis is assigned to a given patient.60, If that does not exist, the patient may not truly have hypertension; if it is so established, however, the patient is at risk for hypertension. These criteria have been established by a large body of insurance and other data, and that risk is clear.55,71 Thus, whereas some authorities suggest that those patients with office (or "white coat") hypertension who have ambulatory pressures that are below levels that are termed as being "hypertensive,"sy others report that these individuals are at a distinctly greater risk.33In general, the number of patients with ambulatory pressures is insufficient to permit definition of normative values?* The issue as to whether ambulatory pressures should be employed for the decision-makingprocess of whether antihypertensive therapy should be instituted in office hypertension clearly is up to the managing physician. Thus, this issue continues to remain one that is highly controversial.

VASCULAR INVOLVEMENT Precapillary and Postcapillary Constriction . In a previous discussion about the role of arteriolar and venular constriction, the author emphasized this important vascular control mechanism for regulating transcapillary fluid transfer and intravascular volume contraction and expansion with respect to the various hypertensive diseases.28The state of volume expansion and pseudotolerance with antihypertensive drug therapy were also discussed as well as the development of hypertensive retinopathy.2s,33-35 Thus, early in hypertension when there is only modest constriction of the arterioles to elevate arterial pressure through an increased total peripheral resistance, venular constriction serves to redistribute the circulating intravascular volume from the peripheral to the central circulation and thus increase cardiac ~ ~ t p Reduction ~ t . ~ of~arterial , ~ pressure ~ ~ with certain antihypertensive agents (e.g., smooth muscle vasodilators and certain adrenergic inhibitors) results in volume expansion and loss of antihypertensive drug effectiveness.lo8Moreover, with rapid progression of hypertensive disease, precapillary and postcapillary constriction serve to increase capillary hydrostatic pressure, resulting in transmigration of water and protein thereby manifesting in edema (e.g., papilledema) and protein deposits (e.g., exudates) or loss in the urine. This concept has been shown to participate in the increased glomerular hydrostatic pressure in experimental hypertensive renal disease and even clinically in diabetic 11,4y This latter concept is discussed in the section dealing nephropathy.lO, with renal involvement in hypertension.

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Endothelial Factors

Over the past decade, much information has appeared demonstrating that the endothelium of vessels is not simply a unicellular layer of the blood vessels that provides a lining to the vessel and smooth means for the viscosity interaction of blood and the vessel in which it flo~s.4~7 57, 73, lo7 The endothelium now appears to be a vital organ, which is the source of a host of vasoactive substances, the source of synthesis of locally active vasodilating and constricting agents, and the site at which many of these substances interact (autocrine/paracrine) in local growth and hemodynamic regulating mechanisms. It is not within the purview of this article to detail each of these local functions, but it is important for the reader to know that a number of hormonal and humoral vasoactive and growth-regulating peptides and other substances are produced in the vascular endothelium. Among these substances are angiotensin 11, bradykinin, endothelin, nitric oxide, and a myriad of growth factors. Endothelin has been found to be a highly potent vasoconstrictor and growth factor that may be involved in the pathogenesis of hypertension, coronary vasoconstriction, and vessel and myocardial wall growth.'@Angiotensin I1 has been shown to be synthesized locally in the vessel wall, myocardium, and other organs, and because each of the components of the renin-angiotensin system has been found locally in vessel, heart, and kidney, it also relates to the presence of the components of the kinin system.22,loo This is because the angiotensin converting enzyme (ACE),which is involved in the synthesis of angiotensin 11, is the same kininase that degrades the potent vasodilator b r a d ~ k i n i n The . ~ ~ third substance that is used as an example of 73, 91 This endothelial synthesis of vasoactive substances is nitric agent, which is synthesized from the amino acid L-arginine, is an extremely potent vasodilator that provides important local regulation of blood flow and other vital local functions. These functions are discussed more extensively in the section dealing with renal involvement in hypertension. Many of the local growth factors (including angiotensin and endothelin as well as platelet-derived growth factor, fibroblast growth factor, insulin growth factor, and many others) have been incriminated in the pathogenesis of vascular and ventricular hypertrophy, atherogenesis, diabetic vasculopathy, and ventriculopathy, among other diseases.6, 23* 59 No doubt, these considerations will be included among discussions in subsequent publications as more clinically pertinent information becomes available. Meanwhile, to emphasize this clinical relevance, use or inhibition of many of these humoral and hormonal substances is already being employed in clinical investigation today for future therapies. Among these agents are atrial natriuretic factor, inhibition of the aminoglycoside that degrades atrial natriuretic factor, and agents that inhibit the endothelins (several of these natural constrictor peptides have already been identified, cloned, and synthesized) as well as L-arginine and nitric oxide.

