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Vasodilators, antihypertensive therapy and the kidney
Vasodilators, AntihypertensiveTherapy 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 hypertension, renal vascular resistance is routinely increased and renal blood flow is often decreased. Reduced sodium intake as a form of therapy will cause a decrease in both renal blood flow and glomerular filtration, most likely due to an angiotensin-induced renal vasoconstriction caused by the reactive increase in renin release. Treatment with diuretics produces the same effects, also angiotensin-mediated. The addition of a /3-adrenergic blocking agent to prevent renin release may be a good choice, but individual 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. Nifedipine 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 potentiated renal vascular response in normotensive patients of hypertensive parents. Angiotensin converting enzyme inhibitors such as captopril and enalapril have produced increased renal blood flow and wellmaintained glomerular filtration in patients with essential hypertension. The agents available for treating hypertension have improved dramatically in the past decade. A salutary effect on the kidney will remain 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 necessarily empirical, but some principles have emerged. Total peripheral resistance is typically high in patients with sustained hypertension, and the wish to reduce it with anihypertensive therapy is a reasonable goal. Thus, treatment of hypertension with a vasodilator is conceptually attractive. Available nonspecific vasodilators unfortunately do not sustain a reduction in blood pressure when used alone. A diuretic is required routinely, and often a /3 blocker as well. KochWeserl suggested a mechanism by which the combination of vasodilator, diuretic agent and @-adrenergic blocking agent was effective, and perhaps less empirical than it seemed. His premise was that the combination of sodium retention, tachycardia and a reactive renin response represented the main physiologic barriers to the sustained efficacy of vasodilator drugs: the
,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 pharmacology for interrupting the renin-angiotensin system that soon followed, but it has become clear that KochWeser’s suggestion was largely correct. Modern antihypertensive therapy reflects the development of agents that act as vasodilators, but for one reason or another-often involving the kidney-avoid the disadvantages of the nonspecific vasodilators. In this essay, I will examine the impact of antihypertensive 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 calcium 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-13and the nature and extent of reactive responses that often limit the response to therapeutic agents.2s5J2,14-16 There are a number of reasons for the long-standing interest in the renal blood supply in relation to
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.
571
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 pathogenesis 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 patient, systems analysis suggests that a renal response must be involved to sustain the elevated blood pressure.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 reduced renal blood flow in about two-thirds of patients.7 Multiple observations suggest that a functional disturbance, active vasoconstriction, is at least partly responsible for altering renal perfusion and glomerular filtration rate. From moment to moment, blood flow to the kidney varies much more in patients with essential 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 Abnormalities in the renal arteriogram are reversed, often completely, 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 conditioned 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 renal blood flow and glomerular filtration rate in animals and in man. The evidence that angiotensininduced renal vasoconstriction, consequent to the reactive 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 angiotensinmediated. 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 reasonable to suspect that the addition of a p-adrenergic blocking agent-many of which also block renin release-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 receptor in the kidney. l8 A propranolol-induced reduction 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 padrenergic blocking agents including oxprenolol, pindolol, acebutolol, atenolol and dichloro-isoproterenol.lO Renal vasoconstriction, however, is not an inevitable concomitant of ,&adrenergic blockade. Nadolol 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 hypertension.z0 What is the impact on the kidney of the “nonspecific” vasodilators? In this general class, we can include hydralazine, minoxidil, diazoxide and sodium nitroprusside. 