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Enalapril in Treatment of Hypertension with Renal Artery Stenosis
Enalapril in Treatment of Hypertension with Renal Artery Stenosis Changes in Blood Pressure, Renin, Angiotensin I and II, Renal Function, and Body Composition
G. P. HODSMAN, M.R.C.P.
J. J. BROWN, F.R.S.E., F.R.C.P. A. D. B. A.
M. M. CUMMING, R.G.N. L. DAVIES, F.R.C.P. W. EAST, Ph.D. F. LEVER, F.R.S.E., F.R.C.P. J. J. MORTON, Ph.D. G. D. MURRAY, Ph.D. J. I. S. ROBERTSON, F.R.S.E., F.R.C.P. Glasgow, United Kingdom
From the Medical Research Council Blood Pressure Unit, and the University Department of Medicine, Western Infirmary; the Scottish Universities' Research and Reactor Centre, East Kilbride; and the Department of Statistics, University of Glasgow, Glasgow, United Kingdom. Requests for reprints should be addressed to J.I.S. Robertson, MRC Blood Pressure Unit, Western Infirmary, Glasgow, G11 6NT, United Kingdom.
52
August 20, 1984
The converting enzyme inhibitor enalapril, in single daily doses of 10 to 40 mg, was given to 20 hypertensive patients with renal artery stenosis. The decrease in blood pressure six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II, and to the concurrent decrease in angiotensin II. Blood pressure decreased further with continued treatment; the long-term decrease was not significantly related to pretreatment plasma renin or angiotensin II levels. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low, and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, decreased further. The increase in active renin during long-term treatment was proportionately greater than the increase in angiotensin I; this probably reflects the diminution in renin substrate that occurs with converting enzyme inhibition. Long-term enalapril treatment increased renin secretion by more than 10-fold, and renal venous and peripheral plasma renin concentration by more than 20-fold; however, the mean renal venous renin ratio was not changed. Enalapril caused a reduction in effective renal plasma flow via the affected kidney but a marked and consistent increase on the contralateral side, where renal vascular resistance decreased. The overall increase in effective renal plasma flow was significantly related to the decrease in angiotensin II. Overall glomerular filtration rate was lowered, and serum creatinine and urea increased. Enalapril alone caused a longterm reduction in exchangeable sodium, with slight but distinct increases in serum potassium. In five patients with bilateral renal artery lesions, enalapril given alone for three months did not cause renal function to deteriorate. Enalapril was well tolerated and provided effective long-term control of hypertension; only two of the 20 patients studied required concomitant diuretic treatment. We have previously reported on [1 ,2] the use of the orally active converting en~yme inhibitor captopril in the preoperative treatment of hypertension associated with unilateral renal artery stenosis. Long-term captopril therapy effectively controlled hypertension in the majority of such patients. Moreover, it showed promise as a predictor of the blood pressure response to surgery; this latter aspect has since been confirmed [3]. We have also observed that the administration of oral captopril in a dose of 150 mg three times daily resulted in sustained suppression of peripheral plasma angiotensin II concentration throughout 24 hours [4]; however, the efficacy, in this respect, of the lower doses of captopril currently rec-
The American Journal of Medicine
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
ommended [5] remains to be established. We present herein data on the long-term use of oral enalapril, given in a single daily dose, in 20 patients with hypertension and renal artery stenosis. Some aspects of this work have already been reported [6,7].