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CARDIAC INVOLVEMENT

Left Ventricular Hypertrophy

Hypertensive heart disease is manifested by the development of left ventricular hypertrophy (LVH), and its development provides a major risk factor for premature cardiovascular morbidity and mortality. This risk is independent of the height of systolic or diastolic pressure and development of LVH and is even greater than that of the elevated p r e s ~ u r e . The 3 ~ ~echocardiogram ~ provides an extremely sensitive means for the clinical demonstration of LVH, greater than that provided by the electrocardiogram (ECG) and far greater than that of the chest roentgen~gram.~~ The echocardiogram, however, need not be employed to demonstrate LVH in all patients with hypertension, especially if this is already demonstrable by the ECG. Were this technology to be employed in every patient, the cost of evaluating all patients with hypertension would be prohibitive. Notwithstanding, the echocardiogram is most usefully employed in those patients in whom the presence of LVH is in some doubt, most frequently in those with stages I and I1 hypertension. These are the largest groups of patients with hypertension, and the costeffectiveness of the technique may be offset by the clinical use of the limited echocardiogram.96 Pathophysiology

The mechanism(s) that explains the increased risk of premature death and morbidity associated with LVH is not known precisely, although several have been p ~ s t u l a t e dIn . ~the ~ earlier clinical studies, that risk has been related to the higher frequency of cardiac dysrhythmias 70 More recently, although still believed to particiassociated with LVH.26, pate in the sudden death associated with LVH, the basis of the risk from dysrhythmia may more likely be related to abnormal coronary hemodynami~s.'~ Presently the more plausible explanation pathophysiologically is based on the state of coronary arterial insufficiency associated with LVH.33,34, 44, 79 Thus, LVH is associated with an increased coronary arteriolar resistance as well as a reduced absolute (and relative) coronary blood flow to the hypertrophied myocardium.54,79, 94 Moreover, after a coronary arterial vasodilator (such as intravenous papaverine, dipyridimole, or adenosine clinically or carbachrome experimentally) is given, minimal coronary vascular resistance is significantly higher in LVH than in hearts without LVH, and the coronary blood flow reserve is significantly reduced. The coronary insufficiency of LVH may also be explained on the basis of the increased myocardial tension produced by the greater transverse cardiac diameter and the higher systolic arterial pressure.92These factors promote a reduced supply of arterial blood, and an increased myocardial oxygen demand may be exacerbated by hypertension, which accelerates the process of atherogenesis and, thereby, further reduces oxygen delivery to the myocardium.

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Other mechanisms may be involved with the risk associated with LVH. Thus, it is now known that the coronary arterial endothelium in patients with hypertension (as well as in patients with atherosclerosis, hypercholesterolemia, and tobacco addiction, and older patients) has an impaired ability to synthesize the local vasodilator nitric oxide.13,15,47, 48, 85, Io2 Experimentally, it has been shown that this impairment of coronary blood flow associated with reduced nitric oxide synthesis is associated with increased myocardial fibrosis and myocardial infarctions.83Other local hemodynamic mechanisms may be related to the increased blood viscosity associated with hypertension (contracted plasma volume) that may produce local microrheologic alterations to intracoronary nutrient blood flow. Left Ventricular Hypertrophy Reversal

Experimental and clinical research has demonstrated that every antihypertensive agent is able to reverse LVH if it is used for a long enough period of time.38Early studies by the author and colleagues in the spontaneously hypertensive rat (SHR) demonstrated that this reversal can be produced within 3 weeks with the centrally active adrenergic inhibitors,58,86, 93 P-adrenergic receptor blocking 88 calcium antagonists? ACE inhibitors? 5, 40, 42, 76 and the angiotensin I1 (type 1) receptor antagonist~.~~ These findings were subsequently confirmed 18, 20, 29, 50 There have been no studies, however, that have thus ~linically.~, far demonstrated that reversal or regression of LVH pharmacologically is associated with a reduction of the increased risk of morbidity and mortality that is associated with the LVH. Thus, to demonstrate that the risk associated with LVH is reversed by pharmacotherapy, this must be shown to be independent of the improved risk associated with reduction of arterial pressure, increased coronary blood flow, or the antiarrhythmic properties of the antihypertensive agents used to reduce the left ventricular mass. Changes Related to Pharmacotherapy

Experimental studies have shown that even within the same class of antihypertensive agents not all agents are associated with the same effects of reducing left ventricular mass. Thus, some agents (but not all) may also reduce right ventricular and aortic mass.5o,93 Other agents (particularly with the calcium antagonists clinically as well as experimentally) may increase right ventricular wall mass while left ventricular mass also d e c r e a ~ e s .29,~ 43, ~ ,50 This increase in right ventricular mass is not the result of ventricular hypertrophy but is associated with increased deposition of collagen in the right ventricular wall, which can be prevented entirely by the coadministration of an ACE inhibit~r.~, The ACE inhibitor, however, did not reduce the amount of left ventricular collagen any further than when the ACE inhibitor is administered alone?, Still more recent studies in the author’s laboratory in SHRs treated for

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more prolonged periods (12 weeks) with an angiotensin I1 (type 1) receptor antagonist together with an ACE inhibitor showed not only reduced left ventricular mass and improved left ventricular hemodynamics (increasing coronary blood flow and flow reserve while reducing coronary vascular resistance and minimal resistance), but also that it was more effective than when the angiotensin I1 (type 1)receptor antagonist was administered Thus, these experimental and clinical studies demonstrated that pharmacologic therapy of hypertension may be expected to reverse LVH. They also suggested strongly that it may be possible to reduce cardiovascular risk associated with LVH; however, clinicians must await the initiation of prospective, controlled, multicenter studies that are designed to demonstrate that the reversal of LVH will be associated with a reduced risk of premature death associated with the LVH. Antihypertensive Therapy and Coronary Heart Disease