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, especially the decrease in blood pressure, clearly plays an important role. For example, diazoxide is a potent renal vasodilator when infused into the renal artery, and this vasodilatation is accompanied by a striking natriuresis.21When the agent is given intravenously, however, an equally striking antinatriuresis occurs-presumably because of the blood pressure decrease.gJ7*20 The impact of these nonspecific vasodilators on renal blood supply and renal sodium handling varies widely in the individual patient, but there is clear evidence that hydralazine, diazoxide and minoxidil1416,22,23 routinely produce antinatriuresis, sodium retention 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: calcium antagonists, converting enzyme inhibitors and dopamine analogs. The ubiquitous role of calcium in biologic processes,including those involving renal perfusion and function, has led to a host of laboratory and clinical studies, as reviewed recently.2-28 Available information suggests an action-depending on the circumstances 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, revealed 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
rate, presumably reflecting fixed organic renal vascular changes, showed little response. Subsequent studies of the acute responses to agents in this class have confirmed these observations in man.24-34 The intriguing observation that normotensive offspring of hypertensive parents often show a potentiated 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 diltiazem.26,30-40 An additional question is whether the various calcium 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 presentalthough their precise clinical relevance remains somewhat obscure. Zanchetti and Leonetti,z4 for example, recently compared the acute natriuretic response to nifedipine and verapamil, in doses adjusted to induce the same decrease in blood pressure. Nifedipine was found to induce a substantially larger diuresis and natriuresis 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 activated the sympathetic and renin-angiotensin systems 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 hypertension.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 therapy 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 decrease in arterial blood pressure.5 SC) 20881 also induced an acute natriuresis and an increase in glomerular 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 wellmaintained glomerular filtration rate.42v43 Perhaps this class of agent owes its sustained impact on hypertension, 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 vasodilation 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 nephrosclerosis and finally renal failure? There is a relatively hopeful answer .45-47Initially, therapy for hyperten-
THE AMERICAN
JOLJRNAL OF CARDIOLOGY
Volume 60
591
sion appears to aggravate the already compromised renal function. With persistent lowering of the elevated arterial blood pressure, however, renal function is usually improved, and sometimes improved dramatically. 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 considered one of the great successes of modern therapeutics. We do not know whether essential hypertension represents a combination of unrelated diseases or is a single process, which has been modified in the individual 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 dramatically in the past decade and are likely to continue to improve over the next decade.51We 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.
References 1. Koch-Weser J. Vasodilator drugs in the treatment of hypertension. Arch Intern Med 1974;133:1017-1027. 2. Page IH. The mosaic theory of arterial hypertension-its intepretotion. Perspect Biol Med 1967;10:325-333. 3. Guyton AC, Coleman TF, Crowley AW, &heel KW. Manning RD, Norman RA. Arterial pressure regulation: overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med 1972;52:584-594. 4. Hollenberg NK, Adams DF, Solomon H, Chenitz WR, Burger BM, Abrams HL, Merrill JP. Renal vascular tone in essential and secondary hypertension: hemodynamic and ongiographic responses to vosodilators. Medicine 1975; 5429-44. 5. Williams GH, Hollenberg NK. Accentuated vascular and endocrine response to SQ 20881 in hypertension. N Engl / Med 1977;297:184-188. 6. Hollenherg NK, Williams GH, Taub KH, Ishikawa I, Brown C, Adams DF. Renal vascular response to interruption of the renin-angiotensin system in normal man. Kidney Int 1977;12:285-293. 7. Hollenberg NK, Borucki LJ, Adams DF. The renal vasculature in early essential hypertension: evidence for a pathogenetic role. Medicine 1978; 57:167-178. 8. Hollenberg NK, Sandor T. Vasomotion of renal blood flow in essential hypertension: oscillations in xenon transit. Hypertension 1984x3:579-585. 9. Hollenberg NK, Swartz SL, Passan DR, Williams GH. Increased glomeru-
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HEART AND KIDNEY
