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The kidney and antihypertensive therapy
The Kidney and AntihypertensiveTherapy 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 vasodilators. This review examines the impact of antihypertensive 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 channel 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 nature 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 algorithm that might be considered prescient t0day.l He pointed out that treatment of hypertension with a vasodilator was conceptually attractive, because total peripheral resistance is typically high in patients with this disease, and one would wish to decrease it with antihypertensive therapy. Unfortunately, the nonspecific vasodilators then available were not able to sustain a decrease in blood pressure (BP]. Kochwaser’s 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 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. His solution was straightforward: The /3-adrenergic blocking agent blunted renin release and prevented the tachycardia; the diuretic reversed the sodium retention. Definition of the precise role played by the renin system in that response awaited advances in pharmacology that soon followed, but it has become clear that Kochwaser’s suggestion was largely correct.
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 antihypertensive agents on renal perfusion and function and relate that to their efficacy in decreasing high BP. Special attention will be given to ,8-adrenergic blocking agents that have a minimal impact on the kidney, converting 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 involving the renal blood supply in essential hypertension,2-10 the role of newer pharmacologic agents in therapy5zg-13and the nature and extent of reactive responses that often limit the response to therapeutic agents.2.5.12.14-16 There has been a long-standing interest in the renal blood supply as it impacts on various aspects of hypertension. 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 becoming 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,
From the Departments of Medicine and Radiology, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts. 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 Administration. Address for reprints: Norman K. Hollenberg, MD, PhD, 75 Francis Street, Boston, Massachusetts 02115. 76A
I--“--” oalluary
q~, L.J
uremia. The sharp reduction in the frequency of this complication represents one of the triumphs of modern 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 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 than in normal subjects-an abnormality 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 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 BP and the direct and indirect effects of the therapeutic agent. Restriction of sodium intake is the simplest available therapy for hypertension. This maneuver decreases 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.“z17 When diuretics are used as therapy, there is now clear evidence that the reactive increase in plasma renin activity limits the decrease in BP.ll By analogy with the studies of sodium restriction, it is reasonable to conclude that the decrease in renal blood flow and filtration 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 release-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 receptor in the kidney. I8 A propranolol-induced decrease 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 decrease in cardiac output induced by the negative inotropic 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 variety of /3-adrenergic blocking agents including oxpren0101,pindolol, acebutolol, atenolol and dichloro-isoproterenol.” Renal vasoconstriction, however, is not an
1987
THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Volume
59
77A