Sophisticated statistical meta-analysis of the first 14 controlled, multicenter clinical trials involving antihypertensive therapy has provoked unwarranted assertions about the ability of the earlier conventional antihypertensive therapy to reverse mortality from coronary heart disease (CHD).16,66 These studies predicted that antihypertensive therapy should reduce deaths from stroke by 40% to 45% and deaths from CHD by 20% to 25%. In fact, this meta-analysis did demonstrate the predicted reduction in deaths from strokes, but it also demonstrated that the reduction in deaths from CHD was only 14%. As a result of these findings, many concluded that antihypertensive therapy failed to protect the patients from deaths from myocardial infarction. This, of course, was not so because the 14% reduction was highly significant ( P < .001), but the conclusion about myocardial infarction was also inaccurate. According to the epidemiologists' design of the 14 studies, CHD was not synonymous with myocardial infarction. In addition to including myocardial infarction among CHD fatal events, they also included other events, such as lethal arrhythmias, lethal congestive heart failure, sudden death not explained by the foregoing events, and severe angina pectoris without autopsy-confirmed myocardial infarction. Nevertheless, some incriminated the diuretic therapy for accelerating atherogenesis (by hyperlipidemia), thereby increasing deaths from myocardial infarction. A subsequent meta-analysis, however, of more recent studies involving elderly patients with hypertension who were also treated with lower doses of diuretics (25 to 50 mg hydrochlorothiazide or its equivalent) than that used in the earlier studies (100 mg or more of hydrochlorothiazide), actually confirmed the first report of a 20% reduction in deaths from stroke and the predicted decrease in deaths from CHD (26% reduction).lO'The differences between the first meta-analysis16, and the late oneTo1may well be related to the thiazide doses, which may not reflect the atherosclerotic or hyperlipidemic potential of diuretics but,

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rather, their potential to produce cardiac dysrhythmias and sudden deaths from hypokalemia or hypomagnesemia. This conclusion may be supported by data from the Multiple Risk Factor Intervention Trial (MRFIT). In that study, there were more deaths in the study group receiving more vigorous treatment than in the usual-care group; in the former group, there were a greater number of patients with ECG abnormalities at the outset of the study.74 Thus, it seems clear that antihypertensive therapy will significantly reduce the risk of deaths from stroke as well as from CHD. These findings, however, offer no explanation for the inability of increasing numbers of patients treated for hypertension that progress on to end-stage renal disease (ESRD); this is also discussed in the section dealing with renal involvement in hypertension. Congestive Heart Failure

A report from the Framingham Heart Study in the early 1970s demonstrated that hypertension was the first and major cause of development of congestive heart failure in the United States.62The second most common cause of congestive heart failure was hypertension associated with ischemic (i.e., atherosclerotic) heart disease; hypertension was also listed among the other major causes of congestive heart failure (e.g., hypertension associated with rheumatic heart disease). A report from the same study has once again indicated that hypertension remains the most common cause of congestive heart failure, and the authors speculate that the explanation may be related to the increasing age of the patient^.^ There is no explanation why hospitalizations for congestive heart failure continue to increase in the United States. In part, this may be related to the large number of patients with hypertension that remain untreated, to the inadequate dosing with ACE inhibitors employed at this time,@or to other factors including the aging of the population. RENAL INVOLVEMENT

End-Stage Renal Disease

As indicated earlier, despite the increased number of patients treated for hypertension in the United States, the number of patients progressing to ESRD continues to rise; this is related to patients with hypertension or diabetes mellitus, especially if they are AfricanAmeri~an.~, Io6 Why this should occur is a matter of speculation by hypertensionologists and nephrologists. Among the suggested explanations are inability of the antihypertensive agents employed in earlier years to reverse hypertensive renal disease; specificity of certain antihypertensive therapy for the target organs of the disease; failure to reduce blood pressure to a level that would reverse renal involvement from

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hypertensive disease; and, perhaps, inability of any antihypertensive therapy to reverse any renal involvement from hyperten~ion.~~ Pathophysiology

Normal renal excretory function in patients with hypertension depends on the maintenance of normal glomerular hydrostatic pressure in the facing of increasing afferent and efferent glomerular arteriolar resistance and a decreasing renal blood flow.1° Even in the face of a reduced renal blood flow and rising afferent glomerular arteriolar resistance, glomerular hydrostatic pressure increases as a result of efferent glomerular arteriolar constriction. In response to the increased glomerular hydrostatic pressure, there is glomerular and protein hyperfiltration, pari passu, with eventual development of glomerulosclerosis and the further impairment of renal function.lO,49, 53 This obviously leads to the cycle responsible for the development of ESRD. Antihypertensive Therapy and Renal Function

