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Strategies in Antihypertensive Therapy: Implications of the Kidney

NORMAN K. HOLLENBERG, M.D., Ph.D.

Boston, Massachusetts

Because we so rarely know the cause of hypertension, antihypertensive therapy remains empiric. However, certain principles of treatment are emerging; one of these concerns the critical role of the kidney in antihypertensive therapy. Whether or not the kidney is primarily responsible for hypertension in a patient, it is the patient’s renal response to treatment that determines, to a major degree, an agent’s efficacy. Vasodilators have been a conceptually attractive approach to the treatment of high blood pressure, because they decrease total peripheral resistance, which is considered to be the mechanism responsible for this condition in most patients. Nonspe- cific vasodilators exert a series of actions on the kidney-including profound sodium retention and reactive renin release-that limits therapeutic response. For reasons that are not yet clear, but are apparently related to specific action on calcium entry into vascular smooth muscle, endocrine function, and renal hemodynamics, calcium channel blocking agents, such as nifedipine, have an advan- tage in the treatment of hypertension. They cause little or no sodium retention; thus, the addition of a diuretic agent is not required. In fact, there is evidence that sodium loading in certain patients may potentiate the antihypertensive efficacy of these drugs. The renin- angiotensin system seems to be activated to a somewhat lesser degree by calcium channel blocking agents than it is by nonspecific vasodilators; in addition, these agents interfere with the actions of angiotensin on aldosterone release. Moreover, their dilator action on the renal blood supply favors sodium excretion. Nifedipine either has no effect on the renal blood supply or induces an increase in renal blood flow and maintains glomerular filtration rate, both of which combine to support the ensuing natriuresis.

Despite its empiric basis, our ability to treat high blood pressure effec- tively and safely must be considered one of the great successes of modern day therapeutics. We do not know whether essential hypertension reflects several unrelated diseases or is a single process that has been modified in the individual patient by age, gender] race, inherited traits, such environmental factors as diet and stress, and the duration of the process. A skilled debater could defend either view, marshaling substantial evidence to substantiate his/her claim.

Although we remain ignorant at this fundamental level, a number of relevant therapeutic principles have emerged. Among the more important is the role of the kidney as a determinant of the effectiveness of antihypertensive therapy-the subject of this article. In addressing this topic, it is necessary to review the functional abnormalities involving the renal

From the Departments of Medicine and Radiology, Harvard Medical School and Brigham and Wom- en’s Hospital, Boston, Massachusetts. Personal research cited in this article was supported by grants from the National Institutes of Health (HL- 14944, HL-07236, CA-32849, HL-05832, and RR- 00888) and the National Aeronautics and Space Administration (NSG-9078). Requests for reprints should be addressed to Dr. Norman K. Hollenberg, 75 Francis Street, Boston, Massachusetts 02115.

December 15, 1986 The American Journal of Medicine Volume 81 (suppl 6A) 15

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-HOLLENBERG

blood supply in essential hypertension [l--7], the role of potentiated renal vascular response, abnormalities in the newer pharmacologic agents in drug therapy [2,6-l I], renal arteriogram are reversed (often completely) by vas- and both the nature and the extent of reactive responses odilators. that often limit the effectiveness of therapeutic agents [2,9, 12-141. EFFECTS OF ESTABLISHED AGENTS

RENAL BLOOD SUPPLY

Direct-acting arteriolar vasodilators have always provided an attractive approach to the treatment of hypertension, because the hemodynamic defect typically responsible for the elevated pressure is an increase in peripheral resistance mediated, at least in part, by vasoconstriction [15]. Nonspecific vasodilators, however, have been of limited use, because they activate compensatory systems [12]- e.g., they induce a prominent renal response that involves both sodium retention and increased renin release. This article focuses on some of the practical implications of our increased understanding of the kidney’s role in sustaining hypertension, howsoever it is initiated [16].

There has been considerable interest in the renal blood supply and its effects on the glomerular filtration rate, sodium handling by the kidney, and renal renin release in hypertension. A reduction in renal blood flow due to renal artery stenosis represents the most common curable form of secondary hypertension, and is still believed by many investigators to contribute to the pathogenesis of essential hypertension in some patients. Whatever factors initiate the onset of hypertension in a patient, it is becoming clear that a renal response must be involved in order to sustain elevated blood pressure [16]. Perhaps most important, it is now evident that the effectiveness of antihypertensive therapy, regardless of the therapeutic agent employed, is largely determined by the renal response. Finally, the con- tinuing damage to the renal microvasculature in uncon- trolled severe hypertension leads to uremia, one of the major complications of this disorder. The sharp reduction in the frequency of occurrence of this complication represents one of the triumphs of modern antihypertensive therapy.

