The Kidney and Effective Antihypertensive Therapy

NORMAN K. HOLLENBERG, MD, PhD

Whether or not the kkiney is involved in the genesis of hypertendon in an indhddual patient, it becomes a major determinant of the response to antihypertensive therapy once a treatment strategy is adopted. The major mechanisms through wMch the kidney influ- ences blood pressure are renh release and sodium retention, either together or separately, but additional mechanisms may also contribute. When sodium in- take is restrkted or a diuretic is used, the reactive increase h plasma renin activity makes a substantial contribution to limtthg the btood pressure fall. when vasodilators or agents that bkxk the sympathetic ner-

vous system are used, sodium retention plays an important role. Amorg newer agents, the effective- ness of calcium channel blockers, converting enzyme inhibitors and perhaps dopamhe analogs reflects, for reasons that differ from 1 class of agent to another, a special actktn on the kkhey that limits the reactive renal response to the redwtion in blood pressure. Treatment strategies that address the problem of the renal response are more likely to be effective than approaches that avoki or i9nore it.

(Am J Cardiof 1985;58:52H45H)

Much of the strategy in designing antihypertensive therapy-a substantial amount of which was initially empirical-has involved the renal compensatory re- sponses to the agents, whichever drug therapy was selected. Direct acting arteriolar vasodilators, for ex- ample, have always provided an attractive approach to the treatment of hypertension, because in most pa- tients the hemodynamic defect responsible for the ele- vated pressure is an increase in peripheral resistance, at least partly mediated by vasoconstriction.l The use of nonspecific vasodilators has largely been limited by activation of compensatory systems,2 including a prominent renal response that involves both retention of sodium and increase in renin release. This article will focus on some of the more practical implications of our increased understanding of the kidney’s role in sustaining hypertension, however it is initiated.3 A review of the functional abnormalities involving the renal blood supply in essential hypertension,&lO the role of newer pharmacologic agents in therapy5tg-l3 and the nature and extent of the reactive responses that often limit the effectiveness of therapeutic agen~W,l2,14-16 is necessary to achieve this goal.

Investigators studying hypertension have several reasons for their long-standing interest in the renal

From the Departments of Medicine and Radiology, Harvard Medical School, Brigham and Women’s Hospital, Boston Massachusetts.

Address for reprints: Norman K. Hollenberg, MD, PhD, 75 Francis Street, Boston, Massachusetts 02 115.

blood supply as it affects glomerular filtration rate (GFR), sodium handling by the kidney and renal renin release. First, a reduction in renal blood flow due to renal artery stenosis is the most common curable form of secondary hypertension and is still believed by many investigators to contribute in some patients to the pathogenesis of essential hypertension. Second, whatever factors initiate the hypertension process in an individual patient, it is becoming evident that a renal response must be involved in order to sustain the elevated blood pressure.3 Third, it is also becoming clear that the effectiveness of antihypertensive thera- py, whatever agent is used, is determined to a substan- tial degree by the renal response. Finally, the con- tinuing damage to the renal microvasculature by uncontrolled severe hypertension previously accounted for one of the major complications-uremia. The sharp reduction in the frequency of this complication is one of the triumphs of modern antihypertensive therapy.

A decrease in renal perfusion is common in essential hypertension; recent estimates suggest that about two-thirds of patients with essential hypertension have an inappropriately decreased renal blood flo~.~ Multiple lines of evidence now suggest that a function- al disturbance-active vasoconstriction-plays a role in the abnormal renal perfusion and GFR in patients with essential hypertension. Renal perfusion varies in a moment-to-moment fashion much more in patients with essential hypertension than in normal subjects,

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December 6, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 56 53H

an abnormality that must be due to active vasocon- striction. Renal vasomotion is also increased in essen- tial hypertension.8 Moreover, when nonspecific vaso- dilators such as acetylcholine are administered into, the renal artery, renal blood flow increases much more strikingly in patients with essential hypertension than in normal subjects.4 With this potentiated renal vascu- lar response, abnormalities in the renal arteriogram are reversed, often completely, by the vasodilators.

