- Email: [email protected]
The kidney and effective antihypertensive therapy
The Kidney and Effective Antihypertensive NORMAN
K. HOLLENBERG,
Therapy
MD, PhD
Whether or not the kkiney is involved in the genesis of hypertendon in an indhddual patient, it becomes a major determinant of the response to antihypertensive therapy once a treatment strategy is adopted. The major mechanisms through wMch the kidney influences blood pressure are renh release and sodium retention, either together or separately, but additional mechanisms may also contribute. When sodium intake is restrkted or a diuretic is used, the reactive increase h plasma renin activity makes a substantial contribution to limtthg the btood pressure fall. when vasodilators or agents that bkxk the sympathetic ner-
vous system are used, sodium retention plays an important role. Amorg newer agents, the effectiveness of calcium channel blockers, converting enzyme inhibitors and perhaps dopamhe analogs reflects, for reasons that differ from 1 class of agent to another, a special actktn on the kkhey that limits the reactive renal response to the redwtion in blood pressure. Treatment strategies that address the problem of the renal response are more likely to be effective than approaches that avoki or i9nore it.
Much of the strategy in designing antihypertensive therapy-a substantial amount of which was initially empirical-has involved the renal compensatory responses to the agents, whichever drug therapy was selected. Direct acting arteriolar vasodilators, for example, have always provided an attractive approach to the treatment of hypertension, because in most patients the hemodynamic defect responsible for the elevated pressure is an increase in peripheral resistance, at least partly mediated by vasoconstriction.l The use of nonspecific vasodilators has largely been limited by activation of compensatory systems,2 including a prominent renal response that involves both retention of sodium and increase in renin release. This article will focus on some of the more practical implications of our increased understanding of the kidney’s role in sustaining hypertension, however it is initiated.3 A review of the functional abnormalities involving the renal blood supply in essential hypertension,&lO the role of newer pharmacologic agents in therapy5tg-l3 and the nature and extent of the reactive responses that often limit the effectiveness of therapeutic agen~W,l2,14-16 is necessary to achieve this goal. Investigators studying hypertension have several reasons for their long-standing interest in the renal
blood supply as it affects glomerular filtration rate (GFR), sodium handling by the kidney and renal renin release. First, a reduction in renal blood flow due to renal artery stenosis is the most common curable form of secondary hypertension and is still believed by many investigators to contribute in some patients to the pathogenesis of essential hypertension. Second, whatever factors initiate the hypertension process in an individual patient, it is becoming evident that a renal response must be involved in order to sustain the elevated blood pressure.3 Third, it is also becoming clear that the effectiveness of antihypertensive therapy, whatever agent is used, is determined to a substantial degree by the renal response. Finally, the continuing damage to the renal microvasculature by uncontrolled severe hypertension previously accounted for one of the major complications-uremia. The sharp reduction in the frequency of this complication is one of the triumphs of modern antihypertensive therapy. A decrease in renal perfusion is common in essential hypertension; recent estimates suggest that about two-thirds of patients with essential hypertension have an inappropriately decreased renal blood flo~.~ Multiple lines of evidence now suggest that a functional disturbance-active vasoconstriction-plays a role in the abnormal renal perfusion and GFR in patients with essential hypertension. Renal perfusion varies in a moment-to-moment fashion much more in patients with essential hypertension than in normal subjects,
(Am J Cardiof 1985;58:52H45H)
From the Departments of Medicine and Radiology, Harvard Medical School, Brigham and Women’s Hospital, Boston Massachusetts. Address for reprints: Norman K. Hollenberg, MD, PhD, 75 Francis Street, Boston, Massachusetts 02 115.