inevitable concomitant of ,6-adrenergic blockade. Nadolol, 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, unpublished observation). This may account for its remarkable success with hypertension? The Veterans Administration Cooperative Study Group reported that 77% of a large group of white men with mild to moderate essential hypertension achieved goal BP with nadolol,?” substantially more than those in a parallel study who were given other p blockers.‘” What of the impact on the kidney of the “nonspecific” vasodilators? In this general class, we can include hydralazine, minoxidil, diazoxide, sodium nitroprusside and trimethepan-or at least those aspects of the latter’s effect that are due to its potent, nonspecific vasodilator component.15,1fiCertain features are common to all. One of these is sodium retention,15.1” which is often striking and the factor limiting their therapeutic 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, diazoxide is a potent renal vasodilator when infused into the renal artery, and this vasodilatation is accompanied by a striking natriuresis.“’ When the agent is given intravenously, however, an equally striking anti-natriuresis 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 minoxidill?--‘“,Z”,‘“-produce an antinatriuresis, with 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 entry-blocking agents, converting enzyme inhibitors 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 filtration 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 response. Subsequent studies of the acute responses to agents in this class have confirmed these observationsZ5-‘” The intriguing observation that normotensive offspring of hypertensive parents often show a potential renal vascular response to a calcium entryblocking agent, diltiazem,3fl 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.26~3n~36 An additional question is whether the various calcium channel blocking agents currently available have
78A
A SYMPOSIUM:
THE CALCIUM
ION, CARDIAC
MYOCYTE
AND VASCULAR
the same effect on hypertension. 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,28 for example, recently compared the acute natriuretic response to nifedipine and verapamil, in doses adjusted to induce the same decrease in BP. 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 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 hypertension.37 These agents are often effective even in patients with very severe hypertension in whom the disease has been resistant to standard triple therapy with a diuretic, hydralazine and a /3-adrenergic blocking agent.12Recent studies suggest that this class of agent will exert an especially useful action on the kidneye5vg In patients with essential hypertension, the nonapeptide SQ 20881induced 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, captopril and enalapril, have shown similar results; the essential hypertensive subject enjoys a larger renal blood flow response and, despite the decrease in arterial BP, a well-maintained glomerular filtration rate.3*j3gPerhaps 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,40have been studied too little in man to allow any conclusions about their therapeutic potential. How do antihypertensive agents affect the process by which a microvascular abnormality in the kidney of a hypertensive patient leads to advanced nephrosclerosis 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 relatively hopeful answer .41-43In 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 improved, and sometimes improved dramatically. In
SMOOTH MUSCLE IN HYPERTENSION
AND ITS TREATMENT
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 history was obtained. One-year survival in the 3 series was 55%, 76% and 80%--with stable or even improved 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 natural 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 successesof modern day therapeutics. We do not know if essential hypertension represents a combination of unrelated diseases or is a single process, which has been modified in the individual patient by age, gender, race, related inherited traits, environmental 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 dramatically in the past decade and are likely to continue to improve over the next decade.44We 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 manuscript.
