Strategies in antihypertensive therapy: Implications of the kidney
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Strategies in Antihypertensive Therapy: Implications of the Kidney
NORMAN K. HOLLENBERG, M.D., Ph.D.
Because we so rarely know the cause of hypertension, antihyper- tensive therapy remains empiric. However, certain principles of treatment are emerging; one of these concerns the critical role of the kidney in antihypertensive therapy. Whether or not the kidney is primarily responsible for hypertension in a patient, it is the patients renal response to treatment that determines, to a major degree, an agents efficacy. Vasodilators have been a conceptually attractive approach to the treatment of high blood pressure, because they decrease total peripheral resistance, which is considered to be the mechanism responsible for this condition in most patients. Nonspe- cific vasodilators exert a series of actions on the kidney-including profound sodium retention and reactive renin release-that limits therapeutic response. For reasons that are not yet clear, but are apparently related to specific action on calcium entry into vascular smooth muscle, endocrine function, and renal hemodynamics, cal- cium channel blocking agents, such as nifedipine, have an advan- tage in the treatment of hypertension. They cause little or no sodium retention; thus, the addition of a diuretic agent is not required. In fact, there is evidence that sodium loading in certain patients may potentiate the antihypertensive efficacy of these drugs. The renin- angiotensin system seems to be activated to a somewhat lesser degree by calcium channel blocking agents than it is by nonspecific vasodilators; in addition, these agents interfere with the actions of angiotensin on aldosterone release. Moreover, their dilator action on the renal blood supply favors sodium excretion. Nifedipine either has no effect on the renal blood supply or induces an increase in renal blood flow and maintains glomerular filtration rate, both of which combine to support the ensuing natriuresis.
Despite its empiric basis, our ability to treat high blood pressure effec- tively and safely must be considered one of the great successes of mod- ern day therapeutics. We do not know whether essential hypertension reflects several unrelated diseases or is a single process that has been modified in the individual patient by age, gender] race, inherited traits, such environmental factors as diet and stress, and the duration of the process. A skilled debater could defend either view, marshaling substan- tial evidence to substantiate his/her claim.
Although we remain ignorant at this fundamental level, a number of relevant therapeutic principles have emerged. Among the more important is the role of the kidney as a determinant of the effectiveness of antihy- pertensive therapy-the subject of this article. In addressing this topic, it is necessary to review the functional abnormalities involving the renal
From the Departments of Medicine and Radiology, Harvard Medical School and Brigham and Wom- ens Hospital, Boston, Massachusetts. Personal research cited in this article was supported by grants from the National Institutes of Health (HL- 14944, HL-07236, CA-32849, HL-05832, and RR- 00888) and the National Aeronautics and Space Administration (NSG-9078). Requests for reprints should be addressed to Dr. Norman K. Hollenberg, 75 Francis Street, Boston, Massachusetts 02115.
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blood supply in essential hypertension [l--7], the role of potentiated renal vascular response, abnormalities in the newer pharmacologic agents in drug therapy [2,6-l I], renal arteriogram are reversed (often completely) by vas- and both the nature and the extent of reactive responses odilators. that often limit the effectiveness of therapeutic agents [2,9, 12-141. EFFECTS OF ESTABLISHED AGENTS
RENAL BLOOD SUPPLY
Direct-acting arteriolar vasodilators have always provided an attractive approach to the treatment of hypertension, because the hemodynamic defect typically responsible for the elevated pressure is an increase in peripheral resist- ance mediated, at least in part, by vasoconstriction . Nonspecific vasodilators, however, have been of limited use, because they activate compensatory systems - e.g., they induce a prominent renal response that involves both sodium retention and increased renin release. This article focuses on some of the practical implications of our increased understanding of the kidneys role in sustaining hypertension, howsoever it is initiated .