Renal perfusion is often reduced in patients with essential hypertension. Recent estimates [4] suggest that about two thirds of these patients have an inappropriately reduced renal blood flow. Multiple lines of evidence now suggest that a functional disturbance-active vasoconstriction-plays a ‘role in the abnormality of renal perfusion and glomerular filtration rate in patients with essential hypertension. Renal perfusion varies from moment to moment much more in patients with essential hypertension than it does in normal subjects, an abnormality that must be due to active vasoconstriction [4]. Renal vasomotion is also increased in essential hypertension [5]. More- over, renal blood flow increases more dramatically in patients with essential hypertension than it does in normal subjects when nonspecific vasodilators, such as acetyl- choline, are administered into the renal artery [I]. With the

To the extent that such a functional abnormality involving the renal blood supply plays a role in the etiology of hypertension, one might anticipate that individually titrated doses of an appropriate vasodilator would reverse these abnormalities and, thus, improve renal perfusion and filtration rate. In fact, the renal response to therapy is condi- tioned largely by the relative influence on the kidney of both the decrease in blood pressure and the direct and indirect effects of the therapeutic agent on the kidney.

Restriction of sodium intake is the simplest available therapeutic approach to hypertension. However, this maneuver reduces renal blood flow and glomerular filtration rate in animals and in humans. The evidence [3,17] that angiotensin-induced renal vasoconstriction, conse- quent to the reactive increase in renin release, entirely accounts for the renal vasoconstriction is unequivocal. There is now clear evidence [8] that when diuretics are employed as therapy, the reactive increase in plasma renin activity limits the decrease in blood pressure. On the basis of results of studies on the influence of restriction of sodium intake, it is reasonable to conclude that the reductions in renal blood flow and filtration rate induced by a diuretic are also angiotensin-mediated.

Since activation of the renin-angiotensin system plays such a central role in limiting the response to restriction of sodium intake and diuretics, it is reasonable to suspect that the addition of beta-adrenergic blocking agents- many of which block renin release (to the extent that it is mediated by beta-adrenergic receptors in the juxtaglomerular apparatus)-would reverse the impact of restriction of sodium intake and diuretics on the kidney [I 21. Un- fortunately, propranolol, the most widely studied and uti- lized beta-adrenergic blocking agent, induces renal vasoconstriction directly, apparently through its action on alpha-adrenergic receptors in the kidney [I 81. A propranolol-induced reduction in renal blood flow, with parallel reductions in glomerular filtration rate, sodium retention, and ability to handle sodium loads, has also been well documented [19] in humans. It was thought that this effect might be due to a decline in cardiac output induced by the negative inotropic and chronotropic actions of beta blockers on the heart; however, the renal response occurs with doses too small to influence cardiac output [7]. Similar renal responses have been documented [6] for a wide variety of beta-adrenergic blocking agents, including oxprenolol, pindolol, acebutolol, atenolol, and dichloroiso- proterenol.

Renal vasoconstriction, however, is not an inevitable outcome of all beta-adrenergic blockade. Nadolol, a long- acting, hydrophilic beta-adrenergic blocking agent, in-

16 December 15, 1986 The American Journal of Medicine Volume 81 (suppl 6A)


duces a dose-related increase in renal blood flow at doses exceeding those at which it reduces heart rate and, thus, cardiac output in humans [7]. Further, nadolol does not induce antinatriuresis in the dog: indeed, it appears to increase sodium excretion (personal communication from K. Duchin).

What is the effect of the nonspecific vasodilators on the kidney? This general class includes hydralazine, minoxidil, diazoxide, sodium nitroprusside, and trimethaphan, which includes a potent nonspecific vasodilator compo- nent [13,14]. Although these agents produce a broad spectrum of renal responses, certain effects are common to all of them. For example, despite their range of direct actions on the renal blood supply, all of these agents induce sodium retention [13,14]; this result often is striking, and can be the limiting factor for therapeutic efficacy 1201. The mechanism of this effect has not yet been completely delineated, but it is clear that the systemic response, especially the drop in blood pressure, plays an important role in such retention. For example, diazoxide is a potent renal vasodilator when infused into the renal artery; this vasodilation is accompanied by a striking natriuresis [21]. When the agent is given intravenously, however, an equally striking antinatriuresis occurs-presumably because of the decrease in blood pressure [6,17,22].

angiotensin II. Although calcium channel blockers can blunt adrenal aldosterone release, this does not entirely explain the acute natriuresis seen after the administration of nifedipine (Figure 1) [30]. Several lines of evidence [I 7,31-371 suggest that intrarenal angiotensin II concen- trations may actually represent one determinant of renal- sodium handling, presumably through the control of tubular-glomerular feedback. One could speculate that the salutary response to calcium channel blockers may reflect their ability to reverse these intrarenal actions of angiotensin II.

The impact of systemically administered nonspecific vasodilators on the renal blood supply and renal sodium handling varies widely from patient to patient-from a net increase to a net decrease in renal blood flow. However, antinatriuresis with sodium retention and, typically, a decrease in glomerular filtration rate occurs with even the most potent direct renal vasodilators in this class-i.e., hydralazine, diazoxide, and minoxidil [13,14,20,23,24]. Thus, to date, the use of a nonspecific vasodilator for its vasodilatory effect on the kidney has not spared patients the negative renal influence of these agents.