lar filtration rate after converting enzyme inhibition in essential hypertension. N Engl J Med 1979;301:9-12. 10. Hollenberg NK. fl-adrenergic blocking agents-the treatment of hypertension and the kidney. Royal Socity of Medicine International Congress and Symposium. 1982;51:1-8. 11. Gavras H, Ribierto AR, Gavras I, Brunner HR. Reciprocal relation between renin dependency and sodium dependency in essential hypertension. N Engl J Med 1976;295:1278-1283. 12. Gavras HR, Brunner HR, Turini GA, Kewshaw GR, Tifft CP, Cuttlelod S, Gavras I, Vukovich RA, McKinstry DN. Antihypertensive effect of the oral angiotensin converting enzyme inhibitor SQ 14225 in man. N Engl J Med 1978;298:991-995. 13. Veterans Administration Cooperative Study Group in Antihypertensive Agents. Oxprenolol versus propranolol: a randomized, double-blind mufticlinic trial in hypertensive patients. Hypertension 1981;3:250-256. 14. Finnerty FA Jr. Relationshipb ofextracellular fluid volume to the development of drug resistance in the hypertensive patient. Am Heart J 3971;81:563565. 15. Nickerson M, Ruedy J. Antihypertensive agents and the drug therapy of hypertension. In: Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics. New York: MacMillan, 1975;705-728. 16. Page LB, Sidd JJ.Medical management of primary hypertension. N Engl J Med 1972;287:960-967. 17. Kimbrough HM Jr, Vaughan ED Jr, Carey RM, Ayers CR. Effect of intrarenal angiotensin II blockade on renal function in conscious dogs. Circ Res 1977;40:174-178. 18. Carriere C. Effect of norepinephrine, isoproterenol, and adrenergic blockers upon the intrarenal distribution of blood flow. Can J Physiol Pharmaco1 1969;47:199-208. 19. Krauss XH, Schalekamp MADH, Kolsters G, Zaal GA, Birkenhager WH. Effects of chronic beta-adrenergic blockade on systemic and renal hemodynamic responses to hyperosmotic saline in hypertensive patients. Clin Sci 1972:43:385-391. 20. Freis ED. Effectiveness of nadolol vs bendroflumethazide alone and in combination in the treatment of hypertension. In: Hollenberg NK, ed. The Hoemodynamics of Nadolol. Second International Symposium. London: The Royal Society of Medicine, 1982;51-58. 21. Greene JA Jr. Effects of diazoxide on renal function in the dog. Proc Sot Exp Biol Med 1967;125:375-379. 22. Onesti G. Renal phormacodynamics of antihypertensive drugs: clinical applications. Am 1 Cardiol 1966;17:668-672. 23. Zins GR. Alterations in renal function during vasodilator therapy. In: Wesson LG, Fanelli GM, eds. Recent Advances in Renal Physiology and Pharmacology. Baltimore: Baltimore University Park Press, 1974;165-172. 24. Zanchetti A, Leonetti G. Natriuretic effect of calcium antagonists. J Cardiovasc Pharmacol 1985;7:33-37. 25. Loutzenhiser R, Epstein M. Effects of calcium antagonists on renal hemodynamics. Am J Physiol 1985;249:F819-F629. 26. Bauer JH, Sunderrajan S, Reams G. Effects of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid composition. Am J Cardiol 1985; 56:62H-678. 27. Bauer JH, Reams G. Short- and long-term effects of calcium entry blockers on the kidney. Am r Cardiol 1987;59:66A-71A. 28. Romero JC, Raij L, Granger JP,Ruilope LM, Rodicio JL. Multiple effects of calcium entry blockers on renal function in hypertension. Hypertension 1987;10:148-151.
29. Klutsch VK, Schmidt P, GroBwendt J. Der Einflub von BAY a 1040auf die Nierenfunktion des Hypertonikers. Arineimitteiforsch 1972;22:377-386. 30. Olivari MT, Bartorelli C, Polese A, Fiorentini C, Morvezz P, Gauzzi MD. Treatment of hypertension with nifedipine, a calcium antagonistic agent.
Circulation 1979;59:1056-1062. 31. Kinoshita M, Kusukawa R, Shimono Y, Motomura M, Tomonaga G, Hoshino T. Effects of diltiazem hydrochloride on renal hemodynamics and urinary electrolyte excretion. Jpn Circ J 1978;42:553-560. 32. Yokoyama S, Kaburagi T. Clinical effects of intravenous nifedipine on renal function. J Cardiovasc Pharmacol 1983;5:67-71. 33. Christensen CK, Pedersen OL, Mikkelsen E. Renal effects of acute calcium blockade with nifedipine in hypertensive patients receiving beta-odrenoceptor-blocking drugs. Clin Pharmacol Ther 1982;32:572-576. 34. Blackshear J, Garnic D, Williams G, Harrington D, Hollenberg NK. Exaggerated renal vascular response to calcium entry blockade in first degree relatives of essential hypertensives: possible role of intrarenaf angiotensin II. Hypertension 1987;9:384-389. 35. Tsuchiya N, Watanabe K, Aijiro H, Tojo S. Action of diltiazem (CRD-4011 on diseased kidney. Jpn J Exp Med 1975;52:611-616. 36. Kinoshita M, Kushukawa R, Shimono Y, Montomura M, Tomonaga G, Hoshino T. The effect of diltiazem hydrochloride upon sodium diuresis and renal failure in chronic congestive heart failure. Arzneimittelforschung 1979;29:676-681. 37. Abe Y, Okahara T, Yamamoto K. Effect of D-3-acetoxy-2,3-dihydro-5,2(dimethylamino] ethyl-2-(p-methoxyphenyl)l,-1,5-benzothiazepine derivative (CRDJ on renal function in the dog. Jpn Circ 1 1972;36:1002-1003. 38. Yamaguchi I, Ikezawa K, Takada T, Kiyomoto A. Studies on a new 1,5benzothiazepine derivative (CRD-401). VI. Effects on renal blood flow and renal function. Jpn J Pharmacol 1974;24:511-512. 39. Loutzenhiser R, Horton C, Epstein M. Effects of diltiazem and margauese on renal hemodynamics: studies in the isolated perfused rat kidney. Nephron 1985;39:382-388. 