Converting enzyme inhibition with captopril in patients with primary hyperaldosteronism The humoral and hemodynamic effects of converting enzyme inhibition with captopril are presented in two patients with primary hyperaldosteronism (PHA). In all, 20 patients with resistant hypertension were treated with the angiotensin converting enzyme inhibitor captopril. In 18 patients with essential or renovascular hypertension mean (±SEM) plasma renin activity (PRA) rose from 5.0 ± 1.4 to 35.3 ± 5.3 nglmllhr (P <0.001) and mean (±SEM) plasma aldosterone (PA) declined from 25.8 ± 2.9 to 15.1 ± 1.9 nglinl (P < 0.01) after captopril. In two patients with PHA the PRA was not stimulated by converting enzyme inhibition, although there was modest decline in PA and a temporary reduction in blood pressure. After surgical removal of aldosterone-producing adenomas, PRA responsed appropriately to captopril. These cases illustrate that a disease process can modify the response to a drug and demonstrate that, in patients with PHA, captopril does not stimulate PRA, induces only minor decrements in PA, and is relatively ineffective as an antihypertensive. John R. Luderer, M.D.,* Laurence M. Demers, Ph.D., Timothy S. Harrison, M.D., and Arthur H. Hayes, Jr., M.D. Hershey, Pa. Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, and Departments of Surgery and Pathology, The Milton S. Hershey Medical Center, The Pennsylvania State University Characteristics of primary hyperaldosteronism (PHA) include suppressed plasma renin activity (PRA) and inability to stimulate renin with various provocative maneuvers. The angiotensin I converting enzyme inhibitor captopril has been shown to induce marked increases Presented, in part, at The Endocrine Society Meetings, Washington, D.C., June 20, 1980. Received for publication July 31, 1981. Accepted for publication Oct. 15, 1981. Reprint requests to: Dr. John R. Luderer, Division of Clinical Pharmacology, The Milton S. Hershey Medical Center, Hershey, PA 17033. *Supported, in part, by a Faculty Development Award in Clinical Pharmacology from the Pharmaceutical Manufacturers Association Foundation. 0009-92361821030305+07500.7010 © in PRA in patients with essential and renovascular hypertension* 3' 4' 8 This increase can be attributed to both a baroreceptor-mediated response to the fall in blood pressure and to a decline in circulating angiotensin II, which normally exerts a negative feedback effect on renin release." We recently gave captopril to a group of 20 hypertensive patients. During the course of the study we identified two subjects whose PRA did not increase with converting enzyme inhibition; subsequent evaluation of the patients established a diagnosis of PHA. We present the humoral and hemodynamic effects of converting enzyme inhibition in two patients with PHA. Each was studied before and after extirpation of an aldosterone-producing adenoma. 1982 The C. V. Mosby Co. 305 306 Clin. Pharmacol. Ther. March 1982 Luderer et al. ESSENTIAL HYPERTENSION RENOVASCULAR HYPERTENSION PRIMARY HYPERALDOSTERON ISM 100.0 50.0 20.0 10.0 5.0 1.0 0.5 0.1 Fig. 1. The effect of captopril on PRA in various forms of hypertension. The symbols (o) on the left side of each column show the PRA before captopril and those on the right after captopril. The solid symbols under the PHA column represent patients 1 and 2 (a is) before surgery. The open symbols (o---o, D---E) represent the same patients after surgical removal of aldosterone-producing adenomas. The scale is logarithmic. All patients were randomized with respect to receiving captopril either before or after furosemide. ( ) Methods All study patients were referred to us because their blood pressures were poorly controlled on conventional therapy. They were enrolled in a protocol that was originally designed to assess the effect of short- (3 days) and long-term (14 days) furosemide pretreatment on the antihypertensive and humoral actions of captopril; the original protocol was not intended to screen for PHA. All antihypertensive drugs were discontinued 2 wk before the study. The patients were admitted to the hospital and maintained on a 100-mEq sodium and 60-mEq potassium diet. The patients were randomly assigned to one of three groups. After a 3-day placebo lead-in the first group (six patients) received furosemide (40 mg by mouth twice daily) followed by captopril The initial dose of captopril was 25 mg by mouth three times a day and was doubled every 48 hr until the patient's blood pressure was controlled (diastolic 90 mm Hg) or a dose . of 200 mg three times a day was reached. A second group (eight patients) had received the 40-mg dose of furosemide for 2 wk before hospitalization. The furosemide was continued, and after a 3-day placebo lead-in, captopril was added