There has been considerable interest in the renal blood supply and its effects on the glomerular filtration rate, so- dium handling by the kidney, and renal renin release in hypertension. A reduction 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 to the pathogenesis of essential hypertension in some patients. Whatever factors initiate the onset of hypertension in a patient, it is becoming clear that a renal response must be involved in order to sustain elevated blood pressure . Perhaps most important, it is now evident that the effectiveness of antihypertensive therapy, regardless of the therapeutic agent employed, is largely determined by the renal response. Finally, the con- tinuing damage to the renal microvasculature in uncon- trolled severe hypertension leads to uremia, one of the major complications of this disorder. The sharp reduction in the frequency of occurrence of this complication repre- sents one of the triumphs of modern antihypertensive therapy.
Renal perfusion is often reduced in patients with essen- tial hypertension. Recent estimates  suggest that about two thirds of these patients have an inappropriately re- duced renal blood flow. Multiple lines of evidence now suggest that a functional disturbance-active vasocon- striction-plays a role in the abnormality of renal perfu- sion and glomerular filtration rate in patients with essential hypertension. Renal perfusion varies from moment to moment much more in patients with essential hyperten- sion than it does in normal subjects, an abnormality that must be due to active vasoconstriction . Renal vasomo- tion is also increased in essential hypertension . More- over, renal blood flow increases more dramatically in pa- tients with essential hypertension than it does in normal subjects when nonspecific vasodilators, such as acetyl- choline, are administered into the renal artery [I]. With the
To the extent that such a functional abnormality involving the renal blood supply plays a role in the etiology of hyper- tension, one might anticipate that individually titrated doses of an appropriate vasodilator would reverse these abnormalities and, thus, improve renal perfusion and fil- tration rate. In fact, the renal response to therapy is condi- tioned largely by the relative influence on the kidney of both the decrease 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. However, this maneuver reduces renal blood flow and glomerular filtra- tion rate in animals and in humans. The evidence [3,17] that angiotensin-induced renal vasoconstriction, conse- quent to the reactive increase in renin release, entirely accounts for the renal vasoconstriction is unequivocal. There is now clear evidence  that when diuretics are employed as therapy, the reactive increase in plasma renin activity limits the decrease in blood pressure. On the basis of results of studies on the influence of restriction of sodium intake, it is reasonable to conclude that the reduc- tions in renal blood flow and filtration rate induced by a diuretic are also angiotensin-mediated.
Since activation of the renin-angiotensin system plays such a central role in limiting the response to restriction of sodium intake and diuretics, it is reasonable to suspect that the addition of beta-adrenergic blocking agents- many of which block renin release (to the extent that it is mediated by beta-adrenergic receptors in the juxtaglo- merular apparatus)-would reverse the impact of restric- tion of sodium intake and diuretics on the kidney [I 21. Un- fortunately, propranolol, the most widely studied and uti- lized beta-adrenergic blocking agent, induces renal vaso- constriction directly, apparently through its action on alpha-adrenergic receptors in the kidney [I 81. A propran- olol-induced reduction in renal blood flow, with parallel reductions in glomerular filtration rate, sodium retention, and ability to handle sodium loads, has also been well documented  in humans. It was thought that this effect might be due to a decline in cardiac output induced by the negative inotropic and chronotropic actions of beta block- ers on the heart; however, the renal response occurs with doses too small to influence cardiac output . Similar renal responses have been documented  for a wide variety of beta-adrenergic blocking agents, including ox- prenolol, pindolol, acebutolol, atenolol, and dichloroiso- proterenol.
Renal vasoconstriction, however, is not an inevitable outcome of all beta-adrenergic blockade. Nadolol, a long- acting, hydrophilic beta-adrenergic blocking agent, in-
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duces a dose-related increase in renal blood flow at doses exceeding those at which it reduces heart rate and, thus, cardiac output in humans . Further, nadolol does not induce antinatriuresis in the dog: indeed, it appears to in- crease sodium excretion (personal communication from K. Duchin).