52H
December
an abnormality that must be due to active vasoconstriction. Renal vasomotion is also increased in essential hypertension.8 Moreover, when nonspecific vasodilators such as acetylcholine are administered into, the renal artery, renal blood flow increases much more strikingly in patients with essential hypertension than in normal subjects.4 With this potentiated renal vascular response, abnormalities in the renal arteriogram are reversed, often completely, by the vasodilators. To the extent that such a functional abnormality involving the renal blood supply plays a role in the individual patient, one might anticipate that suitable doses of an appropriate vasodilator agent would reverse these abnormalities and thus improve renal perfusion and filtration rate. The renal response to therapy is conditioned to a major degree by both the relative influence of the fall in blood pressure and the direct and indirect effects of the therapeutic agent on the kidney. Restriction of sodium intake is the simplest available therapeutic approach to hypertension. This maneuver reduces renal blood flow and GFR in animals and in man. The evidence is unequivocal that angiotensin-induced renal vasoconstriction, consequent to the reactive increase in renin release, accounts entirely for renal vasoconstriction.6J7 There is now clear evidence that when diuretics are used as therapy, the reactive increase in plasma renin activity limits the fall in blood pressure.ll Thus, it is reasonable to conclude that the decrease in renal blood flow and GFR induced by a diuretic is also angiotensin-mediated. Because activation of the renin-angiotensin system plays such a central role in limiting the response to restriction of sodium intake and diuretics, it was reasonable to suspect that the addition of a /3-adrenergic blocking agent-many of which block renin release when it is mediated by /3-adrenergic receptors in the juxtaglomerular apparatus-would reverse the impact of restriction of sodium intake and diuretics on the kidney.2 Unfortunately, propranolol, the most widely used and studied fl-adrenergic blocking agent, directly induces renal vasoconstriction, apparently through an action on an a-adrenergic receptor in the kidney.18 A propranolol-induced decrease in renal blood flow, with a parallel reduction in GFR, sodium retention and a reduced ability to handle sodium load, has also been well documented in man.lg Although this renal response could be due to a decrease in cardiac output induced by the negative inotropic and chronotropic actions of these agents on the heart, it actually occurs with doses insufficient to influence cardiac output.lO A similar renal response has been documented for a wide variety of P-adrenergic blocking agents including oxprenolol, pindolol, acebutolol, atenolol and dichloroisoproterenoLg Renal vasoconstriction, however, is not an inevitable result of fi-adrenergic blockade. Nadolol, a longacting hydrophilic P-adrenergic blocking agent, induces a dose-related increase in renal blood flow over the dose range at which it decreases heart rate and thus cardiac output in man.‘O As opposed to the pro-
6, 1985
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
56
53H
pranolol-induced decrease in sodium excretion, antinatriuresis did not occur with nadolol in the dog; indeed, nadolol increased sodium excretion (K. Duchin, unpublished observations). The clinical implication of this observation may be the remarkable frequency with which nadolol achieves goal blood pressure.20 The Veterans Administration Cooperative Study Group reported that 77% of a large group of white subjects with mild to moderate essential hypertension achieved goal blood pressure with nadolol,20 substantially more than achieved good blood pressure in a parallel study by the same Study Group on responses to other @blockers.13 What impact do the “nonspecific” vasodilators have on the kidney? This general class includes hydralazine, minoxidil, diazoxide, sodium nitroprusside and, in part, trimethapan.15J6 The spectrum of their renal response is wide, but certain features are common to all. Despite the range of direct actions on the renal blood supply, sodium retention-often striking-occurs with uP5J6 and is the factor that limits their therapeutic efficacy.14 The mechanism of the sodium retention has not yet been clearly delineated, but it is evident that the systemic response, especially the drop in blood pressure, plays an important role. For example, d&oxide is a potent renal vasodilator when infused into the renal artery, and this vasodilatation is accompanied by a striking natriuresis.21 When the agent is given intravenously, however, an equally striking antinatriuresis occurs-presumably because of the blood pressure fa11.gJ7~20 The impact of these agents on renal blood supply and renal sodium handling when given systemically varies widely among individual patients, from a net increase to a net decrease in renal blood flow. However, antinatriuresis with sodium retention and, typically, a decrease in GFR occur, with even the