Just as the beta blockers have different effects on the kidney, calcium channel blockers may also have a different impact. Although no direct comparisons of renal vascular responses have been made, data on potentially relevant systems do exist. These data indicate that differ- ences may be present-although their precise clinical rel- evance remains somewhat obscure. Zanchetti and Leonetti [28] recently compared the short-term natriuretic response to nifedipine with the response to verapamil. Dosages were adjusted to achieve identical decreases in blood pressure. Although normal subjects did not differ in their response to the two agents, the diuresis and natriuresis induced by nifedipine in patients with essential hypertension were substantially greater than those induced by verapamil (Figure 2).

EFFECTS OF NEW AGENTS

The development of angiotensin converting enzyme inhibitors also represents a new approach to antihypertensive therapy and a new tool for examining the underly- ing mechanisms of hypertension [38]. These agents have proven to be effective even in severe cases of hypertension, such as those resistant to standard triple-drug therapy with a diuretic, hydralazine, and a beta-adrenergic blocking agent [9]. Recent studies [2,6,39] suggest that agents in this class exert an especially beneficial action on the kidney. In patients with essential hypertension, the nonapeptide SQ 20881 induced a potentiated increase in renal blood flow [2] that exceeded by a factor of two the

Three new classes of agents have been developed that may have special implications for the kidney: calcium channel blocking agents, converting enzyme inhibitors, and dopamine analogues. The first study [I I] demonstrat- ing a short-term renal response to a calcium channel blocking agent used nifedipine and revealed a substantial increase in renal plasma flow, a well-maintained glomerular filtration rate, and a brisk diuresis and natriuresis. Pa- tients with the lowest baseline renal plasma flow and glomerular filtration rate, presumably reflecting fixed organic renal vascular changes, showed little response. These salutary responses to nifedipine have been amply con- firmed, as have such responses to other agents in this class [25-291.

In both human and animal studies, calcium channel blockers have been shown to act acutely as antagonists to the pressor, adrenal, and renal vascular responses to

Figure 7. HelatlonstJlp between Increases In plasma anglo- tensin II levels and changes in plasma aldosterone levels during angiotensin II infusion in patients with mild essential hypertension. Horizontal and vertical bars represent mean k SEM. Reprinted with permission from PO].

December 15, 1986 The American Journal of Medicine Volume 81 (suppl SA) 17


Normotensives n = 10 Hypertensives n = 14

170

SBP 150 * (mm 40 p 1.005 Iso ** p <.OOl 110

90

Ha0 800 (mL/Gh)

400

0 150

0 Placebo Na+ 100

(mmol/6h) m Nifedipine

50 m Verapamil

n

increase in blood flow induced in normal subjects; this effect was achieved despite a larger decrease in blood pressure. In addition, despite the decrease in arterial blood pressure, SQ 20881 induced an increase in glomerular filtration rate and, with it, a natriuresis [6].

More recent studies [31,40] performed with the orally effective analogues captopril and enalapril have shown a similar influence; patients with essential hypertension have a greater renal blood flow response and, despite the decrease in arterial blood pressure, a well-maintained glomerular filtration rate.

The dopamine analogues, which are potent renal vasodilators in animal models [41], have not been sufficiently studied in humans to provide any conclusion about their therapeutic potential.

COMMENTS

What influence do antihypertensive agents have on the progression of the renal microvascular abnormality to advanced nephrosclerosis and renal failure in hypertension? The impact of these agents is most evident when the assessment is made in the treatment of severe hypertension that is already complicated by some degree of renal insufficiency. Three studies [42-441 published in the past decade provide some insight into this issue, as well as a relatively optimistic outlook.

The 80 patients in these three studies were treated ag- gressively for prolonged periods, In each case, therapy for hypertension appeared to initially aggravate the already compromised renal function; but, with time and persistent

Figure 2. Maximum decrease in systolic blood pressure (SBP) and water (H,O) and sodium (Na+) excretion during the six hours after oral administration of placebo, 70 mg of nifedipine, or 160 mg of verapamil on different days in 10 normo- tensive patients (left) and 14 hypertensive patients (right). Reprinted with permission from [28].

lowering of the elevated arterial blood pressure, renal function usually improved-sometimes dramatically. In each series, a diuretic was employed to reverse the sodium retention induced l$y dilators and active vasodilators, especially hydralazine; methyldopa and oral diazoxide were used for blood pressure control.

The quality of agents available for the treatment of hypertension has improved dramatically in the past decade and is likely to continue to improve over the next. For the

In this pooled population, in whom renal failure was the

first time, we have the luxury of being able to methodically

common mode of death (routinely accounting for greater than 80 percent of one-year mortality, generally in the

select agents on the basis of therapeutic objectives. It is to

form of uremia), a striking improvement in natural history was obtained. One-year survival rates in the three series were 55, 76, and 80 percent, respectively-with stable or

be hoped that newer agents will demonstrate the highly

even improving renal excretory function [42,44]. Whether the newer vasodilators, calcium channel blocking agents,

important characteristic of a salutary effect on the kidney,

angiotensin converting enzyme inhibitors, or dopamine

since such an effect is integral to the achievement of our

analogues will produce an even more beneficial influence on natural history and renal function is not yet known.

therapeutic objectives.

ACKNOWLEDGMENT

It is a pleasure to acknowledge the assistance of Ms. Diana Page in preparing this article.

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