What is the effect of the nonspecific vasodilators on the kidney? This general class includes hydralazine, minoxi- dil, diazoxide, sodium nitroprusside, and trimethaphan, which includes a potent nonspecific vasodilator compo- nent [13,14]. Although these agents produce a broad spectrum of renal responses, certain effects are common to all of them. For example, despite their range of direct actions on the renal blood supply, all of these agents in- duce sodium retention [13,14]; this result often is striking, and can be the limiting factor for therapeutic efficacy 1201. The mechanism of this effect has not yet been completely delineated, but it is clear that the systemic response, es- pecially the drop in blood pressure, plays an important role in such retention. For example, diazoxide is a potent renal vasodilator when infused into the renal artery; this vasodilation is accompanied by a striking natriuresis . When the agent is given intravenously, however, an equally striking antinatriuresis occurs-presumably be- cause of the decrease in blood pressure [6,17,22].
angiotensin II. Although calcium channel blockers can blunt adrenal aldosterone release, this does not entirely explain the acute natriuresis seen after the administration of nifedipine (Figure 1) . Several lines of evidence [I 7,31-371 suggest that intrarenal angiotensin II concen- trations may actually represent one determinant of renal- sodium handling, presumably through the control of tu- bular-glomerular feedback. One could speculate that the salutary response to calcium channel blockers may reflect their ability to reverse these intrarenal actions of angioten- sin II.
The impact of systemically administered nonspecific vasodilators on the renal blood supply and renal sodium handling varies widely from patient to patient-from a net increase to a net decrease in renal blood flow. However, antinatriuresis with sodium retention and, typically, a de- crease in glomerular filtration rate occurs with even the most potent direct renal vasodilators in this class-i.e., hydralazine, diazoxide, and minoxidil [13,14,20,23,24]. Thus, to date, the use of a nonspecific vasodilator for its vasodilatory effect on the kidney has not spared patients the negative renal influence of these agents.
Just as the beta blockers have different effects on the kidney, calcium channel blockers may also have a differ- ent impact. Although no direct comparisons of renal vas- cular responses have been made, data on potentially rele- vant systems do exist. These data indicate that differ- ences may be present-although their precise clinical rel- evance remains somewhat obscure. Zanchetti and Leonetti  recently compared the short-term natriuretic response to nifedipine with the response to verapamil. Dosages were adjusted to achieve identical decreases in blood pressure. Although normal subjects did not differ in their response to the two agents, the diuresis and natri- uresis induced by nifedipine in patients with essential hy- pertension were substantially greater than those induced by verapamil (Figure 2).
EFFECTS OF NEW AGENTS
The development of angiotensin converting enzyme inhibitors also represents a new approach to antihyper- tensive therapy and a new tool for examining the underly- ing mechanisms of hypertension . These agents have proven to be effective even in severe cases of hyperten- sion, such as those resistant to standard triple-drug ther- apy with a diuretic, hydralazine, and a beta-adrenergic blocking agent . Recent studies [2,6,39] suggest that agents in this class exert an especially beneficial action on the kidney. In patients with essential hypertension, the nonapeptide SQ 20881 induced a potentiated increase in renal blood flow  that exceeded by a factor of two the
Three new classes of agents have been developed that may have special implications for the kidney: calcium channel blocking agents, converting enzyme inhibitors, and dopamine analogues. The first study [I I] demonstrat- ing a short-term renal response to a calcium channel blocking agent used nifedipine and revealed a substantial increase in renal plasma flow, a well-maintained glomeru- lar filtration rate, and a brisk diuresis and natriuresis. Pa- tients with the lowest baseline renal plasma flow and glo- merular filtration rate, presumably reflecting fixed organic renal vascular changes, showed little response. These salutary responses to nifedipine have been amply con- firmed, as have such responses to other agents in this class [25-291.
In both human and animal studies, calcium channel blockers have been shown to act acutely as antagonists to the pressor, adrenal, and renal vascular responses to
Figure 7. HelatlonstJlp between Increases In plasma anglo- tensin II levels and changes in plasma aldosterone levels during angiotensin II infusion in patients with mild essential hypertension. Horizontal and vertical bars represent mean k SEM. Reprinted with permission from PO].