There is a paucity of studies that have demonstrated improvement of renal function and renal histologic changes with antihypertensive therapy. Investigators from the Hypertension and Detection Follow-Up Program (HDFP) demonstrated that vigorous antihypertensive therapy is expected to improve renal function (the reciprocal of the serum creatinine c~ncentration).~~ This study was a randomly allocated and controlled treatment program involving diuretics and other antihypertensive Another widely quoted study, involving severely hypertensive patients with renal functional impairment, demonstrated improvement in renal function in patients treated with a loop acting diuretic, hydralazine or minoxidil, and other antihypertensive therapy.14,87 Other than these studies, the data are meager to permit further conclusions. Experimental Micropuncture Studies

A number of animal models for ESRD have been developed to understand better the pathophysiology and treatment of ESRD.36, They have all involved administration of toxic chemicals, nephrectomy alone or with subtotal ablation of the remaining kidney, or the additional administration of other substances that exacerbate the hypertension. The author and colleagues followed SHRs with naturally developing genetic hypertension until they were 72 weeks of age when they developed severe hypertensive nephrosclerosis.64Renal disease was manifested by massive proteinuria, severely elevated arterial pressure, reduced renal blood flow, and severe afferent and efferent glomerular arteriolar constriction with markedly elevated glomerular hydrostatic pressure. Half of these rats were treated for 3 weeks with an ACE inhibitor and the other half with only tap water. After the 3 weeks of this treatment, the

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proteinuria markedly decreased, the renal function significantly improved, and these physiologic changes were associated with a significant improvement in both the glomerular and the arteriolar pathologic lesions of hypertensive nephrosclerosis.64Because it is not possible to purchase 72-week-old SHRs and younger rats (e.g., 20 weeks old) that have normal renal function, micropuncture dynamics, no proteinuria, Io3, Io4 the changes of aging were mimand normal histologic finding~,7~? icked" by inhibiting the endothelial production of nitric oxide chemically with L-NAME in 20-week-old SHRS.~OIn these studies, all of the physiologic and histologic changes (and the proteinuria) were reproduced within 3 weeks.a0 Having thus developed a model for producing nephrosclerosis in young SHRs, the author and colleagues then divided 20-week-old SHRs into three groups: one received only the L-NAME, one received the LNAME with an ACE inhibitor for 3 weeks, and one received L-NAME for 3 weeks and then the same ACE inhibitor for the following 3 weeks. In these studies, not only was the development of hypertension/LNAME-induced nephrosclerosis prevented, but also the development of the nephrosclerosis that had been demonstrated by renal biopsy at the end of the L-NAME treatment period was reversed.*l This reversal of hypertensive nephrosclerosis was accomplished with suboptimal reduction of arterial pressure. In another subsequent study, the young 20week-old SHRs were treated with either L-NAME alone or hydrochlorothiazide. Arterial pressure was reduced to the same levels that the author and colleagues obtained with ACE inhibitor studies with the diuretic; however, instead of reversing the physiologic, pathologic, and proteinuria effects of the hypertension and L-NAME,the thiazide exacerbated the proteinuria, impaired renal and glomerular dynamics, and glomerular disease.82Hence, experimental findings demonstrated that the magnitude of goal blood pressure reduction was less important than the specificity of the antihypertensive therapy in reversing the renal disease. Thus, the ACE inhibitor most likely reduced the generation of locally produced angiotensin 11, whereas the hydrochlorothiazide 51 These findings provide enmay have increased its local produ~tion.'~, couraging support for ongoing and future clinical studies designed to intervene, reverse, or prevent the development of hypertensive nephrosclerosis and its consequence, ESRD. These efforts have received considerable support from prospectively designed and controlled multicenter studies in hypertensive and diabetic patients with diabetic nephropathy receiving ACE inhibitors.a,65, 67, Microalbuminuria It is now possible to assess more precisely microquantitative amounts of the daily urinary excretion of albumin.72This simple but, as yet, fairly costly methodology should permit early development of renal parenchymal involvement from hypertension, diabetes mellitus, and

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other renal diseases. Indeed, early studies suggest its value in evaluating risk for morbidity and mortality from cardiovascular diseases.' Using the current methodology, the normal range for urinary albumin excretion is 30 to 300 mg/day (20 to 200 ~ g / m i n u t e ) .The ~ ~ present cost for this determination is much greater than for the conventional dipstick method. An innovative microalbuminuria dipstick method is currently under evaluation'; if it provides valid and relatively inexpensive results, it should permit an earlier means for the diagnosis of hypertensive, diabetic, and other forms of nephropathy. Hyperuricemia The finding of hyperuricemia is fairly common among untreated patients with essential hypertensi011.9~It does not necessarily relate solely to abnormalities in urate metabolism, but may also reflect early evidence of hypertensive nephrosclerosis. Several years ago, the author and colleagues demonstrated that the height of serum uric acid concentration was directly related to the height of renal vascular resistance and, therefore, was inversely related to renal blood flow in untreated patients with otherwise uncomplicated essential hyperten~ion.~~ Uric acid is a substance that is delivered to the glomerulus for filtration; it is subsequently secreted and reabsorbed by the renal tubule. Each of these functions depends on renal blood flow in addition to the active secretory and absorptive functions of the renal tubule. Subsequent work was conducted in patients with essential hypertension without LVH (by ECG) or renal functional impairment (by measurement of serum creatinine or blood urea nitrogen concentrations). This study showed that when echocardiographic evidence of LVH was demonstrated, renal blood flow was not reduced. When renal blood flow was reduced (less than 16% of the cardiac output), however, echocardiographic evidence of LVH was demonstrable consistently; these patients also had elevated In another study, involving hypertensive serum uric acid c~ncentration.~~ patients with renal arterial disease, serum uric acid concentration declined after corrective repair of the arterial lesion.78The author and colleagues have subsequently confirmed these clinical observations in rats with malignant hypertension and in SHRs with severe hypertension and reduced renal blood flow. CONCLUSIONS