500
Enalapril
400
PATIENTS AND METHODS
All patients gave informed consent to the study, which was approved by the hospital's ethical supervisory committee. Two distinct study protocols were followed, in two separate groups. Group 1 consisted of 10 patients with unilateral renal artery stenosis and good overall renal function. All previous antihypertensive therapy was discontinued so that detailed measurement of blood pressure, serum and body electrolytes, and components of the renin-angiotensin system could be made during the administration of a placebo and then during long-term enalapril therapy. Group 2 comprised 10 patients with unilateral or bilateral renal artery disease in whom severe or resistant hypertension necessitated the continuation of previous antihypertensive therapy up to the time that enalapril was introduced. Group 1. Of these 10 patients (aged 37 to 56 years; two women), nine had unilateral renal artery stenosis, and one had unilateral occlusion. On renal arteriography, nine had roentgenologic evidence of atheromatous stenosis and one of fibromuscular hyperplasia. Isotope renography [8) showed reduced renal plasma flow on the affected side in all patients (Figure 1). Bilateral renal vein renin measurements [9) were also performed in all but one patient, a man with unilateral renal artery occlusion, and showed higher values on the stenotic side. In seven patients, additional divided ureteric catheter studies were performed [1 OJ that confirmed the diagnosis; these studies were not performed in the patient with renal artery occlusion on arteriography, and the procedure was technically unsatisfactory in two others. All patients had normal serum electrolyte values and normal or near-normal overall renal function (mean serum creatinine 103 ± 8 SEM JLmol/liter). Seven of the 10 had previously had poor blood pressure control with the combination of a beta blocker and diuretic, together with either hydralazine (three patients), prazosin (one patient), minoxidil (one patient), or methyldopa (one patient). One patient had received a diuretic alone with poor response, and two patients had not received any previous antihypertensive therapy. Three patients had proteinuria of 0.3 to 1.3 g per 24 hours. Mean outpatient blood pressure during previous treatment was 183/109 ± 10/3 (SEM) mm Hg. All treatment was stopped at least 14 days before enalapril therapy was started in all but one subject who received prazosin alone [11] until two days before enalapril was given. The patients were admitted to the hospital and ate a normal ward diet; previous studies have shown that in these circumstances, plasma renin, angiotensin II, and aldosterone values are similar to those obtained during strictly controlled sodium and potassium intake [12]. A matching placebo was given at 10 A.M. each day for five days before the active drug was administered; thereafter, enalapril was given at 10 A.M. every day. Two patients received a placebo for only two days before the administration of enalapril was begun because of se-
Untreated
ERPF
ml/min 300
200
100 50
I~I
Stenotic sJde
Mean ± SEM
Figure 1. Effective renal plasma flow (ERPF; means ± SEM) via the post-stenotic and unaffected kidneys in Group 1 patients before and at the third month of enalapril therapy.
verely elevated blood pressure. The patients began a regimen of 10 mg enalapril daily, which was continued for each of the six days of inpatient stay. After discharge, the enalapril dose was adjusted in all 10 patients until supine and erect blood pressure measurements were below 140 mm Hg systolic and 90 mm Hg diastolic (phase V) four hours after the morning dose was given, or until a maximal dose of 40 mg daily was reached. No drugs other than enalapril were given in this study. After three months of treatment with enalapril, the patients were readmitted and studied under circumstances identical to those at the start of therapy. Peripheral venous blood was taken for measurement of plasma active renin concentration [9) (normal range 10 to 50 mU/Iiter), blood angiotensin I [13] (normal range 3 to 18 pmol/ liter), plasma aldosterone [14) (normal range less than 500 pmol/liter; less than 18 ng/dl), plasma converting enzyme activity, [15] and plasma angiotensin II [16) (normal range 5 to 35 pmol/liter) after 30 minutes of recumbency, before the first dose of enalapril was given, and six and 24 hours later. Supine and erect pulse rate and blood pressure readings (after two minutes standing) were recorded after blood sampling by the same observer (G.P.H.). The Hawksley random-zero sphygmomanometer [17) was employed, and phase V was taken as diastolic. These measurements were repeated under identical conditions after six days and after 12 weeks of treatment. Measurements were made of exchangeable sodium [18) and total body potassium [19) before and at the
August 20, 1984
The American Journal of Medicine
53
CONVERTING ENZVME INHIBITION-HODSMAN ET AL
Placebo
~
160 .
BP mmHg
,00 140
ACE )JMOI/ml/h
1.0 0.5
120 100 80
"~ 0
All
pg/ml
~j 25 20 15 10
5 AI pg/ml
.. 200 300 100
~
0
Active renin )JU/ml
, ~ 750 500 250
1~ j 0
AI do. ng/dl
1st day
6th day
3 months
~ 0. 0- o·· EnalaPrll
~• ..
•
I
1""'
•
•
•
~!..::_!
.---~
..