most potent direct renal vasodilators in the series-hydralazine, diazoxide and minoxidi1.14-16~22~23 Thus, to date, selection of nonspecific vasodilators for the vasodilator action on the kidney has not spared the patient the negative renal influence of these agents. Three new classes of agents have been developed that may have special implications for the kidney: calcium entry-blocking agents, converting enzyme inhibitors and dopamine analogs. Claims have been made that vasodilatation induced by calcium entryblocking agents may be associated with less sodium retention.24l25 However, rigorous evidence is not yet available, and the question remains controversial because the reports have involved small numbers of patients treated for a relatively short time. Calcium entry-blocking agents do provide an attractive potential. Diltiazem, 1 of the 3 calcium entry-blocking agents currently marketed in the United States, appears to have a special action on the renal blood supply, favoring a sustained or increased GFR and natriuresis despite the fall in arterial blood pressure.26s27 The intriguing observation that normotensive offspring of hypertensive parents often show a potentiated renal vascular response to diltiazem28 raises the interesting
54H
A SYMPOSIUM:
ROLE
OF CALCIUM
ENTRY-BLOCKING
DRUGS
possibility of a special renal action of this agent in essential hypertension. The development of converting enzyme inhibitors provides a new approach to therapy and new tools for examining the underlying mechanisms of this disorder.2s These agents are often effective even in severe hypertension, which has been resistant to standard triple therapy with a diuretic, hydralazine and a /3adrenergic blocking agent.12 Recent studies suggest that this class of agents will exert an especially useful action on the kidney. 5*gIn patients with essential hypertension, the nonapeptide SQ 20881 induced a potentiated increase in renal blood flow5 that was twice the increase in blood flow induced in normal subjects, despite a larger fall in blood pressure. Also, despite the fall in arterial blood pressure, SQ 20881 often induced an increase in GFR and, with it, natriuresisg More recent studies performed with the orally effective analogs, captopril and enalapril, have shown a similar influence; the essential hypertensive patient enjoys a larger renal blood flow response and, despite the fall in arterial blood pressure, a well-maintained GFR.31*32 Perhaps their influence on the kidney accounts for this class of agents’ remarkable, often sustained impact on hypertension even in patients in whom traditional therapy has been ineffective. The dopamine analogs, which are striking renal vasodilators in animal models,32 have undergone too little study in man to allow any conclusion about their therapeutic potential. What is the influence of antihypertensive agents on progression of renal microvascular abnormality to advanced nephrosclerosis and renal failure in hypertension? The impact of these agents is most evident when they are assessed in the treatment of severe hypertension already complicated by some degree of renal insufficiency. Three studies published in the past decade provide some insight and a relatively hopeful answer.33-35 The 80 patients in the 3 studies were treated aggressively for prolonged periods. In each case, therapy for hypertension initially appeared to aggravate the already compromised renal function; however, with time and persistent lowering of the elevated arterial blood pressure, renal function usually improved, sometimes dramatically. In each study, a diuretic was used to reverse the sodium retention induced by dilators, and active vasodilators, especially hydralazine, methyldopa and oral diazoxide that were used for blood pressure control. In this population, in whom renal failure was the common mode of death-a l-year mortality rate routinely exceeded 80% and was generally due to uremia-a striking improvement in natural history was obtained. One-year survival in the 3 series was 55, 76 and 80%-with stable or even improving renal excretory function.33-35 Whether the newer vasodilators, calcium entry-blocking agents, converting enzyme inhibitors or dopamine analogs will produce an even more marked influence on natural history and renal function is not yet known. In summary, the agents available to us for the treatment of hypertension have improved dramatically in
IN HYPERTENSION
the past decade and are likely to continue to improve over the next decade.36 We have the luxury of being able to select our therapeutic objectives for the first time. Among the characteristics of new agents that are likely to be important, a salutary action on the kidney is high on the list. Acknowledgment: It is a pleasure to acknowledge the assistance of Diana Page in preparing this article. Personal research cited was supported by grants HL14944, HL07236, CA32849, HL05832 and RR00888 from the National Institutes of Health, Bethesda, Maryland, and grant NSG 9078 from the National Aeronautics and Space Administration, Houston. Texas.