Despite a large base of fundamental and clinical information concerning the pathophysiologic alterations associated with essential hypertension, knowledge continues to expand. Much of the newer data relate to the remarkable advances concerning the molecular biologic and inborn genetic alterations associated with the disease. Other clinical investigative studies, however, continue to point to new pathophysiologic

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alterations that involve changes in the vasculature and target organs of the disease. Some of the more exciting advances are summarized in this article.

References 1. Agrawal B, Berger A, Wolf K, et a1 Microalbuminuria screening by reagent strip predicts cardiovascular risk in hypertension. J Hypertens 14:223-228, 1996 2. Ando K, Frohlich ED, Chien Y, et al: Effects of quinapril on systemic and regional hemodynamics and cardiac mass in spontaneously hypertensive and Wistar-Kyoto rats. J Vasc Med Biol 3:117-123, 1991 3. Aristizabal D, Messerli FH, Frohlich E D Disparate structural effects of left and right ventricles by angiotensin converting enzyme inhibitors and calcium antagonists. Am J Cardiol 73:483487, 1994 4. Arita M, Horinaka S, Frohlich E D Biochemical components and myocardial performance after reversal of left ventricular hypertrophy in spontaneously hypertensive rats. J Hypertens 11:951-959, 1993 5. Arita M, Horinaka S, Komatsu K, et a1 Reversal of left ventricular hypertrophy with different classes of drugs causes differing ventricular biochemical changes. J Hypertens ll:S354-S355, 1993 6. Baron AD, Steinberg H O Vascular actions of insulin in health and disease. In Sowers JR (ed): Endocrinology of the Vasculature. Totowa, NJ, Humana Press, 1996, pp 95-107 7. Basan RS, Levy D The role of hypertension in the pathogenesis of heart failure: A clinical mechanistic overview. Arch Intern Med 156:1789-1796,1996 8. Bauer JH, Reams GP, Hewett J, et al: A randomized, double-blind, placebo-controlled trial to evaluate the effect of enalapril in patients with clinical diabetic nephropathy. Am J Kidney Dis 20443457,1992 9. Blyth WB, Maddux F W Hypertension as a causative diagnosis of patients entering end-stage renal disease programs in the United States from 1980 to 1986. Am J Kidney Dis 18:33-37, 1991 10. Brenner BM Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int 23:647455, 1983 11. Brenner BM, Meyer TW, Hostetter T H Dietary protein intake and the progressive nature of kidney disease: The tale of hernodynamically mediated glomerular disease in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 307652659, 1982 12. Brush JE, Cannon RO, Schenke WH, et al: Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med 319~1302-1307,1988 13. Calvier A, Collier J, Vallance P: Inhibition and stimulation of nitric oxide synthesis is in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 90:2548-2554, 1992 14. Campese VM:Minoxidil: A review of its pharmacological properties and therapeutic use. Drugs 22257-278, 1981 15. Casino PR, Kilcoyne CM, Quyyumi AA, et al: The role of nitric oxide in endotheliumdependent vasodilation of hypercholesterolemic patients. Circulation 88:2541-2547, 1993 16. Collins C, Peto R, MacMahon S, et al: Blood pressure, stroke, and coronary heart disease: Part 11. Short-term reductions in blood pressure overview of randomized drug trials in their epidemiological context. Lancet 335:827-838, 1990 17. Cook JL, Chen L, Bhandaru S, et al: The use of antisense oligonucleotides to establish autocrine angiotensin growth effects in human neuroblastoma and mesangial cells. Antisense Res Dev 2199-210, 1992 18. Dunn FG, Oigman W, Ventura HO, et al: Systemic and renal effects on enalapril and its effects on cardiac mass. J Hypertens 2:57-61, 1984

