The kidney and antihypertensive therapy
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The Kidney and Antihypertensive Therapy
NORMAN K. HOLLENBERG, MD, PhD
To a large degree, modern antihypertensive therapy has evolved from the development of agents that act as vasodilators but, for one reason or another, avoid the disadvantages of the nonspecific vasodila- tors. This review examines the impact of antihyper- tensive agents on renal perfusion and function and relates it to their efficacy in reducing high blood pressure. Special attention is given to ,&adrenergic blocking agents that have a minimal impact on the
kidney, converting enzyme inhibitors, calcium chan- nel blockers and dopamine analogs. Also reviewed are the functional abnormalities involving the renal blood supply in essential hypertension, the role of newer pharmacologic agents in therapy and the na- ture and extent of reactive responses that often limit the response to therapeutic agents.
(Am J Cardiol 1987;59:78A-79A)
K ochwaser, in the early 197Os, developed an algo- rithm that might be considered prescient t0day.l He pointed out that treatment of hypertension with a vaso- dilator was conceptually attractive, because total pe- ripheral resistance is typically high in patients with this disease, and one would wish to decrease it with antihypertensive therapy. Unfortunately, the nonspe- cific vasodilators then available were not able to sus- tain a decrease in blood pressure (BP]. Kochwasers novel suggestion involved the mechanism by which a then new treatment strategy worked: the combination of a vasodilator, a diuretic agent and a @-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. His solution was straightforward: The /3-adrenergic block- ing agent blunted renin release and prevented the tachycardia; the diuretic reversed the sodium reten- tion. Definition of the precise role played by the renin system in that response awaited advances in pharma- cology that soon followed, but it has become clear that Kochwasers suggestion was largely correct.
From the Departments of Medicine and Radiology, Harvard Medical School, Brigham and Womens Hospital, Boston, Mas- sachusetts. Personal research cited was supported by grants HL 14944, HL 07236, CA 32849, HL 05832 and RR 00888 from the National Institutes of Health, Bethesda, Maryland, and grant NSG 9078 from the National Aeronautics and Space Adminis- tration.
Address for reprints: Norman K. Hollenberg, MD, PhD, 75 Francis Street, Boston, Massachusetts 02115.
To a major degree, antihypertensive therapy has evolved from the development of agents that act as vasodilators but, for one reason or another, avoid the disadvantages of the nonspecific vasodilators.
This article will examine the impact of antihyper- tensive agents on renal perfusion and function and relate that to their efficacy in decreasing high BP. Spe- cial attention will be given to ,8-adrenergic blocking agents that have a minimal impact on the kidney, con- verting enzyme inhibitors, calcium channel blockers and dopamine analogs.
To achieve the goals of this review, it will also be necessary to review the functional abnormalities in- volving the renal blood supply in essential hyperten- sion,2-10 the role of newer pharmacologic agents in therapy5zg-13 and the nature and extent of reactive re- sponses that often limit the response to therapeutic agents. 184.108.40.206-16
There has been a long-standing interest in the renal blood supply as it impacts on various aspects of hyper- tension. A decrease 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 in some patients to the pathogenesis of essential hypertension. Whatever the initiating factors in an individual patient, it is be- coming clear that a renal response must be involved to sustain the elevated BP.3 Perhaps most important for this article, it has become clear that the effectiveness of antihypertensive therapy, regardless of which agent is used, is determined to a substantial degree by the renal response. Finally, the continuing damage to the renal microvasculature of uncontrolled severe hypertension once accounted for one of the major complications,
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uremia. The sharp reduction in the frequency of this complication represents one of the triumphs of mod- ern antihypertensive therapy.