References 1. Page IH. The mosaic theory of arterial hypertension-its interpretation. Perspect Biol Med 1967;10:325-333. drugs in the treatment of hypertension. Arch 2. Koch Weser J. Vasodiiator Intern Med 1974;133:1017-1027. AC, Coleman TF, Crowley AW, S&eel KW, Manning RD, Nor3. Guyton man RA. Arterial pressure regulation: overriding dominance of the kidnevs in lona-term reauiation and in hvoertension. Am J Med 1972: . 52:584-594: 4. Hollenberg NK, Adams DF, Solomon H, Chenltz WR, Burger BM, Abrams HL. Merrill JP. Renal vascular tone in essential and secondarv hvoertenslon: hemodynamic and angkgraphic responses to vasodiiators. Medicine 1975;54:29-44. GH, Hollenberg NK. Accentuated vascular and endocrine re5. Wllllams sponse to SQ 20881 In hypertension. N Engl J Med 1977;297:184-188. 6. Hollenberg NK, Wllllams GH, Taub KH, lshlkawa I, Brown C, Adams DF. Renal vascular response to interruption of the renin-angiotensln system in normal man. Kidney Int 1977;12:285-293. NK, Boruckl LJ, Adams DF. The renal vasculature in early 7. Hollenberg essential hypertension: evidence for a pathogenetic role. Medicine 1978;57:187-178. NK, Sandor 1. Vasomotion of renal blood flow in essential 8. Hollenberg frtgy$;sion: oscillations in xenon transit. Hypertension 1984;6: -,-
“_“.
9. Hollenberg NK, Swartz SL, Passan DR, Wllllams GH. increased glomeruiar filtration rate after converting enzyme inhibition in essential hypertension. N Engl J Med 1979;301:9-12. 10. Hollenberg NK, Adams DF, McKlnstry DN, Wllllams OH, Boruckl LJ, Sulllvan JM. Beta adrenoceptor blocking agents and the kidney: effect of nadoioi and orooranoioi on the renal circulation. Br J Ciin Pharmacoi 1979;7:supp~21’9s-225s. 11. Gavras H, Rlblerto AR, Gavras I, Brunner HR. Reciprocal relation between renin dependency and sodium dependency in essential hypertension. N Engi J Med 1976;295:1278-1283. 12. Gavras HR, Brunner HR, Turlnl GA, Kershaw GR, Tfffl CP, Cutlelod S, Cavras I, Vukovlch RA, McKlnstry DN. Antihypertensive effect of the oral angiotensin converting enzyme inhibitor SQ 14225 in man. N Engl J Med 197&298-991-995. 13. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Oxprenoiol versus propranoloi: a randomized, double-blind multiclinic trial in hypertensive patients. Hypertension 1981;3:250-256. 14. Flnnerty FA Jr. Relationship of extracellular fluid volume to the development of drug resistance in the hypertensive patient. Am Heart J 1971;81:564-565. 15. Nlckerson M, Ruedy J. Antihypertensive agents and the drug therapy of hypertension. in: Goodman LS, Giiman A, eds. The Pharmacological Basis of Therapeutics. New York: MacMillan, 1975705-726. 16. page LB, Sldd JJ. Medical management of primary hypertension. N Engl J Med 1972;287:960-967. 17. Klmbrough HM Jr, Vaughan ED Jr, Carey RM! Ayers CR. Effect of intrarenal angiotensin Ii blockade on renal funcbon in conscious dogs. Circ Res 1977;40:174-178. 18. Carrlere C. Effect of norepinephrine, isoproterenoi, and adrenergic blockers uoon the intrarenal distribution of blood flow. Can J Phvsiot Pharmacol’l969;47:199-208. 19. Krauss XH, Schalekamp MADH, Kolsters 0, Zaal GA, Blrkenhager WH. Effects of chronic beta-adreneraic blockade on svstemic and renal hemodynamic responses to hyperosmotic saline in hypertensive patients. Clin Sci 1972:43:385-391. 20. iiels ED. Effectiveness of nadoiol vs. bendrofiumethazide alone and in combination in the treatment of hypertension. In: Hoiienberg NK, ed. The Haemodynamics of Nadoioi, Second international Symposium. London: Rovai Societv of Medicine. 1982:51-58. 21. Greene JA Ji. Effects of dfazoxide on renal function in the dog. Proc Sot EXD Bioi Med 1967:125:375-379. 22. Or&l 0. Renal pharmacodynamics of antihypertensive drugs: clinical applications. Am J Cardioi 1966:17:668-672. 23. Zlns OR. Alterations in renal function during vasodilator therapy. In: Wesson LG, Faneiii GM. eds. Recent Advances in Renal Physiology and Pharmacology. Baltimore: University Park Press, 1974165-172. 24. Ollvarl MT. Bartorelll C. Polese A. Florentlnl C. Morverz P. Gauzrl MD. Treatment-of hypertension with nifedipine, a calcium antagonistic agent. Circulation 1979;59:1058-1082.