40. Blackshear JL, Orlandi C, Williams GH, Hollenberg NK. The renal response to diltiazem and nifedipine: comparison with nitroprusside. J Cardiovast Pharmacol 1986;8:37-43. 41. Ondetti MA, Rubin B, Cushman DW. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 1977;196:441-444. 42. Hollenberg NK, Meggs LG, Williams GH. Katz J, Garnic JD, Harrington DP. Sodium intake ond renal response to captopril in normal man and essential hypertension. Kidney Int 1981;20:240-245. 43. Redgrave JE, Rabinowe SL, Williams GH, Hollenberg NK. Correction of abnormal renal blood flow response to angiotensin II by converting-enzyme inhibition in essential hypertensives. J Clin Invest 1985;75:1285-1290, 44. Ackerman DM, Blumberg AL, McCafferty JP, Sherman SS, Weinstock J, Kaiser C, Berkowitz B. Potential usefulness of renal vasodilators in hypertension and renal disease: SKbF 82526. Fed Proc 1983;42:186-190. 45. Davidov M, Mroczek W, Gavrilovich L, Finnerty F Jr. Long-term followup of aggressive medical therapy of accelerated hypertension with azotemia. Angiology 1975;26:396-407. 46. Pohl JEF, Thurston H, Swales JD. Hypertension with renal impairment: influence of intensive therapy. Q [ Med 1974;43:569-581. 47. Woods JW, Blythe WB, Huffines WD. Management of malignant hypertension complicated by renal insufficiency. N Engl J Med 1974;291:10-14. 48. Meyer TW, Anderson S, Rennke HG, Brenner BM. Converting enzyme inhibitor therapy limits progressive glomerular injury in rats with renal insufficiency. Am J Med 1985;79:31-36. 49. Raij L, Chiou XC, Owens R, Wrigley B. Therapeutic implications of hypertension-induced glomerular injury: comparison of enalapril and a combination of hydralazine, reserpine, and hydrochlorothiazide in an experimental model. Am J Med 1985;79:37-41. 50. Bauer JH, Reams GP. Hemodynamic and renal function in essential hypertension during treatment with enalapril. Am J Med 1985;79:10-13. 51. Dollery CT. Hypertension and new antihypertensive drugs: clinical perspectives. Fed Proc 1983;42:207-210.
K.
HOLLENBERG,
MD,
PhD
Both traditional and newer treatments of essential hypertension are discussed in relation to kidney function and renal perfusion. In essential hypertension, renal vascular resistance is routinely increased and renal blood flow is often decreased. Reduced sodium intake as a form of therapy will cause a decrease in both renal blood flow and glomerular filtration, most likely due to an angiotensin-induced renal vasoconstriction caused by the reactive increase in renin release. Treatment with diuretics produces the same effects, also angiotensin-mediated. The addition of a /3-adrenergic blocking agent to prevent renin release may be a good choice, but individual 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. Nifedipine 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 potentiated renal vascular response in normotensive patients of hypertensive parents. Angiotensin converting enzyme inhibitors such as captopril and enalapril have produced increased renal blood flow and wellmaintained glomerular filtration in patients with essential hypertension. The agents available for treating hypertension have improved dramatically in the past decade. A salutary effect on the kidney will remain 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 necessarily empirical, but some principles have emerged. Total peripheral resistance is typically high in patients with sustained hypertension, and the wish to reduce it with anihypertensive therapy is a reasonable goal. Thus, treatment of hypertension with a vasodilator is conceptually attractive. Available nonspecific vasodilators unfortunately do not sustain a reduction in blood pressure when used alone. A diuretic is required routinely, and often a /3 blocker as well. KochWeserl suggested a mechanism by which the combination of vasodilator, diuretic agent and @-adrenergic blocking agent was effective, and perhaps less empirical than it seemed. His premise was that the combination of sodium retention, tachycardia and a reactive renin response represented the main physiologic barriers to the sustained efficacy of vasodilator drugs: the
,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 pharmacology for interrupting the renin-angiotensin system that soon followed, but it has become clear that KochWeser’s suggestion was largely correct. Modern antihypertensive therapy reflects the development of agents that act as vasodilators, but for one reason or another-often involving the kidney-avoid the disadvantages of the nonspecific vasodilators. In this essay, I will examine the impact of antihypertensive 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 calcium 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-13and the nature and extent of reactive responses that often limit the response to therapeutic agents.2s5J2,14-16 There are a number of reasons for the long-standing interest in the renal blood supply in relation to
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.