References 1. Kochwaser 1. Vasodilafor drugs in the treatment of hvuertension. Arch I. Intern Med 19>4;133:1017-1027.” 2. Page IH. The mosaic theory of arterial hypertension-its interpretation. Perspwt Biol Med 1967;10:325-333. 3. Guyton AC, Coleman TF, Crowley AW, Scheel 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 vosculor tone in essential and secondary hypertension: hemodynamic and angiographic responses to vasodilators. Medicine 197.X54: 29-44. 5. Williams GH, Hollenberg NK. Accentuated vascular and endocrine response to SQ 20881 in hypertension. N Engl [ Med 1977;297:184-188. 6. Hollenberg 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:X7-178. 8. Hollenberg NK, Sandor T. Vasomotion of renal blood flow in essential hypertension: oscillations in xenon transit. Ifypertension 1984;6:579-585. 9. Hollenberg NK. Swartz SL, Passan DR. Williams GH. Increased glomeruJar filtration rate after converting enzyme inhibition in essential hypertension. N Enel T Med 1979:301:9-12. 10. HollenYbeig NK, Adams DF, McKinstry DN. Williams GH. Borucki LJ, Sullivan 1M. Reta odrenoceptor blocking agents and the kidney: effect of nadolol &d propranolol on the renal &c&ation. Brit 1 Chin Pharmacol 1979;7:suppl:219S-225s. 11. Gavras H, Ribierto AR, Gavras I. Brunner HR. Reciprocal relution between renin dependency and sodium dependency in essential hypertension. N Engl 1 Med 1976;295:1278-1283. 12. Gavras HR, Brunner HR. Turini GA, Kershaw GR, Tifft CP, Cuttelod S, Gavras I, Vukovich RA, McKinstry DN. Antihypertensive effect of the oral
January
23,
angiotensm converting enzyme Inhibitor SQ 14225 in man N Engl J hled 197R;z.YR:991-99.5. 13. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Oxprrnololversus propron&!: a randomized, double-blind multiclinic trial in hypertensive patients. Hypertension 1981;3:250-256. 14. Finnerty FA Ir. Relationship of extracellular fluid volume to the development of drug resistance in the hypertensive patient. Am IIeart J 1971:Rl: 567-565. I . I 15. Nickcrson M, Ruedy 1, Antihypertensive agents and the drug therapy of hypertension. In: Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics. New York: MacMillan. 1975:705-726. 16. Page LB, Sidd J]. Medical management ofprimary hypertension. N EnglJ Mrd 1972;287:960-967. 17. Kimbrough HM ]r. Vaughan ED Jr, Carey Rh4, 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 odrenergic blockers upon the intrarenal distribution of blood fIow. Can J Physiof Pharmoco1 1969:47:199-20R. 19. Krauss XH, Schalekamp MADH, Kolstcrs G, Zaal GA, Birkenhager WH. Effects of chronic beta-adrenergic blockade on systemic and renal hemodynamic responses to hyperosmotic saline in hypertensive patients. CJin Sci 1972:43:38,5-391. 20. Freis ED. Effectiveness of nadolol vs bendroflumethazide alone and in combination in the treatment of hypertension. In: Hollenberg NK, ed. The Haemodynamics of Nadolol. Second International Symposium. London: The Royal Society of Medicine, 1982:51-58. 21. Greene ]A Jr. Effects of diazoxide on renal function in the dog. Proc Sot E:xpo Biol Mnd 1967;125:375-379. 22. Onesti G. Renal pharmacodynomics of antihypertensive drugs: clinical applications. Am J Cordial 1966;17:666-672 23. Zins GR. Alterations in renal function during vasodilator therapy. In: Wesson LG. Fan& GM, eds. Recent Advances in Renal Physiology and Pharmacology. Baltimore: Baltimore [Jniversity Park Press. 1974:165-172. 24. Klutsch VK. Schmidt P. GroBwendt 1. Der Einflufl van Bay a 1040 auf die Nierrnfunktion des Hypertonikers. Arzneimittelforschung 1972;22:377-380. 25. Olivari MT, Bartorelli C, Polese A. Fiorentini C, Morvczz P, Gauzzi MD. Treatment of hypertension with nifedipine, o calcium antagonistic agent. Circalatlon 1979;59:1056-1062. 26. Kinoshita M, Kusukawa R. Shimono Y, Motomura M, Tomonaga G, Hoshine T Effects of diltiazem hydrochloride on renal hemodynamics and armory electrolyte excretion. Jpn Circ J 1978;42:553-560. 27. Yokoyama S, Kaburagi T. Clinical effects of intravenous nifedipine on renal function. J Cardiovasc Pharmacol 1983;5:67-71. 28. Zanchctti A, Leonetti G. Natriuretic effect of calcium antagonists. J Cardiovasc Pharmacol 1965;7:suppl 433-37.
1987
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AMERICAN
JOURNAL
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CAHDIOLOUY
