Vasodilators, Antihypertensive Therapy and the Kidney

NORMAN K. HOLLENBERG, MD, PhD

Both traditional and newer treatments of essential hypertension are discussed in relation to kidney function and renal perfusion. In essential hyperten- sion, renal vascular resistance is routinely increased and renal blood flow is often decreased. Reduced sodium intake as a form of therapy will cause a de- crease in both renal blood flow and glomerular fil- tration, most likely due to an angiotensin-induced renal vasoconstriction caused by the reactive in- crease in renin release. Treatment with diuretics produces the same effects, also angiotensin-mediat- ed. The addition of a /3-adrenergic blocking agent to prevent renin release may be a good choice, but in- dividual agents within this class must be examined for direct renal vasoconstriction. The effects of “nonspecific” vasodilators on renal perfusion and renal sodium handling vary with the patient but may produce antinatriuresis, sodium retention and de-

crease in glomerular filtration. Studies with calcium antagonists have shown promising results. Nifedi- pine studies show a substantial increase in renal plasma flow, a well-maintained glomerular filtration rate and a brisk diuresis and natriuresis. However, patients with the lowest baseline renal flow do not show these benefits. Diltiazem has shown a potenti- ated renal vascular response in normotensive pa- tients of hypertensive parents. Angiotensin convert- ing enzyme inhibitors such as captopril and enalapril have produced increased renal blood flow and well- maintained glomerular filtration in patients with es- sential hypertension. The agents available for treat- ing hypertension have improved dramatically in the past decade. A salutary effect on the kidney will re- main high on the list of important characteristics to be considered in choosing one of these agents.

(Am J Cardiol 1987;60:57 l-60 I)

1 oday, we have a bewildering array of agents for the treatment of high blood pressure. Because we do not know the pathogenetic mechanism in any individual with essentiai hypertension, the treatment is necessar- ily empirical, but some principles have emerged.

Total peripheral resistance is typically high in pa- tients with sustained hypertension, and the wish to reduce it with anihypertensive therapy is a reasonable goal. Thus, treatment of hypertension with a vasodila- tor is conceptually attractive. Available nonspecific vasodilators unfortunately do not sustain a reduction in blood pressure when used alone. A diuretic is re- quired routinely, and often a /3 blocker as well. Koch- Weserl suggested a mechanism by which the combina- tion of vasodilator, diuretic agent and @-adrenergic blocking agent was effective, and perhaps less empiri- cal than it seemed. His premise was that the combina- tion of sodium retention, tachycardia and a reactive renin response represented the main physiologic bar- riers to the sustained efficacy of vasodilator drugs: the

571

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 02115.

,8-adrenergic blocking agent blunted renin release and prevented tachycardia; the diuretic reversed sodium retention.

Definition of the precise role played by the renin system in that response awaited advances in pharma- cology for interrupting the renin-angiotensin system that soon followed, but it has become clear that Koch- Weser’s suggestion was largely correct. Modern anti- hypertensive therapy reflects the development of agents that act as vasodilators, but for one reason or another-often involving the kidney-avoid the dis- advantages of the nonspecific vasodilators.

In this essay, I will examine the impact of antihy- pertensive agents on renal perfusion and function and attempt to relate that to their efficacy in reducing high blood pressure. Special attention will be given to ,& adrenergic blocking agents that have a minimal impact on the kidney, converting enzyme inhibitors and calci- um antagonists. Special emphasis will be given to the functional abnormalities involving the renal blood supply in essential hypertension,2-10 especially for newer pharmacologic agents,5,g-13 and the nature and extent of reactive responses that often limit the re- sponse to therapeutic agents.2s5J2,14-16

There are a number of reasons for the long-stand- ing interest in the renal blood supply in relation to

581 A SYMPOSIUM: HYPERTENSION-THE HEART AND KIDNEY

hypertension. 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 to contribute in some patients to the pathogene- sis of essential hypertension. Certainly renal blood flow conditions both renal sodium handling and renin release, and both can be pathogenic in hypertension. Whatever the initiating factors in an individual pa- tient, systems analysis suggests that a renal response must be involved to sustain the elevated blood pres- sure.3 The effectiveness of antihypertensive therapy, regardless of which agent is used, is determined to a substantial degree by the renal response. Continuing damage to the renal microvasculature by uncontrolled severe hypertension once accounted for one of the major complications, uremia. The sharp reduction in the frequency of this complication represents one of the triumphs of modern antihypertensive therapy.