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19. Durn FG, Pringle S D Sudden cardiac death, ventricular arrhythmias and hypertensive left ventricular hypertrophy [edit rev]. J Hypertens 11:1003-1010, 1993 20. Dunn FG, Ventura HO, Messerli FH, et al: Time course of regression of left ventricular hypertrophy in hypertensive patients treated with atenolol. Circulation 76:254-258, 1987 21. Dustan HP, Page IH, Tarazi RC, et al: Arterial pressure responses to discontinuing antihypertensive drug treatment. Circulation 37370-379, 1968 22. Dzau VJ, Re RN: Tissue angiotensin system in cardiovascular medicine: A paradigm shift. Circulation 89:493-498, 1994 23. Dzau VJ, Safar ME: Large conduit arteries in hypertension: Role of the vascular reninangiotensin system. Circulation 77947-954, 1988 24. Erdos E: Angiotensin I converting enzyme and the changes in our concepts through the years: Lewis K. Dahl Memorial Lecture [rev]. Hypertension 16363-370, 1990 25. Frohlich ED The mosaic theory: A practical approach to some difficult problem. Mod Med 51:ll-16, 1983 26. Frohlich ED Cardiac hypertrophy in hypertension. N Engl J Med 317831-833, 1987 27. Frohlich ED: Hemodynamic considerations in clinical hypertension. Med Clin North Am 71:803-812, 1987 28. Frohlich ED (ed): Essential Hypertension. Med Clin North Am vol 71, 1987 29. Frohlich ED: State of the Art: The First Irvine H. Page Lecture: The mosaic of hypertension: Past, present, and future. J Hypertens 6:S2-S11, 1988 30. Frohlich ED Left ventricular hypertrophy: An independent factor of risk. In Frohlich ED (ed): Preventive Aspects of Coronary Heart Disease. Philadelphia, FA Davis, 1990, pp 85-94 31 Frohlich ED (ed): American Heart Association Prevention Conference 11. Hypertension 18~1-168,1991 32. Frohlich ED: Current issues in hypertension: Old questions with new answers and new questions. Med Clin North Am 76:1043-1056, f992 33. Frohlich E D Pathophysiology of systemic arterial hypertension. In Schlant RC, Alexander RW, ORourke RA, et a1 (eds): Hurst’s The Heart, ed 8. New York, McGrawHill, 1993, pp 1391-1401 34. Frohlich ED Hypertension and hypertensive heart disease. In Chizner MA (ed): Classic Teachings in Clinical Cardiology: A Tribute to W. Proctor Harvey, M.D. Cedar Grove, NJ, Laennec Publishing, 1995, pp 1249-1274 35. Frohlich ED Clinical classifications of hypertensive diseases. In Fuster V, Ross R, Topol EJ (eds): Atherosclerosis and Coronary Artery Disease. Philadelphia, Lippincott-Raven, 1996, pp 243-258 36. Frohlich E D Arthur C. Corcoran Lecture: Influence of nitric oxide and angiotensin I1 on renal involvement in hypertension. Hypertension 29:188-193, 1997 37. Frohlich ED, Apstein C, Armstrong ML, et al: Workshop: Target organ consequences in hypertension: Pathogenesis and prevention. Hypertension 18:143-145, 1991 38. Frohlich ED, Apstein C, Chobanian AV, et al: The heart in hypertension. N Engl J Med 327998-1008, 1992 39. Frohlich ED, Grim C, Labarthe DR, et al: Report of the Special Task Force Appointed by the Steering Committee, American Heart Association. Vol. 5. Recommendations of the Human Blood Pressure Determination by Sphygmomanometer. Dallas, American Heart Association Publications No. 70-1005 (SA), 1987. Hypertension ll:209A222A, 1988 40. Frohlich ED, Horinaka S Cardiac and aortic effects of angiotensin converting enzyme inhibitors. Hypertension 18:2-7, 1991 41. Frohlich ED, Kozul VJ, Tarazi RC, et al: Physiological comparison of labile and essential hypertension. Circ Res 2755-69, 1970 42. Frohlich ED, Sasaki 0: Dissociation of changes in cardiovascular mass and performance with angiotensin converting enzyme inhibitors in Wistar-Kyoto and spontaneously hypertensive rats. J Am Coll Cardiol 16:1492-1499, 1990 43. Frohlich ED, Sasaki 0, Chien Y, et al: Changes in cardiovascular mass, left ventricular pumping ability, and aortic distensibility after calcium antagonist in Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens 101369-1378, 1992