VOlume
SY
IYA
29. Christensen CK, Petlcrsen OL, Mikkelsen E. Renal &rcls of acuti‘ wit j urn blockade with nifedipine in hypertensive patients receiving brto-adrf~nriceptor-blocking drags. Clin Pharmacol Ther 19/J2;3-7:572-576 30. Garnic JD, Blackshear JL, Harrington DP. Hollcnbcrg NK. C:rrk:~um chari nel blockade and the renal blood supply enhanced vascular wsponws try diltiazem in normotensive offspring of hypertensive patients (abstr) C~rculotion (Port II] 1983:68:III-45. 31. Tsuchiya N, Watanabe K, Aijiro H. Tojo S. Action of diltiawm (CHL)-IfIll on diseased kidney. Jpn J Exp Med 1975;52:611-616. 32. Kinoshita M, Kushukawa R. Shimono I’. Montomura hl. Tomonag.l G. Hoshino T. The effect of diltiazem hydrochloride upon sodium diurws and renal failure in chronic congestive heart failure. Arznrimittelforscllu~~~ 1979;29:676-681. 33. Abe Y, Okahara T, Yamnmoto K. Effect of L)-3-acetox)--L’.3-cllh\ drw.i..: [dimethylammo] ethyl-2-(p-methoxyphen~~]l,-l,S-benzothia~e~~~nt~ &>ril w five (CRDJ on renal function in the dog. Jpn Circ J 1!~72:36:11J1)2’-1(1l1:~. 34. Yamaguchi I. Ikezawa K, Takada T, Kiyomotc A. Studies on a wit’ 1.:. benzothiazepine derivative (CRD401]. VI. Effects on renal blood (lw. and renal function. Jpn J Pharmacol 1974:24:511-512. 35. Ltrrrtzenhiscr R. II&on C. Epstein M. Effects of diltiazem and margaaes” on renal hemodynamlcs: studies in the isolated perfused rat kidney. Nephron 1985;39:382-388, 36. Blackshear Jr.. Orlandi C. Williams GH. Hollcnberg NK. ‘The reoai rc’ sponse to diltiazem and nifedipinr: comparison with nitroprassldr J Cardio vast Pharmacol 1986;8:37-43. 37. Onditti MA, Rabin B. Cushman DW. Design of speclflc mhibitols 01 angiotensin-converting enzyme: new class of orally active antihyprrtrnslr ~1 agents. Science 1977;196:441-444. 38. Hollenberg NK. Meggs LG. Williams GH, Katz J, Garnic JD, Harringtrrn DP. Sodium intake and renal responses to captopril m normal man and essential hypertension. Kidney Int 1963:20:240-245. 39. Redgrave IE, Rabinowe SL. Williams GH. Hollenberg NK. Correctmn of ubnormal renal blood flow response to angiotensin II by convrrting~enz~mr~ inhibition in essential hypertensives. J Clin fnvest 1985;75:1285-1290. 40. Ackerman DM. Blumberg AL, McCafferty JP. Sherman SS, Weinstock [. Kaiser C, Berkowitz B. Potential usefulness of renal vasodilators ln hyprrtension and renal disease: SK&F 82526. Fed Proc 1983;42:186-190. 41. Davidov M, Mroczek W, Gavrilovich I,, Finnerty F ]r. Long-term follow al, of aggressive medical therapy of accelerated hypertension rzith azotrmlo Angiology 1975;26:396-407. 42. Pohl IEF. Thurston H, Swales ID. tlypertension with renal Impalrmrnl. influence of intensive therapy. Q J Med 1974;43:569-581. 43. Woods ]W, Blythe WB. Huffincs WD. Management of malignant hypcxrtension complicated by renal insufficiency. N Engl f Med 1974;291:10-14. 44. Dollery CT. Hypertension and new antihypertensive drugs: chmcal p”rspectivrs. Fed Proc 1983;42:207-210.
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 vasodilators. This review examines the impact of antihypertensive 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 channel 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 nature 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 algorithm that might be considered prescient t0day.l He pointed out that treatment of hypertension with a vasodilator was conceptually attractive, because total peripheral resistance is typically high in patients with this disease, and one would wish to decrease it with antihypertensive therapy. Unfortunately, the nonspecific vasodilators then available were not able to sustain a decrease in blood pressure (BP]. Kochwaser’s 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 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. His solution was straightforward: The /3-adrenergic blocking agent blunted renin release and prevented the tachycardia; the diuretic reversed the sodium retention. Definition of the precise role played by the renin system in that response awaited advances in pharmacology that soon followed, but it has become clear that Kochwaser’s suggestion was largely correct.