December
25. 28. 27. 28.
29. 30.
Chrlstensen CK, Pedersen OL, Mlkkelsen E. Renal effects of acute calcium blockade with nifedipine in hypertensive patients receiving betaadrenoceptor-blocking drugs. Clin Pharmacol Ther 1982;32:572-576. Kinoshlta M, Kusukawa R, Shlmono Y, Motomura M, Tomonaga 0, Hoshlno T. Effects of diltiazem hydrochloride on renal hemodynamics and urinary electrolyte excretion. Jpn Circ J 1978;42:553-560. lshlkawa H, Matsushima M, Matsul H, Honjo A, Hayashl M, Shindo T, Morifujl T, Okabyashl M. Effects of diltiazem hydrochloride (CRD-401) on renal hemodynamics of dogs. Arzneimitteiforsch 1978;28:402-406. Garnlc JD, Blackshear JL, Harrlngton DP, Hollenberg NK. Calcium channel blockade and the renal blood supply: enhanced vascular responses to diltiazem in normotensive offspring of hypertensive parents (abstr). Presented at American Heart Association, 1983. Ondettl MA, Rubln B, Cushman DW. Design of specific inhibitors of anoiotensin-convertina enzvme: new class of orallv active antihvpertensivs agents. Science 7977{196:441-444. . Hollenberg NK, Meggs LG, Wllllams GH, Katz J, Garnic JD, Harrlngton DP. Sodium intake and renal responses to captopril in normal man and
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OF CARDIOLOGY
Volume
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essential hypertension. Kidney Int 1981;20:240-245. Redgrave JE, Rabinowe SL, Wllllams GH, Hollenberg NK. Converting enzyme inhibition corrects the altered renovascular responsiveness to angiotensin II in essential hypertension (abstr). Clin Res 1984;32:338A. 32. Ackerman DM, Blumberg AL, McCafferty JP, Sherman SS, Welnstock J, Kaiser C, Berkowltr B. Potential usefulness of renal vasodilators in hypertension and renal disease. SK&F 82526. Fed Proc 1983;42: 186-190. 33. Davldov M, Mrocrek W, Gavrllovlch L, Flnnerty F Jr. Long-term followup of aggressive medical therapy of accelerated hypertension with azotemia. Angiology 1975;26:396-407. 34. Pohl JEF, Thurston H, Swales JD. Hypertension with renal impairment: influence of intensive therapy. Q J Med 1974;43:569-581. 35. Woods JW, Blythe WB, Hufflnes WD. Management of malignant hypertension complicated by renal insufficiency. N Engl J Med 1974;291 10-14. 36. Dollery CT. Hypertension and new antihypertensive drugs: clinical perspectives Fed Proc 1983;42:207-210. 31.
K. HOLLENBERG,
Therapy
MD, PhD
Whether or not the kkiney is involved in the genesis of hypertendon in an indhddual patient, it becomes a major determinant of the response to antihypertensive therapy once a treatment strategy is adopted. The major mechanisms through wMch the kidney influences blood pressure are renh release and sodium retention, either together or separately, but additional mechanisms may also contribute. When sodium intake is restrkted or a diuretic is used, the reactive increase h plasma renin activity makes a substantial contribution to limtthg the btood pressure fall. when vasodilators or agents that bkxk the sympathetic ner-
vous system are used, sodium retention plays an important role. Amorg newer agents, the effectiveness of calcium channel blockers, converting enzyme inhibitors and perhaps dopamhe analogs reflects, for reasons that differ from 1 class of agent to another, a special actktn on the kkhey that limits the reactive renal response to the redwtion in blood pressure. Treatment strategies that address the problem of the renal response are more likely to be effective than approaches that avoki or i9nore it.