as in the first group. A third group (six patients) received no diuretic pretreatment and after the 3-day placebo period captopril was started exactly as above. In this group, 200 mg captopril three times a day alone was not effective in controlling blood pressure and furosemide was added. Supine PRA and plasma aldosterone (PA) and 24-hour urinary aldosterone (UA) were determined as described by us5 after 3 days on placebo, after furosemide or captopril alone, and after receiving a combination of captopril (at the maximum dose) and furosemide. PRA and PA levels were determined 90 min after captopril. Twenty-fourhour urinary catecholamine levels were normal in all of the patients. Renovascular hypertension was diagnosed by arteriographic findings and by lateralizing renal vein renins. The patients discussed in cases and 2 below were subsequently evaluated formally for PHA using the protocol of Weinberger et al.' Selective adrenal vein catheterization was performed by a femoral approach and adrenal venous sampling was done during adrenocorticotropic hormone administration (5 IU/hr in 500 ml 5% dextrose). Adrenal isotopic scanning with iodocholesterol was performed under dexamethasone suppression (0.5 mg by mouth every 6 hr). Scans were performed 3, 5, 7, and 9 days after the isotope. Statistical significance was determined by Student's paired t test. 1 Case reports Case 1. A 54-yr-old white woman with a 7-yr history of hypertension was referred to the Clinical Pharmacology Service because of failure to control her blood pressure on a combination of hydrochlorothiazide (100 mg/day), alpha-methyldopa (2000 mg/ day), and propranolol (320 mg/day). She complained of frequent headaches but denied a history of neuromuscular complaints, polyuria, or licorice ingestion. She had documented hypokalemia (3.0 to 3.3 mmol//) while on hydrochlorothiazide but the serum potassium concentration had not been determined before initiation of diuretic therapy. Two weeks after discontinuation of hydrochlorothiazide her serum potassium was 3.3 mmol//. Urinary catecholamines and a hypertensive intravenous pyelogram were reported "normal." Physical examination revealed a slightly Volume 31 Number 3 obese woman with a blood pressure of 180/110 and a pulse of 66. Bilateral arteriolar narrowing was observed by funduscope. The patient's chest was clear and her heart was normal. There were no abdominal bruits, striae, or peripheral edema. She was chosen at random to receive captopril for 8 days followed by furosemide in combination with captopril. Case 2. A 53-yr-old white man with a 6-yr history of hypertension was referred because of failure to control his blood pressure on a combination of hydrochlorothiazide (100 mg/day), prazosin (20 mg/ day), and propranolol (120 mg/day). He complained of nonspecific muscle weakness and leg cramps but denied polyuria or licorice ingestion. Serum potassium determinations were reported from 2.3 to 3.2 mmol// while on hydrochlorothiazide but the potassium level was not measured before the institution of diuretic therapy. Two weeks after discontinuation of hydrochlorothiazide, serum potassium was 3.3 mmol/ 1. A hypertensive intravenous pyelogram and urinary catecholamines levels were normal. Physical examination revealed a slightly obese white man with a blood pressure of 174/110 and a pulse of 64. Arteriolar narrowing was observed by funduscope. The remainder of the physical examination was unremarkable. The subject was placed, at random, on the captopril/furosemide protocol (furosemide for 3 days followed by captopril in combination with furosemide). Results The results of monitoring PRA in patients placed at random on the captopril/furosemide protocol are shown in Fig. 1. Except for those in the two isolated case studies all patients with essential hypertension and renovascular hypertension had a dramatic rise in PRA after captopril. This was seen immediately in those patients given captopril first, with only a slight enhancement after the furosemide that followed. In those patients receiving furosemide first a modest increase in PRA was noted, but 80% to 90% of the total increase occurred after the captopril was added to the treatment regimen. Grouped together the mean PRA (±SEM, n = 18) for those patients with renovascular and essential hypertension was 5.0 ± 1.4 ng/ ml/hr before and 35.3 -± 5.5 ng/ml/hr after captopril (P < 0.001). As shown in Fig. 1, in both patients in whom PHA was suspected, PRA was not elevated after captopril. In case 1, the patient's supine PRA was 0.13 ng/ml/hr during the placebo period and had not risen by the ninth day of captopril (200 mg by mouth three times a day). When furosemide was given with the captopril, Captopril in primary hyperaldosteronism 60 ESSENTIAL HYPERTENSION