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Normotensives n = 10 Hypertensives n = 14
SBP 150 * (mm 40 p 1.005 Iso ** p
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Adams DF: Renal vascular response to interruption of the physiology and pharmacology. Baltimore: Baltimore Univer- renin-angiotensin system in normal man. Kidney Int 1977; 12: 285-293.
4. Hollenberg NK, Borucki LJ, Adams DF: The renal vasculature in early essential hypertension: evidence for a pathogenetic role. Medicine (Baltimore) 1978; 57: 167-178.
5. Hollenberg NK, Sandor T: Vasomotion of renal blood flow in essential hypertension: oscillations in xenon transit. Hyper- tension 1984; 6: 579-585.
6. Hollenberg NK, Swartz SL, Passan DR, Williams GH: Increased glomerular filtration rate after converting enzyme inhibition in essential hypertension. N Engl J Med 1979; 301: 9-12.
7. Hollenberg NK, Adams DF, McKinstry DN, Williams GH, Borucki LJ, Sullivan JM: Beta adrenoceptor blocking agents and the kidney: effect of nadolol and propranolol on the renal circula- tion. Br J Clin Pharmacol 1979; 7 (suppl): 219S-225s.
8. Gavras H, Ribierto AR, Gavras I, Brunner HR: Reciprocal rela- tion between renin dependency and sodium dependency in essential hypertension. N Engl J Med 1976; 295: 1278-l 283.
9. Gavras HR, Brunner HR, Turini GA, et al: Antihypertensive ef- fect of the oral angiotensin converting enzyme inhibitor SQ 14225 in man. N Engl J Med 1978; 298: 991-995.
10. Veterans Administration Cooperative Study Group on Antihy- pertensive Agents: Oxprenolol versus propranolol: a random- ized, double-blind multiclinic trial in hypertensive patients. Hypertension 1981; 3: 250-256.
11, Klutsch VK, Schmidt P, Grosswendt J: Der Einfluss von BAY a 1040 auf die Nierenfunktion des Hypertonikers. Arzneimit- telforschung 1972; 22: 377-380.
12. Koch-Wester J: Vasodilator drugs in the treatment of hyperten- sion Arch Intern Med 1974; 133: 1017-1027.
13. 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: MacMil!an Publishing Company, 1975; 705-726.
14. Page LB, Sidd JJ: Medical management of primary hyperten- sion. N Engl J Med 1972; 287: 960-967.
15. Page IH: The mosaic theory of arterial hypertension-its inter- pretation. Perspect Biol Med 1967; 10: 325-333.
16. Guyton AC, Coleman TF, Crowley AW, Scheel KW, Manning RD, Norman RA: Arterial pressure regulation: overriding dom- inance of the kidneys in long-term regulation and in hyperten- sion. Am J Med 1972; 52: 584-594.
17. Kimbrough HM Jr, Vaughan ED Jr, Carey RM, Ayers CR: Effect of intrarenal angiotensin II blockade on renal function in con- scious dogs. Circ Res 1977; 40: 174-178.
18. Carriere C: Effect of norepinephrine, isoproterenol, and adren- ergic blockers upon the intrarenal distribution of blood flow. Can J Physiol Pharmacol 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 hyperos- motic saline in hypertensive patients. Clin Sci 1972; 43: 385- 391.
20. Finnerty FA Jr: Relationship of extracellular fluid volume to the development of drug resistance in the hypertensive patient. Am Heart J 1971; 81: 563-565.
21. Greene JA Jr: Effects of diazoxide on renal function in the dog. Proc Sot Exp Biol Med 1967; 125: 375-379.
22. Freis ED: Effectiveness of nadolol vs. bendroflumethiazide alone and in combination in the treatment of hypertension. In: Hollenberg NK, ed. The haemodynamics of nadolol, Proceed- ings of the 2nd International Symposium. London: The Royal Society of Medicine, 1982; 51-58.