Renal vascular resistance is routinely increased and renal perfusion is often decreased in the patient with essential hypertension; estimates suggest a re- duced renal blood flow in about two-thirds of pa- tients.7 Multiple observations suggest that a functional disturbance, active vasoconstriction, is at least partly responsible for altering renal perfusion and glomeru- lar filtration rate. From moment to moment, blood flow to the kidney varies much more in patients with essen- tial hypertension in normal subjects-an abnormality that must be due to active vasoconstriction.7 Renal vasomotion is also increased.* Moreover, the injection of a nonspecific vasodilator into the renal artery of these patients increases renal blood flow far more strikingly than it does in normal subjects.4 Abnormali- ties in the renal arteriogram are reversed, often com- pletely, by a vasodilator such as acetylcholine.

One might expect that these agents, by reversing functional abnormalities in the renal blood supply, would improve renal perfusion and filtration rate. The renal response to therapy is, in fact, largely condition- ed by the decrease in blood pressure and the direct and indirect effects of the therapeutic agent.

Restriction of sodium intake is the simplest therapy available for hypertension. This maneuver reduces re- nal blood flow and glomerular filtration rate in ani- mals and in man. The evidence that angiotensin- induced renal vasoconstriction, consequent to the re- active increase in renin release, accounts entirely for the reduced renal blood flow is unequivocal.6J7 When diuretics are used as therapy, the reactive increase in plasma renin activity is a major contributor to limiting the decrease in blood pressure.ll It is reasonable to conclude that the reduction in renal blood flow and filtration rate induced by a diuretic is 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 was rea- sonable to suspect that the addition of a p-adrenergic blocking agent-many of which also block renin re- lease-would reverse the impact of sodium restriction and diuretics on the kidney.l Propranolol, the most widely used and studied P-adrenergic blocking agent,

unfortunately induces renal vasoconstriction directly, apparently through an action on an a-adrenergic re- ceptor in the kidney. l8 A propranolol-induced reduc- tion in renal blood flow, with a parallel decrease in glomerular filtration rate, sodium excretion and ability to handle sodium load, has also been well documented in man.lg The renal response occurs with doses too small to influence cardiac output.lO A similar renal response has been documented for a wide variety of p- adrenergic blocking agents including oxprenolol, pin- dolol, acebutolol, atenolol and dichloro-isoprotere- nol.lO Renal vasoconstriction, however, is not an inevitable concomitant of ,&adrenergic blockade. Na- dolol increases renal blood flow acutely over the dose range at which it reduces heart rate, and thus cardiac output, in man.1° Moreover, a series of studies have shown that renal blood flow is well maintained during long-term treatment with nadolol.1° This may account for its special effectiveness in Caucasians with hyper- tension.z0

What is the impact on the kidney of the “nonspecif- ic” vasodilators? In this general class, we can include hydralazine, minoxidil, diazoxide and sodium nitro- prusside. Certain features are common to all. One of these is sodium retention,l5J6 which is often striking and the factor limiting their therapeutic efficacy.14 The mechanisms responsible for sodium retention have not yet been defined, but the systemic response, espe- cially the decrease in blood pressure, clearly plays an important role. For example, diazoxide is a potent re- nal vasodilator when infused into the renal artery, and this vasodilatation is accompanied by a striking natri- uresis.21 When the agent is given intravenously, how- ever, an equally striking antinatriuresis occurs-pre- sumably because of the blood pressure decrease.gJ7*20

The impact of these nonspecific vasodilators on re- nal blood supply and renal sodium handling varies widely in the individual patient, but there is clear evi- dence that hydralazine, diazoxide and minoxidil14- 16,22,23 routinely produce antinatriuresis, sodium reten- tion and, typically, a decrease in glomerular filtration rate. Thus, to date, selection of these agents for their vasodilator action on the kidney has not spared the patient a number of negative effects.

Three new classes of agents have been developed that may have special implications for the kidney: cal- cium antagonists, converting enzyme inhibitors and dopamine analogs.