RENOVASCULAR HYPERTENSION 307 PRIMARY HYPERALDOSTERONISM 50 40 30 20 10 5 Fig. 2. The effect of captopril on PA in various forms of hypertension. The symbols (e) on the left side of each column show the PA before captopril and those on the right after captopril. The solid symbols under the primary aldosterone column represent patients 1 to) and 2 is) before surgery. The open symbols (o---o, ri---o) represent the same patients after surgical removal of aldosterone-producing adenomas. The scale is logarithmic. ( ( the PRA was still only 0.36 ng/ml/hr 3 days later. In case 2 the patient's supine PRA was 0.05 ng/ml/hr after 3 days on placebo. After 40 mg furosemide by mouth twice a day for 3 days, PRA was still only 0.06 ng/ml/hr. When 200 mg captopril by mouth three times a day was added, supine PRA remained at 0.1 ng/ml/hr. Thus, in both patients subsequently shown to have PHA, the combination of captopril and furosemide did not stimulate PRA. Fig. 2 shows the effect of captopril on PA. Results of the same order (not shown) were obtained for UA. In almost all of the patients there was a marked decline in both PA and UA in response to captopril. During the placebo period the patient in case 1 had a PA level of 53.3 ng/ml and a UA level of 41.7 ,ug/24 hr. On the ninth day of captopril therapy PA fell to 29.8 ng/ml and UA to 34 ,ug/24 hr. When furosemide was then given in combination with captopril, PA rose to 33.2 ng/ml, whereas UA was essentially unchanged at 33 ,ag/24 hr. The patient in case 2 had a PA level of 21.4 ng/ml and a UA level of 21.9 /I g/24 hr after 3 308 Luderer et al. OM. Pharmacol. Ther. March 1982 Table I. Blood pressure response to captopril Case Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 BP (mm Hg)* 182/115 172/112 169/109 159/107 160/110 164/108 162/103 173/113 168/109 164/107 154/102 154/104 140/90 142/96 129/90 130/84 139/93 Case 2 1 Treatment C (75 ml)t C (75 mg) C (150 mg) C (150 mg) C (300 mg) C (300 mg) C (600 mg) C (600 IT4) C (600 mg) C (600 mg) + C (600 mg) + C (600 mg) + P + F P + F BP (mm Hg) Treatment 174/107 176/107 184/107 165/110 168/103 164/98 151/90 151/95 148/93 153/95 156/98 151/92 149/95 147/90 145/87 159/98 150/95 C (75 mg) + F C (75 mg) + F C (150 mg) + F C(150 mg) + F C (300 mg) + F C (300 mg) + F C (600 mg) + F C (600 mg) + F C (600 mg) + F P + F P + F P =- placebo; C = captopril; F = furosemide. *Blood pressure was measured by cuff every 2 hr while the patient was awake. The values reported here represent the mean of nine determinations. -1 Represents the total daily dose that was given in three equal divided doses at 6 A.M. and 2 and 10 P.M. #Furosemide was given at a dose of 40 mg at 6 A.M. and 4 P.M. days on placebo. After furosemide for three days PA rose to 28.2 ng/ml and the UA to 27.4 g124 hr. Captopril was then started and on the ninth day of captopril therapy PA fell to 25.8 ng/ml and UA to 19.6 in/24 hr. As shown in Fig. 2, neither the basal PA results nor the response of PA to captopril served to distinguish the patients with PHA from those with essential or renovascular hypertension. In contrast, the response of PRA to captopril, at least in this group of patients, was sufficient to distinguish the patients with PHA (Fig. 1). It should be emphasized, however, that our subject group did not include a significant number of those with low renin activity. Table I outlines the blood pressure response to captopril in each of these case studies. In case 1, the patient's blood pressure was 169/109 (mean of nine determinations) on the third day of placebo and there was no fall in blood pressure associated with the first dose of captopril. Dose was then doubled every 48 hr, and on the ninth day blood pressure had dropped to only 154/104; with the addition of furosemide pressure fell to 129/90. After captopril was stopped and placebo reinstituted, the patient's blood pressure rose over the next 48 hr to 139/93. There was a similar slow rise in pressure back toward control in the other patients after abrupt discontinuation of captopril. In the patient discussed in case 1 the addition of furosemide resulted in a 1.2-kg loss in body weight by the third day on furosemide (day 15 in Table I). Despite what was seemingly a good blood pressure response to the combination of captopril and furosemide, when seen 2 wk after discharge from the hospital the patient's blood pressure was poorly controlled (165/110). This elevation in blood pressure was not associated with weight gain and was not improved by increasing the dose of furosemide. Compliance with the prescribed captopril regimen was supported by pill counts and the fact that the patient developed a typical captopril-induced skin rash. Table I also shows the blood pressure responses in case 2. The patient was initially