Much of the strategy in designing antihypertensive therapy-a substantial amount of which was initially empirical-has involved the renal compensatory responses to the agents, whichever drug therapy was selected. Direct acting arteriolar vasodilators, for example, have always provided an attractive approach to the treatment of hypertension, because in most patients the hemodynamic defect responsible for the elevated pressure is an increase in peripheral resistance, at least partly mediated by vasoconstriction.l The use of nonspecific vasodilators has largely been limited by activation of compensatory systems,2 including a prominent renal response that involves both retention of sodium and increase in renin release. This article will focus on some of the more practical implications of our increased understanding of the kidney’s role in sustaining hypertension, however it is initiated.3 A review of the functional abnormalities involving the renal blood supply in essential hypertension,&lO the role of newer pharmacologic agents in therapy5tg-l3 and the nature and extent of the reactive responses that often limit the effectiveness of therapeutic agen~W,l2,14-16 is necessary to achieve this goal. Investigators studying hypertension have several reasons for their long-standing interest in the renal
blood supply as it affects glomerular filtration rate (GFR), sodium handling by the kidney and renal renin release. First, a reduction in renal blood flow due to renal artery stenosis is the most common curable form of secondary hypertension and is still believed by many investigators to contribute in some patients to the pathogenesis of essential hypertension. Second, whatever factors initiate the hypertension process in an individual patient, it is becoming evident that a renal response must be involved in order to sustain the elevated blood pressure.3 Third, it is also becoming clear that the effectiveness of antihypertensive therapy, whatever agent is used, is determined to a substantial degree by the renal response. Finally, the continuing damage to the renal microvasculature by uncontrolled severe hypertension previously accounted for one of the major complications-uremia. The sharp reduction in the frequency of this complication is one of the triumphs of modern antihypertensive therapy. A decrease in renal perfusion is common in essential hypertension; recent estimates suggest that about two-thirds of patients with essential hypertension have an inappropriately decreased renal blood flo~.~ Multiple lines of evidence now suggest that a functional disturbance-active vasoconstriction-plays a role in the abnormal renal perfusion and GFR in patients with essential hypertension. Renal perfusion varies in a moment-to-moment fashion much more in patients with essential hypertension than in normal subjects,
(Am J Cardiof 1985;58:52H45H)
From the Departments of Medicine and Radiology, Harvard Medical School, Brigham and Women’s Hospital, Boston Massachusetts. Address for reprints: Norman K. Hollenberg, MD, PhD, 75 Francis Street, Boston, Massachusetts 02 115.
52H
December
an abnormality that must be due to active vasoconstriction. Renal vasomotion is also increased in essential hypertension.8 Moreover, when nonspecific vasodilators such as acetylcholine are administered into, the renal artery, renal blood flow increases much more strikingly in patients with essential hypertension than in normal subjects.4 With this potentiated renal vascular response, abnormalities in the renal arteriogram are reversed, often completely, by the vasodilators. To the extent that such a functional abnormality involving the renal blood supply plays a role in the individual patient, one might anticipate that suitable doses of an appropriate vasodilator agent would reverse these abnormalities and thus improve renal perfusion and filtration rate. The renal response to therapy is conditioned to a major degree by both the relative influence of the fall in blood pressure and the direct and indirect effects of the therapeutic agent on the kidney. Restriction of sodium intake is the simplest available therapeutic approach to hypertension. This maneuver reduces renal blood flow and GFR in animals and in man. The evidence is unequivocal that angiotensin-induced renal vasoconstriction, consequent to the reactive increase in renin release, accounts entirely for renal vasoconstriction.6J7 There is now clear evidence that when diuretics are used as therapy, the reactive increase in plasma renin activity limits the fall in blood pressure.ll Thus, it is reasonable to conclude that the decrease in renal blood flow and GFR induced by a diuretic is also angiotensin-mediated. Because activation of the renin-angiotensin system plays such a central role in