571
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 pathogenesis 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 patient, systems analysis suggests that a renal response must be involved to sustain the elevated blood pressure.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 reduced renal blood flow in about two-thirds of patients.7 Multiple observations suggest that a functional disturbance, active vasoconstriction, is at least partly responsible for altering renal perfusion and glomerular filtration rate. From moment to moment, blood flow to the kidney varies much more in patients with essential 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 Abnormalities in the renal arteriogram are reversed, often completely, 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 conditioned 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 renal blood flow and glomerular filtration rate in animals and in man. The evidence that angiotensininduced renal vasoconstriction, consequent to the reactive 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 angiotensinmediated. 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 reasonable to suspect that the addition of a p-adrenergic blocking agent-many of which also block renin release-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 receptor in the kidney. l8 A propranolol-induced reduction 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 padrenergic blocking agents including oxprenolol, pindolol, acebutolol, atenolol and dichloro-isoproterenol.lO Renal vasoconstriction, however, is not an inevitable concomitant of ,&adrenergic blockade. Nadolol 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 hypertension.z0 What is the impact on the kidney of the “nonspecific” vasodilators? In this general class, we can include hydralazine, minoxidil, diazoxide and sodium nitroprusside. 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, especially the decrease in blood pressure, clearly plays an important role. For example, diazoxide is a potent renal vasodilator when infused into the renal artery, and this vasodilatation is accompanied by a striking natriuresis.21When the agent is given intravenously, however, an equally striking antinatriuresis occurs-presumably because of the blood pressure decrease.gJ7*20 The impact of these nonspecific vasodilators on renal blood supply and renal sodium handling varies widely in the individual patient, but there is clear evidence that hydralazine, diazoxide and minoxidil1416,22,23 routinely produce antinatriuresis, sodium retention 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: calcium antagonists, converting enzyme inhibitors and dopamine analogs. The ubiquitous role of calcium in biologic processes,including those involving renal perfusion and function, has led to a host of laboratory and clinical studies, as reviewed recently.2-28 Available information suggests an action-depending on the circumstances 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, revealed 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
rate, presumably reflecting fixed organic renal vascular changes, showed little response. Subsequent studies of the acute responses to agents in this class have confirmed these observations in man.24-34 The intriguing observation that normotensive offspring of hypertensive parents often show a potentiated 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 diltiazem.26,30-40 An additional question is whether the various calcium 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 presentalthough their precise clinical relevance remains somewhat obscure. Zanchetti and Leonetti,z4 for example, recently compared the acute natriuretic response to nifedipine and verapamil, in doses adjusted to induce the same decrease in blood pressure. Nifedipine was found to induce a substantially larger diuresis and natriuresis 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 activated the sympathetic and renin-angiotensin systems 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 hypertension.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 therapy 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 decrease in arterial blood pressure.5 SC) 20881 also induced an acute natriuresis and an increase in glomerular 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 wellmaintained glomerular filtration rate.42v43 Perhaps this class of agent owes its sustained impact on hypertension, 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 vasodilation 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 nephrosclerosis and finally renal failure? There is a relatively hopeful answer .45-47Initially, therapy for hyperten-
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sion appears to aggravate the already compromised renal function. With persistent lowering of the elevated arterial blood pressure, however, renal function is usually improved, and sometimes improved dramatically. 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 considered one of the great successes of modern therapeutics. We do not know whether essential hypertension represents a combination of unrelated diseases or is a single process, which has been modified in the individual 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 dramatically in the past decade and are likely to continue to improve over the next decade.51We 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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