treated with furosemide alone (40 mg by mouth twice daily) for 3 days, resulting in a fall in blood pressure from 184/107 to 164/98. Captopril was then started and he exhibited a minimal response to the first dose with a maximum decrease of 6 mm Hg decline in systolic pres- Volume 31 Number 3 Captopril in primary hyperaldosteronism BEFORE AFTER SURGERY SURGERY CASE #10-111 CASE #2 50.0 0-0 -11 20.0 NORMALS 100 309 10.0 50 20 10 BEFORE AFTER SALINE SALINE (upright) (supine) 0.1 BEFORE FUROSEMIDE (upright) AFTER FUROSEMIDE (upright) Fig. 3. Responses of PA (left panel) and plasma renin (right panel) to suppressive and stimulating maneuvers. The solid symbols represent patients 1 e) and 2 (. e) before surgery. The open symbols (o---o, o---o) represent the same patients after surgical removal of aldosteroneproducing adenomas. Normals for posture and salt intake are depicted as mean (open bars) ± 95% confidence limit. The cross bar represents the mean value. ( sure that occurred approximately 2 hr after the first dose. After 9 days on a combination of furosemide and captopril, however, the blood pressure fell ,to 145/87. The patient was then discharged from the hospital and when seen 2 wk later his pressure had risen to 170/100 and over the next month rose to 200/106. Compliance with the captopril regimen was supported by pill counts. In both of these patients it is possible that prolonged hospitalization and controlled sodium intake resulted in antihypertensive action independent of medication. Failure of PRA to rise after converting enzyme inhibition in both of these patients suggested the diagnosis of PHA and for this reason both patients were formally evaluated for this disorder by the protocol of Weinberger et al.'2 Fig. 3 shows the response of PA to saline in these two patients and demonstrates the inadequate suppression after a 4-hr intravenous infusion of 0.9% NaC1 (500 ml/hr). Fig. 3 also shows the failure of a 10-mEq sodium diet, upright posture, and furosemide (40 mg by mouth three times a day) to stimulate PRA in these subjects. Iodocholesterol scanning, selective adrenal vein sampling, and computerized axial tomography demonstrated adrenal adenomas in both patients. At surgery, the patient in case 1 had a 1.0-cm adenoma of the left adrenal gland with a surrounding zone of hyperplasia and a single microadenoma on sectioning; the patient in case 2 had a solitary adenoma of the right adrenal. Four to six months after surgery the patients were examined using the original protocols. Fig. 1 shows that postoperative PRA was stimulated appropriately with captopril in both patients. Fig. 3 illustrates the normal suppression of PA levels after intravenous saline solution in these two patients subsequent to removal of the adenomas and the normal PRA stimulation after furosemide. Six months after surgery patient 1 was normotensive. In case 2 the patient's blood pressure was adequately controlled (140/90) by a combination of furosemide (40 mg twice daily) and captopril (25 mg three times a day), whereas preoperatively blood pressure was not controlled (170/105) on a much higher dose of Clin. Pharmacol. Ther. March 1982 310 Luderer et al. captopril (200 mg three times a day) and the same dose of furosemide. Discussion Captopril stimulates PRA by at least two mechanisms: first, by a reduction in blood pressure that can stimulate renin release by activation of the baroreceptor cells of the afferent arterioles in the kidney and, second, by converting enzyme inhibition that will usually decrease circulating levels of angiotensin II and thereby interrupt a mechanism for negative feedback control of renin release." The latter seems to be, quantitatively, the more important stimulus since captopril increases renin activity even in the absence of a change in blood pressure.6 In addition, the increase in PRA in this and other studies" 4' 7 appears much greater than would be expected from blood pressure reduction alone. Finally, the angiotensin II derivative desasp'-ileu8-angiotensin II will block captoprilinduced increases in PRA without affecting blood pressure .8 After the surgical removal of aldosteroneproducing adenomas in our patients their PRA was stimulated with captopril. Although this could be due, in part, to lowering of aldosterone levels, it could also be accounted for by the fact that after surgery the baseline PRA (and by inference angiotensin II) was higher (it has been demonstrated by some investigators that the higher the baseline PRA the greater its susceptibility to stimulation by captopri1.3 Thus, it is not totally surprising that the renin response to interruption of angiotensin II feedback was quantitatively less when the patient's angiotensin II level was itself very low and was quantitatively greater when