limiting the response to restriction of sodium intake and diuretics, it was reasonable to suspect that the addition of a /3-adrenergic blocking agent-many of which block renin release when it is mediated by /3-adrenergic receptors in the juxtaglomerular apparatus-would reverse the impact of restriction of sodium intake and diuretics on the kidney.2 Unfortunately, propranolol, the most widely used and studied fl-adrenergic blocking agent, directly induces renal vasoconstriction, apparently through an action on an a-adrenergic receptor in the kidney.18 A propranolol-induced decrease in renal blood flow, with a parallel reduction in GFR, sodium retention and a reduced ability to handle sodium load, has also been well documented in man.lg Although this renal response could be due to a decrease in cardiac output induced by the negative inotropic and chronotropic actions of these agents on the heart, it actually occurs with doses insufficient to influence cardiac output.lO A similar renal response has been documented for a wide variety of P-adrenergic blocking agents including oxprenolol, pindolol, acebutolol, atenolol and dichloroisoproterenoLg Renal vasoconstriction, however, is not an inevitable result of fi-adrenergic blockade. Nadolol, a longacting hydrophilic P-adrenergic blocking agent, induces a dose-related increase in renal blood flow over the dose range at which it decreases heart rate and thus cardiac output in man.‘O As opposed to the pro-
6, 1985
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
56
53H
pranolol-induced decrease in sodium excretion, antinatriuresis did not occur with nadolol in the dog; indeed, nadolol increased sodium excretion (K. Duchin, unpublished observations). The clinical implication of this observation may be the remarkable frequency with which nadolol achieves goal blood pressure.20 The Veterans Administration Cooperative Study Group reported that 77% of a large group of white subjects with mild to moderate essential hypertension achieved goal blood pressure with nadolol,20 substantially more than achieved good blood pressure in a parallel study by the same Study Group on responses to other @blockers.13 What impact do the “nonspecific” vasodilators have on the kidney? This general class includes hydralazine, minoxidil, diazoxide, sodium nitroprusside and, in part, trimethapan.15J6 The spectrum of their renal response is wide, but certain features are common to all. Despite the range of direct actions on the renal blood supply, sodium retention-often striking-occurs with uP5J6 and is the factor that limits their therapeutic efficacy.14 The mechanism of the sodium retention has not yet been clearly delineated, but it is evident that the systemic response, especially the drop in blood pressure, plays an important role. For example, d&oxide is a potent renal vasodilator when infused into the renal artery, and this vasodilatation is accompanied by a striking natriuresis.21 When the agent is given intravenously, however, an equally striking antinatriuresis occurs-presumably because of the blood pressure fa11.gJ7~20 The impact of these agents on renal blood supply and renal sodium handling when given systemically varies widely among individual patients, from a net increase to a net decrease in renal blood flow. However, antinatriuresis with sodium retention and, typically, a decrease in GFR occur, with even the most potent direct renal vasodilators in the series-hydralazine, diazoxide and minoxidi1.14-16~22~23 Thus, to date, selection of nonspecific vasodilators for the vasodilator action on the kidney has not spared the patient the negative renal influence of these agents. Three new classes of agents have been developed that may have special implications for the kidney: calcium entry-blocking agents, converting enzyme inhibitors and dopamine analogs. Claims have been made that vasodilatation induced by calcium entryblocking agents may be associated with less sodium retention.24l25 However, rigorous evidence is not yet available, and the question remains controversial because the reports have involved small numbers of patients treated for a relatively short time. Calcium entry-blocking agents do provide an attractive potential. Diltiazem, 1 of the 3 calcium entry-blocking agents currently marketed in the United States, appears to have a special action on the renal blood supply, favoring a sustained or increased GFR and natriuresis despite the fall in arterial blood pressure.26s27 The intriguing observation that normotensive offspring of hypertensive parents often show a potentiated renal vascular response to diltiazem28 raises the interesting
54H
A SYMPOSIUM:
ROLE
OF CALCIUM
ENTRY-BLOCKING
DRUGS