CURRENT CLINICAL PATHOPHYSIOLOGIC CONSIDERATIONS

1127

44. Frohlich ED, Tarazi RC, Dustan HI? Clinical-physiological correlations in the development of hypertensive heart disease. Circulation 44:44&455, 1971 45. Frohlich ED, Tarazi RC, Ulrych M, et al: Tilt test for investigation of a neural component in hypertension and its correlation with clinical characteristics. Circulation 36:387-393, 1967 46. Furchgott RF: Role of endothelium in responses of vascular smooth muscle. Circ Res 53557-573,1983 47. Gerhard M, Roddy MA, Creager SJ, et a1 Aging progressively impairs endotheliumdependent vasodilation in forearm resistance vessels of humans. Hypertension 278494353,1996 48. Gilligan DM, Guetta V, Panza JA, et al: Selective loss of microvascular endothelial function in human hypercholesterolemia. Circulation 90:3541, 1994 49. Goldring W, Chasis H, Ranges HA, et a 1 Effective renal blood flow in subjects with essential hypertension. J Clin Invest 20:637-653, 1941 50. Grossman E, Oren S, Garavaglia GE, et al: Systemic and regional hemodynamic and humoral effects of nitrendipine in essential hypertension. Circulation 781394-1400, 1988 51. Horiba N, Nomura K, Shizume K. Exogenous and locally synthesized angiotensin I1 and glomerular cell functions. Hypertension 15:190-197, 1990 52. Horinaka S, Frohlich E D Cardiovascular mass and ventricular function after celiprolo1 in Wistar-Kyoto and spontaneously hypertensive rats. Cardiovasc Res 16:396400,1992 53. Hostetter TH, Olson JL, Rennke HG, et al: Hyperfiltration in remnant nephros: A potentially adverse response to renal ablation. Am J Physiol 241:F8!%F93, 1981 54. Houghton JL, Frank MJ, Carr AA, et a1 Relations among impaired coronary flow reserve, left ventricular hypertrophy and Thallium perfusion defects in hypertensive patients without destructive coronary artery disease. J Am Coll Cardiol15:43-51,1990 55. Hunt JC, Frohlich ED, Moser M, et al: Devices used for self-measurement of blood pressure: Revised statement of the National High Blood Pressure Education Program. Arch Intern Med 145:2231-2234, 1985 56. Hypertension Detection and Follow-Up Program Cooperative Group: Five-year findings of the Hypertension Detection and Follow-Up Program: I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 252:25622571, 1979 57. Ignarro LJ, Buga GM, Wood KS, et al: Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA M92659269, 1987 58. Ishise S, Pegram BL, Frohlich E D Disparate effects of methyldopa and clonidine on cardiac mass and haemodynamics in rats. Clin Sci 59:449&52s, 1980 59. Itoh H, Mukogama M, Pratt RE, et al: Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin 11. J Clin Invest 91:22682274, 1993 60. Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure: The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 148:1023-1038, 1988 61. Joint National Committee on the Detection, Evaluation, and Treatment of Blood Pressure: The 1992 Report of the Joint National Committee on the Detection, Evaluation, and Treatment of Blood Pressure (JNC-V). Arch Intern Med 1533154-183, 1993 62. Kannel WB, Castelli WP, McNamara PM, et al: Role of blood pressure in the development of congestive heart failure: The Framingham Study. N Engl J Med 287781787, 1972 63. Kobrin I, Frohlich ED, Ventura HO, et a1 Renal involvement follows cardiac enlargement in essential hypertension. Arch Intern Med 146272-276, 1986 64. Komatsu K, Frohlich ED, On0 H, et al: Glomerular dynamics and morphology of aged SHR. Hypertension 25:207-213,1995 65. Lewis EJ, Hunsicker LG, Bain RP,et al: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 329:1456-1462, 1993 66. MacMahon S, Pet0 R, Cutler JA, et al: Blood pressure, stroke, and coronary heart

1128

FROHLICH

disease: Part I. Prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias. Lancet 335:765-774, 1990 67. Maschio G, Alberti D, Janin G, et al: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 334939-945, 1996 68. Materson BJ: ACE inhibitors as a shield against diabetic nephropathy. Arch Intern Med 156239-240, 1996 69. Messerli FH, Frohlich ED, Dreslinski GR, et a1 Serum uric acid in essential hypertension: An indicator of renal vascular involvement. Ann Intern Med 93:817-821, 1980 70. Messerli FH, Ventura HO, Elizardi DJ, et al: Hypertension and sudden death Increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 771822, 1984 71. Metropolitan Life Insurance Company: Blood Pressure: Insurance Experience and Its Implications. Statistical Bulletin. New York, Metropolitan Life Insurance Company, 1961. 72. Mogensen CE: Microalbuminuria as a predictor of clinical diabetic nephropathy. Kidnev Int 3L673-689, 1987 73. Moncada S, Higgs A:.The L-arginine-nitric oxide pathway. N Engl J Med 329:20022012. 1993 74. Multiple Risk Factor Intervention Trial Research Group: Mortality rates after 10.5 years for participants in the Multiple Risk Factor Intervention Trial: Findings to a prior hypothesis of the trial. JAMA 2631795-1801, 1990 75. National High Blood Pressure Education Program Working Group: 1995 Update of the working group reports on chronic renal failure and renovascular hypertension. Arch Intern Med 156:1938-1947, 1996 76. Natsume T, Kardon MB, Pegram BL, et a1 Ventricular performance in spontaneously hypertensive rats with reduced cardiac mass. Cardiovasc Drug Ther 3:433-439, 1989 77. Numabe A, Komatsu K, Frohlich E D Effects of angiotensin-converting enzyme and a,-adrenoceptor inhibition on intrarenal hemodynamics in SHR. Am J Physiol 266R1437-1442, 1994 78. Nunez BD, Frohlich ED, Garavaglia GE, et al: Serum uric acid in renovascular hypertension: Reduction following surgical correction. Am J Med Sci 294419422, 1987 79. Nunez E, Hosoya K, Susic D, et al: Enalapril and losartan reduced cardiac mass and improved coronary hemodynamics in SHR. Hypertension 29(suppl 1):519-524, 1997 80. On0 H, Ono Y, Frohlich E D Nitric oxide synthase inhibition in spontaneously hypertensive rats. Hypertension 26:249-255, 1995 81. On0 H, 01-10 Y, Frohlich E D ACE inhibition prevents and reverses L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats. Hypertension 27176-183, 1996 Y, On0 H, Frohlich E D Hydrochlorothiazide exacerbates nitric oxide blockades 82. 01-10 nephrosclerosis with glomerular hypertension in spontaneously hypertensive rats. J Hypertens 14:823-828, 1996 H, Hosoya K, et a1 Prolonged nitric oxide synthase blockade exacerbated 83. On0 Y, 01-10 hypertensive cardia injury in spontaneously hypertensive rats. Circulation 94:I-589, 1996 84. Packer M: Do angiotensin-converting enzyme inhibitors prolong life in patients with heart failure treated in clinical practice? J Am Coll Cardiol28:1323-1327, 1996 85. Panza JA, Casino PR, Kilcoyne CM, et al: Role of endothelium-derived nitric oxide in the abnormal endothelia-dependent vascular relaxation of patients with essential hypertension. Circulation 873468-1474, 1993 86. Pegram BL, Ishise S, Frohlich E D Effect of methyldopa, clonidine, and hydralazine on cardiac mass and haemodynamics in Wistar-Kyoto and spontaneously hypertensive rats. Cardiovasc Res 1 6 4 M 6 , 1982 87. Pettinger WA, Mitchell HC: Minoxidil: An alternative to nephrectomy for refractory hypertension. N Engl J Med 289:167-173, 1973 88. Pfeffer MA, Pfeffer JM, Weiss AK, et al: Development of SHR hypertension and