~!··
0·
___.--I . ~----~
I
I
Figure 2. Patients of Group 1. Measurements made six hours after dosing on the final day of placebo therapy, on the first day of enalapril therapy, on the sixth day of enalapril therapy, and at the third month of enalapril therapy. BP = blood pressure; ACE = plasma converting enzyme activity; AI = blood angiotensin I concentration; All = plasma angiotensin II concentration; A/do. = plasma aldosterone concentration. Statistical comparisons with placebo values. **=p
<0.01.
third month of enalapril treatment. Creatinine clearances were measured using 24-hour urine collections during the initial placebo phase and again at the third month of enalapril treatment alone. Effective renal plasma flow was measured separately [8] for the two kidneys before treatment and again during longterm enalapril therapy, except in one man with unilateral renal artery occlusion initially, in whom this test was not repeated. The investigation was carried out at the third month of enalapril therapy in seven of the remaining nine patients; this was not possible in two others in whom the repeated investigations were made at 20 and 24 months, respectively. Renal vascular resistance was calculated from the renal blood flow and mean systemic arterial pressure. The renal venous renin measurement was repeated at the third month of enalapril treatment in eight of the 10 patients. Net renin secretion rates for single kidneys were calculated from the effective renal plasma flow and the venoarterial difference in plasma renin concentration across the kidney. Group 2. These 10 patients (aged 15 to 61 years; five female) were more seriously ill and therefore unsuitable for study according to the foregoing protocol. On arteriography, five had unilateral renal artery occlusion. Five had arteria-
54
August 20, 1984
The American Journal of Medicine
graphic evidence of bilateral renal artery disease. Eight had very high blood pressure levels (four were in the malignant phase with bilateral retinal hemorrhages, exudates, and papilledema). One had cardiac failure and recent hypertensive encephalopathy. Three had overall renal impairment (mean ± SEM serum creatinine for the whole group was 132 ± 17 JLmol/liter). Four had proteinuria of 0.7 to 4.2 g per 24 hours. Preceding therapy in the patients of Group 2 included various combinations of diuretics, beta-blocking agents, prazosin, hydralazine, and nifedipine. All were studied as inpatients initially and were readmitted for assessment three months later. A supine blood pressure reading immediately before enalapril was introduced was 190/104 ± 15/5 (SEM) mm Hg. Enalapril was given in a starting dose of 10 mg and increased to a maximum of 40 mg daily, with lower dosage in those with renal impairment. Over 12 weeks, therapy was adjusted, and other drugs were withdrawn whenever possible. Blood pressure was measured as for the patients in Group 1. · The statistical comparisons are based on paired t tests, with biochemical measurements transformed to a logarithmic scale. The correlation coefficients quoted are product-moment correlations, again with biochemical measurements analyzed on a logarithmic scale. Mean arterial pressure (diastolic plus one-third pulse pressure) was taken for correlations involving blood pressure. RESULTS
Group 1. At three months, six patients were receiving 10 mg of enalapril daily, one was receiving 20 mg, and three were receiving 40 mg. In Figure 2, blood pressure and various biochemical measurements obtained six hours after the daily dose of enalapril on the first and sixth days of therapy, and at three months, are compared with those obtained on the final day of placebo therapy at the comparable time after dosing. Six hours after the initial dose of enalapril, there were marked decreases in plasma converting enzyme activity and in angiotensin II, with converse increases in blood levels of angiotensin I and in plasma active renin concentration. The small decrease in mean plasma aldosterone was not significant. A highly significant reduction in blood pressure accompanied the decrease in plasma angiotensin II, and these changes were significantly correlated(r = 0.67; p <0.05); the decrease in blood pressure at six hours also correlated with the plasma concentrations (before enalapril therapy) of active renin (r = 0.76; p <0.05) and angiotensin II (r = 0.70; p <0.05). With continued enalapril treatment, suppression of plasma converting enzyme activity and angiotensin II, similar to that observed on the first day, was seen at six days and at three months, six hours after dosing. Active renin concentration increased progressively from the first to the sixth day and from the sixth day to the third month of treatment. The mean blood concentration of angiotensin I also increased further from the first to the sixth day of enalapril treatment, but there was no further increase
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
3 months enalaprll
Placebo 160 180 140 120 100 80
ACE
)JMOI/ml/h
1.5~
1.0 0.5
0
AI I
pg/ml
AI
pg/ml
29
30 20 15 10 5 300 200 100 0
Active renin )JU/ml
~
~
from last dose
~
24hr
tto
! ...... ......
...... ......
I. . . ......
tt
0
3 months
180 160
BP mmHg
~··
140
120 100
......... ~'!-..._1·
+
I
p<0,001
~
I
----!--!
·---- tt ~
500
250 0
... I
16th day
6hr
80
woo~ 750
Enalapril
Placebo
I .......