the patient's angiotensin II level was higher. Although PHA is an uncommon cause of hypertension, its early recognition is important since surgical intervention is often curative in patients with single adenomas. In the past its diagnosis has depended heavily on maneuvers to stimulate PRA. Such techniques have included dietary sodium restriction, upright posture, and challenge with furosemide. Our data suggest that inhibition of the converting enzyme could provide a useful pharmacologic technique for screening and diagnostic testing. It should be emphasized that this study was not designed to screen for PHA and of the patients who happened to be studied there was not a sufficient number with low renin essential hypertension to permit a comparison to be drawn regarding the humoral responses to captopril in this group and those with PHA. Although it is possible that assessment of the effect of captopril on PRA might be of some diagnostic value in identifying patients with PHA, this would require further study, particularly in patients with forms of low renin hypertension not due to aldosteronism. Others have given captopril to patients with PHA.2' 9 Our results agree with theirscaptopril is a relatively ineffective antihypertensive in patients with this form of hypertension. These earlier studies did not, however, report the response of PRA to captopril for the patients individually, nor were comparative data presented for any patient after surgical correction of the hyperaldosteronism. It is interesting that both of our patients with PHA seemed to experience a definite antihypertensive effect from the combination of captopril and furosemide. This response was not maintained during outpatient therapy, however, despite good evidence of compliance with the prescribed regimen. The prolonged hospitalization and controlled sodium intake may have contributed to the lowering of blood pressure in these patients. Other studies have reported the development of cap- topril resistance after a good initial response. Tarazi et al. '° have studied this phenomenon in a preliminary fashion and have demonstrated that the late resistance to captopril is not related to volume expansion as is usually found when patients develop resistance to antihypertensive medications. Beyond this observation little is known concerning the mechanism of the phenomenon. The patients with PHA studied here exhibited a minimal response to the first dose of captopril and as has been pointed out by Laragh ,9 this suggests a poor long-term response. References Brunner HR, Gavras H, Waeber B, Kershaw GR, Turini GA, Vukovich RA, McKinstry DN, Gavras I: Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med 90:19-23, 1979. Brunner HR, Gavras H, Waeber B, Textor Sc, Volume 31 Number 3 Turini GA, Wauters JP: Clinical use of an orally acting converting enzyme inhibitor captopril. Hypertension 2:558-566, 1980. Brunner FIR, Gavras H, Waeber B, Turine GA, McKinstry DN, Vukovich RA, Gavras I: Orally active angiotensin-converting enzyme inhibitor (SQ 14,225) as a treatment for essential hypertension. Br J Pharmacol 7(suppl. 2):205s211s, 1979. Case DB, Atlas SA, Laragh JH, Sealey JE, Sullivan PA, McKinstry DN: Clinical experience with blockade of the renin-angiotensin aldosterone system by an oral converting enzyme inhibitor (SQ 14,225) in hypertensive patients. Prog Cardiovasc Dis 21:195-206, 1978. Demers LM, Sampson EJ, Hayes AH: Plasma renin activity, plasma aldosterone and urinary aldosteronea normal range study by radioimmunoassay. Clin Biochem 9(5):243-246, 1976. Ferguson RK, Turini GA, Brunner HR, Gavras H, McKinstry DN: A specific orally active inhibitor of angiotensin-converting enzyme in man. Lancet 1:775-778, 1977. Gavras H, Brunner HR, Turine G, Dershaw GR, Tifft CP, Cuttelod S, Gavras I, Vukovich RA, Captopril in primary hyperaldosteronism 311 McKinstry DN: Antihypertensive effect of the oral angiotensin converting enzyme inhibitor SQ 14225 in man. N Engl J Med 298:991-995, 1978. Kono T, Ikeda F, Oseko F, Imura H, Endo J: Suppression of captopril-induced increase in plasma renin activity by des-Asp'-,Ileu8-angiotensin II in man. J Clin Endocrinol Metab 52:354-358, 1981. Laragh JH, Case DB, Atlas SA, Sealy JE: Captopril compared with other antirenin system agents in hypertensive patients: Its triphasic effects on blood pressure and its use to identify and treat the renin factor. Hypertension 2:586593, 1980. Tarazi RC, Bravo EL, Fouad FM, Omvik P, Cody RJ: Hemodynamic and volume changes associated with captopril. Hypertension 2:576585, 1980. Vander AJ, Geelhold GW: Inhibition of renin secretion by angiotensin II. Proc Soc Exp Biol Med 120:399-403, 1965. Weinberger MH, Grim CE, Hollifield VW, et al: Primary hyperaldosteronism. Ann Intern Med 90:386-395, 1979.