23. Onesti G: Renal pharmacodynamics of antihypertensive drugs: clinical applications. Am J Cardiol 1966; 17: 668-672.
24. Zins GR: Alterations in renal function during vasodilator therapy. In: Wesson LG, Fanelli GM, eds. Recent advances in renal
sity Park Press, 1974; 165-172. Olivari MT, Bartorelli C, Polese A, Fiorentini C, Morvezz P,
Guazzi MD: Treatment of hypertension with nifedipine, a cal- cium antagonistic agent. Circulation 1979; 59: 1056-1062.
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.
Yokoyama S, Kaburagi T: Clinical effects of intravenous nifedi- pine on renal function. J Cardiovasc Pharmacol 1983; 5: 67- 71.
Zanchetti A, Leonetti G: Natriuretic effect of calcium antago- nists J Cardiovasc Pharmacol 1985; 7 (suppl 4): 33-37.
Christensen CK, Pedersen OL, Mikkelsen E: Renal effects of acute calcium blockade with nifedipine in hypertensive pa- tients receiving beta-adrenoceptor-blocking drugs. Clin Phar- macol Ther 1982; 32: 572-576.
Marone C, Luisoli S, Bomio F, Beretta-Piccoli C, Bianchetti MG, Weidmann P: Body sodium-blood volume state, aldosterone, and cardiovascular responsiveness after calcium entry block- ade with nifedipine. Kidney Int 1985; 28: 658-665.
Redgrave JE, Rabinowe SL, Williams GH, Hollenberg NK: Cor- rection of abnormal renal blood flow response to angiotensin II by converting-enzyme inhibition in essential hypertensives. J Clin Invest 1985; 75: 1285-l 290.
Steven K: Effect of peritubular infusion of angiotensin II on rat proximal nephron function. Kidney Int 1974; 6: 73-80.
Mendelsohn FAO: Evidence for the local occurrence of angio- tensin II in rat kidney and its modulation by dietary sodium intake and converting enzyme blockade. Clin Science 1979; 57: 173-179.
Harris PJ, Young JA: Dose-dependent stimulation and inhibition of proximal tubular sodium reabsorption by angiotensin II in the rat kidney. Pflugers Arch 1977; 367: 295-297.
Levens NR, Peach MJ, Carey RM: Role of the intrarenal renin- angiotensin system in the control of renal function. Circ Res 1981; 48: 157-167.
Schnermann J, Briggs J: Function of the juxtaglomerular appa- ratus: local control of glomerular hemodynamics. In: Seldin DW, Giebisch G, eds. The kidney: physiology and pathophysi- ology. New York: Raven Press, 1985; 669-698.
Romero JC, Knox FG: Elements of the feedback control system responsible for escape from the sodium-retaining effects of mineralocorticoids. In: Seki K, Casley-Smith JR, eds. Recent advances in edema. Tokyo: Tokyo University Press, 1982; 169-l 82.
Hollenberg NK, Meggs LG, Williams GH, Katz J, Garnic JD, Harrington DP: Sodium intake and renal responses to capto- pril in normal man and essential hypertension. Kidney Int 1981; 20: 240-245.
Ondetti MA, Rubin B, Cushma DW: Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 1977; 196: 441-444.
Ackerman DM, Blumberg AL, McCafferty JP, et al: Potential usefulness of renal vasodilators in hypertension and renal dis- ease: SK&F 82526. Fed Proc 1983; 42: 186-I 90.
Davidov M, Mroczek W, Gavrilovich L, Finnerty F Jr: Long-term follow-up of aggressive medical therapy of accelerated hyper- tension with azotemia. Angiology 1975; 26: 396-407.
Pohl JEF, Thurston H, Swales JD: Hypertension with renal im- pairment: influence of intensive therapy. Q J Med 1974; 43: 569-581.
Woods JW, Blythe WB, Huffines WD: Management of malignant hypertension complicated by renal insufficiency. N Engl J Med 1974; 291: 1 O-l 4.
Dollery CT: Hypertension and new antihypertensive drugs: clini- cal perspectives. Fed Proc 1983; 42: 207-210.
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