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 antihypertensive agents on renal perfusion and function and relate that to their efficacy in decreasing high BP. Special attention will be given to ,8-adrenergic blocking agents that have a minimal impact on the kidney, converting 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 involving the renal blood supply in essential hypertension,2-10 the role of newer pharmacologic agents in therapy5zg-13and the nature and extent of reactive responses that often limit the response to therapeutic agents.2.5.12.14-16 There has been a long-standing interest in the renal blood supply as it impacts on various aspects of hypertension. 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 becoming 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,
From the Departments of Medicine and Radiology, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts. 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 Administration. Address for reprints: Norman K. Hollenberg, MD, PhD, 75 Francis Street, Boston, Massachusetts 02115. 76A
I--“--” oalluary
q~, L.J
uremia. The sharp reduction in the frequency of this complication represents one of the triumphs of modern 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 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 than in normal subjects-an abnormality 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 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 BP and the direct and indirect effects of the therapeutic agent. Restriction of sodium intake is the simplest available therapy for hypertension. This maneuver decreases 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.“z17 When diuretics are used as therapy, there is now clear evidence that the reactive increase in plasma renin activity limits the decrease in BP.ll By analogy with the studies of sodium restriction, it is reasonable to conclude that the decrease in renal blood flow and filtration 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 release-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 receptor in the kidney. I8 A propranolol-induced decrease 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 decrease in cardiac output induced by the negative inotropic 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 variety of /3-adrenergic blocking agents including oxpren0101,pindolol, acebutolol, atenolol and dichloro-isoproterenol.” Renal vasoconstriction, however, is not an
1987
THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Volume
59
77A
inevitable concomitant of ,6-adrenergic blockade. Nadolol, 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, unpublished observation). This may account for its remarkable success with hypertension? The Veterans Administration Cooperative Study Group reported that 77% of a large group of white men with mild to moderate essential hypertension achieved goal BP with nadolol,?” substantially more than those in a parallel study who were given other p blockers.‘” What of the impact on the kidney of the “nonspecific” vasodilators? In this general class, we can include hydralazine, minoxidil, diazoxide, sodium nitroprusside and trimethepan-or at least those aspects of the latter’s effect that are due to its potent, nonspecific vasodilator component.15,1fiCertain features are common to all. One of these is sodium retention,15.1” which is often striking and the factor limiting their therapeutic 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, diazoxide is a potent renal vasodilator when infused into the renal artery, and this vasodilatation is accompanied by a striking natriuresis.“’ When the agent is given intravenously, however, an equally striking anti-natriuresis 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 minoxidill?--‘“,Z”,‘“-produce an antinatriuresis, with 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 entry-blocking agents, converting enzyme inhibitors 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 filtration 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 response. Subsequent studies of the acute responses to agents in this class have confirmed these observationsZ5-‘” The intriguing observation that normotensive offspring of hypertensive parents often show a potential renal vascular response to a calcium entryblocking agent, diltiazem,3fl 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.26~3n~36 An additional question is whether the various calcium channel blocking agents currently available have
78A
A SYMPOSIUM:
THE CALCIUM
ION, CARDIAC
MYOCYTE
AND VASCULAR
the same effect on hypertension. 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,28 for example, recently compared the acute natriuretic response to nifedipine and verapamil, in doses adjusted to induce the same decrease in BP. 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 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 hypertension.37 These agents are often effective even in patients with very severe hypertension in whom the disease has been resistant to standard triple therapy with a diuretic, hydralazine and a /3-adrenergic blocking agent.12Recent studies suggest that this class of agent will exert an especially useful action on the kidneye5vg In patients with essential hypertension, the nonapeptide SQ 20881induced 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, captopril and enalapril, have shown similar results; the essential hypertensive subject enjoys a larger renal blood flow response and, despite the decrease in arterial BP, a well-maintained glomerular filtration rate.3*j3gPerhaps 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,40have been studied too little in man to allow any conclusions about their therapeutic potential. How do antihypertensive agents affect the process by which a microvascular abnormality in the kidney of a hypertensive patient leads to advanced nephrosclerosis 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 relatively hopeful answer .41-43In 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 improved, and sometimes improved dramatically. In
SMOOTH MUSCLE IN HYPERTENSION
AND ITS TREATMENT
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 history was obtained. One-year survival in the 3 series was 55%, 76% and 80%--with stable or even improved 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 natural 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 successesof modern day therapeutics. We do not know if essential hypertension represents a combination of unrelated diseases or is a single process, which has been modified in the individual patient by age, gender, race, related inherited traits, environmental 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 dramatically in the past decade and are likely to continue to improve over the next decade.44We 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 manuscript.
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