To the extent that such a functional abnormality involving the renal blood supply plays a role in the individual patient, one might anticipate that suitable doses of an appropriate vasodilator agent would re- verse these abnormalities and thus improve renal per- fusion and filtration rate. The renal response to thera- py is conditioned to a major degree by both the relative influence of the fall in blood pressure and the direct and indirect effects of the therapeutic agent on the kidney.

Restriction of sodium intake is the simplest avail- able therapeutic approach to hypertension. This ma- neuver reduces renal blood flow and GFR in animals and in man. The evidence is unequivocal that angio- tensin-induced renal vasoconstriction, consequent to the reactive increase in renin release, accounts entirely for renal vasoconstriction.6J7 There is now clear evi- dence that when diuretics are used as therapy, the reactive increase in plasma renin activity limits the fall in blood pressure.ll Thus, it is reasonable to con- clude that the decrease in renal blood flow and GFR induced by a diuretic is also angiotensin-mediated.

Because activation of the renin-angiotensin system plays such a central role in limiting the response to restriction of sodium intake and diuretics, it was rea- sonable to suspect that the addition of a /3-adrenergic blocking agent-many of which block renin release when it is mediated by /3-adrenergic receptors in the juxtaglomerular apparatus-would reverse the impact of restriction of sodium intake and diuretics on the kidney.2 Unfortunately, propranolol, the most widely used and studied fl-adrenergic blocking agent, directly induces renal vasoconstriction, apparently through an action on an a-adrenergic receptor in the kidney.18 A propranolol-induced decrease in renal blood flow, with a parallel reduction in GFR, sodium retention and a reduced ability to handle sodium load, has also been well documented in man.lg Although this renal re- sponse could be due to a decrease in cardiac output induced by the negative inotropic and chronotropic actions of these agents on the heart, it actually occurs with doses insufficient to influence cardiac output.lO A similar renal response has been documented for a wide variety of P-adrenergic blocking agents including ox- prenolol, pindolol, acebutolol, atenolol and dichloro- isoproterenoLg

Renal vasoconstriction, however, is not an inevita- ble result of fi-adrenergic blockade. Nadolol, a long- acting hydrophilic P-adrenergic blocking agent, in- duces a dose-related increase in renal blood flow over the dose range at which it decreases heart rate and thus cardiac output in man.‘O As opposed to the pro-

pranolol-induced decrease in sodium excretion, anti- natriuresis did not occur with nadolol in the dog; in- deed, nadolol increased sodium excretion (K. Duchin, unpublished observations). The clinical implication of this observation may be the remarkable frequency with which nadolol achieves goal blood pressure.20 The Veterans Administration Cooperative Study Group reported that 77% of a large group of white subjects with mild to moderate essential hypertension achieved goal blood pressure with nadolol,20 substan- tially more than achieved good blood pressure in a parallel study by the same Study Group on responses to other @ blockers.13

What impact do the “nonspecific” vasodilators have on the kidney? This general class includes hydral- azine, minoxidil, diazoxide, sodium nitroprusside and, in part, trimethapan.15J6 The spectrum of their renal response is wide, but certain features are common to all. Despite the range of direct actions on the renal blood supply, sodium retention-often striking-oc- curs with uP5J6 and is the factor that limits their therapeutic efficacy.14 The mechanism of the sodium retention has not yet been clearly delineated, but it is evident that the systemic response, especially the drop in blood pressure, plays an important role. For exam- ple, d&oxide is a potent renal vasodilator when in- fused into the renal artery, and this vasodilatation is accompanied by a striking natriuresis.21 When the agent is given intravenously, however, an equally striking antinatriuresis occurs-presumably because of the blood pressure fa11.gJ7~20

The impact of these agents on renal blood supply and renal sodium handling when given systemically varies widely among individual patients, from a net increase to a net decrease in renal blood flow. Howev- er, antinatriuresis with sodium retention and, typical- ly, a decrease in GFR occur, with even the most potent direct renal vasodilators in the series-hydralazine, diazoxide and minoxidi1.14-16~22~23 Thus, to date, selec- tion of nonspecific vasodilators for the vasodilator ac- tion on the kidney has not spared the patient the negative renal influence of these agents.