CURRENT CLINICAL PATHOPHYSIOLOGIC CONSIDERATIONS

1129

cardiac hypertrophy during prolonged beta blockade. Am J Physiol 232H639-H644, 1977 89. Pickering TG, James GD, Boddic C, et al: How common is white coat hypertension? JAMA 259:225-228, 1988 90. Prasad N, Macfadyen RJ, MacDonald T M Ambulatory blood pressure monitoring in hypertension. QM J 89:95-102, 1996 91. Raij L: Nitric oxide and the kidney. Circulation 87(suppl V):26-29, 1993 92. Sarnoff SJ, Braunwald E, Welch GH Jr, et al: Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension time index. Am J Physiol 192148-156, 1958 93. Sasaki 0, Kardon MB, Pegram BL, et al: Aortic distensibility and left ventricular pumping ability after methyldopa in Wistar-Kyoto and spontaneously hypertensive rats. J Vasc Med Biol 1:5946, 1989 94. Scheler S, Wolfgang M, Strauer BE Mechanisms of angina pectoris in patients with systemic hypertension and normal epicardial arteries by arteriogram. Am J Cardiol 73478-482, 1994 95. Sesoko S, Pegram BL, Willis GW, et al: DOCA-salt induced malignant hypertension in spontaneously hypertensive rats. J Hypertens 2:49-54, 1984 96. Sheps SG, Frohlich E D Limited echocardiography for hypertensive left ventricular hypertrophy. Hypertension 29:560-563, 1997 97. Sheps SG, Pickering TG, White WE, et al: Ambulatory blood pressure monitoring. J Am Coll Cardiol23:1511-1513, 1994 98. Shulman NB, Ford CE, Hall WD, et al: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function: Results from the Hypertension Detection and Follow-up Program. Hypertension 13:180-193, 1989 99. Stanton JR, Freis E D Serum uric acid concentration in essential hypertension. Proc SOCExp Biol Med 66193-194, 1947 100. Struijker-Boudier HAJ, vanEssen H, Fazzi G, et al: Disproportional arterial hypertrophy in hypertensive mRen-2 transgenic rats. Hypertension 28:779-784, 1996 101. Thijs L, Fagard R, Lijnen P, et al: A meta-analysis of outcome trials in elderly hypertensives. J Hypertens 10:1103-1109, 1992 102. Treasure CB, Klein JC, Vita JA, et a1 Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary artery resistance vessels. Circulation 8786-93, 1993 103. Uchino K, Frohlich ED, Nishikimi T, et al: Spontaneously hypertensive rats demonstrate increased renal vascular alpha-, adrenergic receptor responsiveness. Am J Physio126OR889-R893,1991 104. Uchino K, Nishikimi T, Frohlich E D Alpha-1 adrenergic receptor blockade reduces afferent and efferent glomerular arteriolar resistances in SHR. Am J Physiol261:R576R580,1991 105. Ulrych M, Frohlich ED, Dustan HI', et al: Cardiac output and distribution of blood volume in central and peripheral circulations in hypertensive and normotensive man. Br Heart J 31:570-574, 1969 106. US. Renal Data Systems: 1995 Annual Data Report: National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases: 111. Incidence and causes of treated ESRD. Am J Kidney Dis 26:S39-S50, 1995 107. Vanhoutte PM, Rubanyi GM, Miller VM, et al: Modulation of vascular smooth muscle contraction by the endothelium. Ann Rev Physiol48:307-320, 1986 108. Weil JV,Chidsey CA: Plasma volume expansion resulting from interference with adrenergic function in normal man. Circulation 375441, 1968 109. Yanigazawa M, Kurihara H, Kimura S, et al: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332411415, 1988

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