Renal perfusion is often reduced in the patient with essential hypertension. Recent estimates suggest this to be true in about two-thirds of such patients7 Multiple lines of evidence now suggest that a functional distur- bance, active vasoconstriction, is at least partly respon- sible for altering renal perfusion and glomerular filtra- tion rate. From moment to moment, blood flow to the kidney varies much more in patients with essential hypertension than in normal subjects-an abnormali- ty that must be due to active vasoconstriction.7 Renal vasomotion is also increased.R 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 subjects4 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 BP and the direct and indirect effects of the therapeutic agent.
Restriction of sodium intake is the simplest avail- able therapy for hypertension. This maneuver de- creases renal blood flow and glomerular filtration rate in animals 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.z17 When diuretics are used as therapy, there is now clear evi- dence that the reactive increase in plasma renin activi- ty limits the decrease in BP.ll By analogy with the studies of sodium restriction, it is reasonable to con- clude that the decrease in renal blood flow and fil- tration rate 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 P-adrenergic blocking agent-many of which also block renin re- lease-would reverse the impact of sodium restriction and diuretics on the kidney. 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. I8 A propranolol-induced de- crease in renal blood flow, with a parallel decrease in glomerular filtration rate, sodium retention and ability to handle sodium load, has also been well documented in man. Although this could have been due to a de- crease in cardiac output induced by the negative ino- tropic and chronotropic actions of these agents on the heart, the renal response occurs with doses too small to influence cardiac output (see reference 10). A similar renal response has been documented for a wide vari- ety of /3-adrenergic blocking agents including oxpren- 0101, pindolol, acebutolol, atenolol and dichloro-iso- proterenol. Renal vasoconstriction, however, is not an
inevitable concomitant of ,6-adrenergic blockade. Na- dolol, a long-acting agent, increases renal blood flow progressively over the dose range at which it reduces heart rate and thus cardiac output in man.l Unlike propranolol, it does not decrease sodium excretion in the dog-but, in fact, increases it (K. Duchin, unpub- lished observation). This may account for its remark- able success with hypertension? The Veterans Ad- ministration Cooperative Study Group reported that 77% of a large group of white men with mild to moder- ate essential hypertension achieved goal BP with na- dolol,? substantially more than those in a parallel study who were given other p blockers.
What of the impact on the kidney of the nonspecif- ic vasodilators? In this general class, we can include hydralazine, minoxidil, diazoxide, sodium nitroprus- side and trimethepan-or at least those aspects of the latters effect that are due to its potent, nonspecific vasodilator component.15,1fi Certain features are com- mon to all. One of these is sodium retention,15.1 which is often striking and the factor limiting their therapeu- tic efficacy.14 Its mechanism has not yet been defined, but the systemic response, especially the decrease in BP, clearly plays an important role. For example, dia- zoxide is a potent renal vasodilator when infused into the renal artery, and this vasodilatation is accompa- nied by a striking natriuresis. When the agent is given intravenously, however, an equally striking anti-natri- uresis occurs-presumably because of the decrease in BP 9.17.3(1
The impact of these nonspecific vasodilators on the renal blood supply and renal sodium handling varies widely in the individual patient, but even the more potent agents-hydralazine, diazoxide and minoxi- dill?--,Z,-produce an antinatriuresis, with sodium retention and, typically, a decrease in glomerular fil- tration 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 entry-blocking agents, converting enzyme inhib- itors and dopamine analogs. The first study on the acute renal response to a calcium channel-blocking agent, nifedipine, revealed a substantial increase in renal plasma flow, a well-maintained glomerular fil- tration rate and a brisk diuresis and natriuresisz4 The patients with the lowest baseline renal plasma flow and glomerular filtration rate, presumably reflecting fixed organic renal vascular changes, showed little re- sponse. Subsequent studies of the acute responses to agents in this class have confirmed these observa- tionsZ5- The intriguing observation that normoten- sive offspring of hypertensive parents often show a potential renal vascular response to a calcium entry- blocking agent, diltiazem,3fl raises the interesting pos- sibility of a special renal action of this class of agent in essential hypertension. Certainly there has been sub- stantial and continuing interest in the striking renal action of diltiazem.26~3n~36