Three new classes of agents have been developed that may have special implications for the kidney: calcium entry-blocking agents, converting enzyme in- hibitors and dopamine analogs. Claims have been made that vasodilatation induced by calcium entry- blocking agents may be associated with less sodium retention.24l25 However, rigorous evidence is not yet available, and the question remains controversial be- cause the reports have involved small numbers of pa- tients treated for a relatively short time. Calcium en- try-blocking agents do provide an attractive potential. Diltiazem, 1 of the 3 calcium entry-blocking agents currently marketed in the United States, appears to have a special action on the renal blood supply, favor- ing a sustained or increased GFR and natriuresis de- spite the fall in arterial blood pressure.26s27 The in- triguing observation that normotensive offspring of hypertensive parents often show a potentiated renal vascular response to diltiazem28 raises the interesting

54H A SYMPOSIUM: ROLE OF CALCIUM ENTRY-BLOCKING DRUGS IN HYPERTENSION

possibility of a special renal action of this agent in essential hypertension.

The development of converting enzyme inhibitors provides a new approach to therapy and new tools for examining the underlying mechanisms of this disor- der.2s These agents are often effective even in severe hypertension, which has been resistant to standard triple therapy with a diuretic, hydralazine and a /3- adrenergic blocking agent.12 Recent studies suggest that this class of agents will exert an especially useful action on the kidney. 5*g In patients with essential hy- pertension, the nonapeptide SQ 20881 induced a po- tentiated increase in renal blood flow5 that was twice the increase in blood flow induced in normal subjects, despite a larger fall in blood pressure. Also, despite the fall in arterial blood pressure, SQ 20881 often induced an increase in GFR and, with it, natriuresisg More recent studies performed with the orally effective ana- logs, captopril and enalapril, have shown a similar influence; the essential hypertensive patient enjoys a larger renal blood flow response and, despite the fall in arterial blood pressure, a well-maintained GFR.31*32 Perhaps their influence on the kidney accounts for this class of agents’ remarkable, often sustained impact on hypertension even in patients in whom traditional therapy has been ineffective.

The dopamine analogs, which are striking renal va- sodilators in animal models,32 have undergone too lit- tle study in man to allow any conclusion about their therapeutic potential.

What is the influence of antihypertensive agents on progression of renal microvascular abnormality to ad- vanced nephrosclerosis and renal failure in hyperten- sion? The impact of these agents is most evident when they are assessed in the treatment of severe hyperten- sion already complicated by some degree of renal in- sufficiency. Three studies published in the past de- cade provide some insight and a relatively hopeful answer.33-35 The 80 patients in the 3 studies were treated aggressively for prolonged periods. In each case, therapy for hypertension initially appeared to aggravate the already compromised renal function; however, with time and persistent lowering of the ele- vated arterial blood pressure, renal function usually improved, sometimes dramatically. In each study, a diuretic was used to reverse the sodium retention in- duced by dilators, and active vasodilators, especially hydralazine, methyldopa and oral diazoxide that were used for blood pressure control. In this population, in whom renal failure was the common mode of death-a l-year mortality rate routinely exceeded 80% and was generally due to uremia-a striking improvement in natural history was obtained. One-year survival in the 3 series was 55, 76 and 80%-with stable or even im- proving renal excretory function.33-35 Whether the newer vasodilators, calcium entry-blocking agents, converting enzyme inhibitors or dopamine analogs will produce an even more marked influence on natural history and renal function is not yet known.

In summary, the agents available to us for the treat- ment of hypertension have improved dramatically in

the past decade and are likely to continue to improve over the next decade.36 We have the luxury of being able to select our therapeutic objectives for the first time. Among the characteristics of new agents that are likely to be important, a salutary action on the kidney is high on the list.

Acknowledgment: It is a pleasure to acknowledge the assistance of Diana Page in preparing this article. Personal research cited was supported by grants HL14944, HL07236, CA32849, HL05832 and RR00888 from the National Insti- tutes of Health, Bethesda, Maryland, and grant NSG 9078 from the National Aeronautics and Space Administration, Houston. Texas.

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