The ubiquitous role of calcium in biologic pro- cesses, including those involving renal perfusion and function, has led to a host of laboratory and clinical studies, as reviewed recently.2-28 Available informa- tion suggests an action-depending on the circum- stances of the study, the afferent arteriole, the efferent arteriole, the glomerular mesangium and the tubular sodium handling.24-28

The first study in hypertensive patients of the acute renal response to a calcium antagonist, nifedipine, re- vealed a substantial increase in renal plasma flow, a well-maintained glomerular filtration rate and a brisk diuresis and natriuresis.2g Patients with the lowest baseline renal plasma flow and glomerular filtration

December 14, 1987 THE AMERICAN JOLJRNAL OF CARDIOLOGY Volume 60 591

rate, presumably reflecting fixed organic renal vascu- lar changes, showed little response. Subsequent stud- ies of the acute responses to agents in this class have confirmed these observations in man.24-34

The intriguing observation that normotensive off- spring of hypertensive parents often show a potentiat- ed renal vascular response to a calcium entry blocking agent, diltiazem,34 raises the interesting possibility of a special renal action of this class of agent in essential hypertension. Certainly there has been substantial and continuing interest in the striking renal action of dil- tiazem.26,30-40

An additional question is whether the various calci- um antagonist agents currently available have the same effect on the kidney. No direct comparisons have been made, but there are data on potentially relevant systems to indicate that differences may be present- although their precise clinical relevance remains somewhat obscure. Zanchetti and Leonetti,z4 for ex- ample, recently compared the acute natriuretic re- sponse to nifedipine and verapamil, in doses adjusted to induce the same decrease in blood pressure. Nifedi- pine was found to induce a substantially larger diure- sis and natriuresis in essential hypertension, although normal subjects did not differ in their response to the 2 agents. When 2 calcium blockers, diltiazem and nifed- ipine, were studied in the anesthetized dog, the former activated the sympathetic and renin-angiotensin sys- tems to a somewhat lesser extent, and had a somewhat smaller impact on renal perfusion and function than nifedipine. However, both agents induced larger changes than those induced by nitroprusside.40

The development of converting enzyme inhibitors has provided a new approach to therapy and new tools for examining the mechanisms underlying hyperten- sion.41 It became apparent early that these agents are often effective in patients with severe hypertension in whom the disease was resistant to standard triple ther- apy with a diuretic, hydralazine and a fi-adrenergic blocking agent .ll Recent studies suggest that this class of agent will exert an especially useful action on the kidney.5,g In patients with essential hypertension, the nonapeptide, SQ 20881, induced an increase in renal blood flow that was twice normal despite a larger de- crease in arterial blood pressure.5 SC) 20881 also in- duced an acute natriuresis and an increase in glomeru- lar filtration ratem The responses to captopril and enalapril have been similar; the essential hypertensive patient enjoys a larger renal blood flow response and, despite the decrease in arterial blood pressure, a well- maintained glomerular filtration rate.42v43 Perhaps this class of agent owes its sustained impact on hyperten- sion, at least in part, to its influence on the kidney, even in patients in whom traditional therapy has been effective.

Some dopamine analogs induce striking renal vaso- dilation in animals,44 but have been studied too little in man to allow any conclusion about their therapeutic potential.

What if hypertension leads to advanced nephros- clerosis and finally renal failure? There is a relatively hopeful answer .45-47 Initially, therapy for hyperten-

sion appears to aggravate the already compromised renal function. With persistent lowering of the elevat- ed arterial blood pressure, however, renal function is usually improved, and sometimes improved dramati- cally. In each of these 3 studies, a diuretic was used to reverse the sodium retention induced by hydralazine, methyldopa and oral diazoxide. In this population of patients, in whom uremia and renal failure were the common mode of death and the l-year mortality rate routinely exceeded 8070, a striking improvement in natural history was obtained. One-year survival in the 3 series was 5570, 76% and 8070, respectively, with stable or even improving renal excretory function.45-47 Whether the newer vasodilators, calcium antagonists and converting enzyme inhibitors will produce an even more striking influence on natural history and renal function is not yet known, but there are reasons to be hopefu1.48-50

Although still empirical, our ability to treat high blood pressure effectively and safely must be consid- ered one of the great successes of modern therapeu- tics. We do not know whether essential hypertension represents a combination of unrelated diseases or is a single process, which has been modified in the indi- vidual patient by age, sex, race, related inherited traits, environmental factors such as diet and stress and the duration of the process. A skilled debator could defend either view, and sometimes does.2

Despite our ignorance, the agents available to us for the treatment of hypertension have improved dramati- cally in the past decade and are likely to continue to improve over the next decade.51 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 remains high on the list.

Acknowledgment: It is a pleasure to acknowledge the assistance of Diana Page in preparing this essay. Personal research cited was supported by grants HL 14944, HL07236, CA 32849, HL05832 and RR 00888 from the National Institutes of Health, Bethesda, Maryland, and grant NSG 9078 from the National Aeronautics and Space Administration.

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