An additional question is whether the various calci- um channel blocking agents currently available have
78A A SYMPOSIUM: THE CALCIUM ION, CARDIAC MYOCYTE AND VASCULAR SMOOTH MUSCLE IN HYPERTENSION AND ITS TREATMENT
the same effect on hypertension. No direct compari- sons have been made, but there are data on potentially relevant systems to indicate that differences may be present-although their precise clinical relevance re- mains somewhat obscure. Zanchetti and Leonetti,28 for example, recently compared the acute natriuretic re- sponse to nifedipine and verapamil, in doses adjusted to induce the same decrease in BP. Nifedipine was found to induce a substantially larger diuresis and na- triuresis in essential hypertension, although normal subjects did not differ in their response to the 2 agents. When 2 calcium blockers, diltiazem and nifedipine, were studied in the anesthetized dog, the former acti- vated the sympathetic and renin-angiotensin systems to a somewhat lesser extent and had a somewhat smaller impact on renal perfusion and function than did nifedipine. However, both agents induced larger changes than those induced by nitroprusside.3
The development of converting enzyme inhibitors has provided a new approach to therapy and new tools for examining the mechanisms underlying hyperten- sion.37 These agents are often effective even in pa- tients with very severe hypertension in whom the dis- ease 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 agent will exert an especially useful action on the kidneye5vg In patients with essential hypertension, the nonapep- tide SQ 20881 induced an increase in renal blood flow5 that was 2 times larger than that induced in normal subjects. For the latter group, this was true despite a larger decrease in arterial BP. At the same time, this new agent, SQ 20881, induced both natriuresis and an increase in glomerular filtration rates9 More recent studies performed with 2 orally effective analogs, cap- topril and enalapril, have shown similar results; the essential hypertensive subject enjoys a larger renal blood flow response and, despite the decrease in ar- terial BP, a well-maintained glomerular filtration rate.3*j3g Perhaps this class of agent owes its striking, often sustained impact on hypertension to its influence on the kidney, even in patients in whom traditional therapy has been effective.
The dopamine analogs, which are striking renal vasodilators in animal models,40 have been studied too little in man to allow any conclusions about their ther- apeutic potential.
How do antihypertensive agents affect the process by which a microvascular abnormality in the kidney of a hypertensive patient leads to advanced nephroscler- osis and finally renal failure? The drugs impact can be seen most clearly when they are used to treat severe hypertension, already complicated by some degree of renal insufficiency. The results of 3 studies published in the past decade provide some insight and a relative- ly hopeful answer .41-43 In these studies, 80 patients were treated aggressively for prolonged periods. In each case, therapy for hypertension initially appeared to aggravate the already compromised renal function. Over time, however, and with persistent lowering of the elevated arterial BP, renal function usually im- proved, and sometimes improved dramatically. In
each study, a diuretic was used to reverse the sodium retention induced by hydralazine, methyl dopa and oral diazoxide. In this patient population, in whom uremia and renal failure were the common mode of death and in whom the l-year mortality rate routinely exceeded 80%, a striking improvement in natural his- tory was obtained. One-year survival in the 3 series was 55%, 76% and 80%--with stable or even im- proved renal excretory function.41-43 Whether the newer vasodilators, calcium entry-blocking agents, converting enzyme inhibitors or dopamine analogs will produce an even more striking influence on natu- ral history and renal function is not yet known.
Despite its empirical basis, our ability to treat high BP effectively and safely must be considered one of the great successes of modern day therapeutics. We do not know if essential hypertension represents a combi- nation of unrelated diseases or is a single process, which has been modified in the individual patient by age, gender, race, related inherited traits, environmen- tal factors such as diet and stress and the duration of the process. A skilled debater could defend either view.
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.44 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 acknowl- edge the assistance of Diana Page in preparing this manuscript.
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