possibility of a special renal action of this agent in essential hypertension. The development of converting enzyme inhibitors provides a new approach to therapy and new tools for examining the underlying mechanisms of this disorder.2s These agents are often effective even in severe hypertension, which has been resistant to standard triple therapy with a diuretic, hydralazine and a /3adrenergic blocking agent.12 Recent studies suggest that this class of agents will exert an especially useful action on the kidney. 5*gIn patients with essential hypertension, the nonapeptide SQ 20881 induced a potentiated increase in renal blood flow5 that was twice the increase in blood flow induced in normal subjects, despite a larger fall in blood pressure. Also, despite the fall in arterial blood pressure, SQ 20881 often induced an increase in GFR and, with it, natriuresisg More recent studies performed with the orally effective analogs, captopril and enalapril, have shown a similar influence; the essential hypertensive patient enjoys a larger renal blood flow response and, despite the fall in arterial blood pressure, a well-maintained GFR.31*32 Perhaps their influence on the kidney accounts for this class of agents’ remarkable, often sustained impact on hypertension even in patients in whom traditional therapy has been ineffective. The dopamine analogs, which are striking renal vasodilators in animal models,32 have undergone too little study in man to allow any conclusion about their therapeutic potential. What is the influence of antihypertensive agents on progression of renal microvascular abnormality to advanced nephrosclerosis and renal failure in hypertension? The impact of these agents is most evident when they are assessed in the treatment of severe hypertension already complicated by some degree of renal insufficiency. Three studies published in the past decade provide some insight and a relatively hopeful answer.33-35 The 80 patients in the 3 studies were treated aggressively for prolonged periods. In each case, therapy for hypertension initially appeared to aggravate the already compromised renal function; however, with time and persistent lowering of the elevated arterial blood pressure, renal function usually improved, sometimes dramatically. In each study, a diuretic was used to reverse the sodium retention induced by dilators, and active vasodilators, especially hydralazine, methyldopa and oral diazoxide that were used for blood pressure control. In this population, in whom renal failure was the common mode of death-a l-year mortality rate routinely exceeded 80% and was generally due to uremia-a striking improvement in natural history was obtained. One-year survival in the 3 series was 55, 76 and 80%-with stable or even improving renal excretory function.33-35 Whether the newer vasodilators, calcium entry-blocking agents, converting enzyme inhibitors or dopamine analogs will produce an even more marked influence on natural history and renal function is not yet known. In summary, the agents available to us for the treatment of hypertension have improved dramatically in
IN HYPERTENSION
the past decade and are likely to continue to improve over the next decade.36 We have the luxury of being able to select our therapeutic objectives for the first time. Among the characteristics of new agents that are likely to be important, a salutary action on the kidney is high on the list. Acknowledgment: It is a pleasure to acknowledge the assistance of Diana Page in preparing this article. Personal research cited was supported by grants HL14944, HL07236, CA32849, HL05832 and RR00888 from the National Institutes of Health, Bethesda, Maryland, and grant NSG 9078 from the National Aeronautics and Space Administration, Houston. Texas.
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essential hypertension. Kidney Int 1981;20:240-245. Redgrave JE, Rabinowe SL, Wllllams GH, Hollenberg NK. Converting enzyme inhibition corrects the altered renovascular responsiveness to angiotensin II in essential hypertension (abstr). Clin Res 1984;32:338A. 32. Ackerman DM, Blumberg AL, McCafferty JP, Sherman SS, Welnstock J, Kaiser C, Berkowltr B. Potential usefulness of renal vasodilators in hypertension and renal disease. SK&F 82526. Fed Proc 1983;42: 186-190. 33. Davldov M, Mrocrek W, Gavrllovlch L, Flnnerty F Jr. Long-term followup of aggressive medical therapy of accelerated hypertension with azotemia. Angiology 1975;26:396-407. 34. Pohl JEF, Thurston H, Swales JD. Hypertension with renal impairment: influence of intensive therapy. Q J Med 1974;43:569-581. 35. Woods JW, Blythe WB, Hufflnes WD. Management of malignant hypertension complicated by renal insufficiency. N Engl J Med 1974;291 10-14. 36. Dollery CT. Hypertension and new antihypertensive drugs: clinical perspectives Fed Proc 1983;42:207-210. 31.