,"'"'
..... , tt
Figure 3. Patients of Group 1. Comparison of values obtained after three months of continuous enalapril therapy alone with those obtained on the final day of placebo therapy. Measurements during enalapril therapy were determined 24 hours and six hours after the preceding dose. Daggers show comparisons with values obtained during placebo therapy: t=p <0.05; tt=p <0.01. Asterisks show comparisons with 24-hour values: *=p <0.05; **=p <0.01. Other abbreviations as for Figure 1.
thereafter. The slight decrease in mean plasma aldosterone remained insignificant. Blood pressure remained controlled at six days and at three months. However, during long-term treatment, the decrease in blood pressure was less closely related than on the first day to either the pretreatment plasma renin or angiotensin II concentrations or to the long-term decrease in plasma angiotensin II (respective correlation coefficients 0.44, 0.42 and 0.56, none significant). In Figure 3, measurements made on the last day of placebo therapy are compared with those at the third month of enalapril treatment, 24 hours after the preceding dose and again six hours after the morning dose of drug. At the third month of active treatment, continued enalapril effect was evident 24 hours after the last dose of the drug, with a marked increase in active renin and angiotensin I, and a converse reduction of converting enzyme activity and angiotensin II. Blood pressure also remained significantly reduced 24 hours after dosing in comparison with pretreatment values. Nevertheless, following the morning dose of enalapril at the third month, significant further reductions in plasma converting enzyme activity and angio-
t
p
Heart rate/ min
100 90
~
80
70
Figure 4. Patients of Group 1. Comparison of supine (open columns) and erect (solid columns) blood pressure levels and pulse rate before and during enalapril therapy. Means (±SEM) of measurements made two, six, and 24 hours after dosing.
tensin II occurred, wherever mean values for active renin and angiotensin I increased. The small additional lowering of arterial pressure six hours after dosing was not statistically significant. Figure 4 shows systolic and diastolic blood pressures and heart rates, with the patients lying and standing, during placebo therapy, and at the sixth day and third month of enalapril treatment. Values are means of measurements made two, six, and 24 hours after dosing. A significant decrease in blood pressure had occurred by the sixth day of enalapril therapy, and a further highly significant decrease by three months without a marked postural component or change in mean heart rate. Good blood pressure control was maintained after the patient's discharge from the ward (seated clinic values 142/82 ± 6/3 mm Hg four hours after dosing). Creatinine clearance decreased by the third month from an initial mean (±SEM) of 105 ± 12 ml per minute to 88 ± 8 (p <0.02). This change was reflected in a significant increase in both serum creatinine and urea (Table I). The increase in serum creatinine was related to the decrease in arterial pressure (r = -0.68; p <0.05). Renal plasma flow changed in different directions in the affected and unaffected kidneys (Figure 1). On the side supplied by the narrowed renal artery, enalapril treatment was associated with a significant reduction in effective renal plasma flow, from a mean of 162 ± 41 (SEM) ml per
August 20, 1984
The American Journal of Medicine
55
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
TABLE I
Measurements (means ± SEM) in Patients after Six Days of Enalapril Therapy and after Three Months of Enalapril Therapy Alone Enalapril Serum Sodium (mmol/liter) Potassium (mmol/liter) Creatinine (ttmol/liter) Urea (mmollliter)
Placebo 140.8 ± 3.8 ± 103 ± 5.1 ±
0.7 0.10 8 0.4
Six Days 140.6 ± 0.5 4.0 ± 0.08
117 ± 9 5.2 ± 0.4
Three Months 140.4 ± 4.3 ± 127 ± 6.2 ±
0.7 0.07** 10*** 0.5*
*p <0.05, **p <0.01' ***p <0.001.
minute to 102 ± 41 (p <0.05). In one man, with a previously tightly stenosed artery supplying a shrunken kidney, renography indicated that renal circulation to the affected side had ceased by the third month; arteriography confirmed occlusion of the diseased renal artery. This patient's overall renal function had not deteriorated seriously, the increase in serum creatinine over three months, from 118 to 127 J.Lmol/liter, being less than the average for Group 1 at that time. In another patient, renal plasma flow was reduced from 103 ml per minute on the affected side before treatment to 19 ml per minute after three months of treatment; serum creatinine had increased conCO!'Jlitantly from 145 to 184 J.Lmol/liter. Further renography at 12 months showed that circulation to the affected kidney had ceased, serum creatinine then being 199 J.Lmol/liter. Renal artery occlusion was detected by renography in two other patients, respectively, at 20 and 24 months of enalapril therapy. In the first of these, serum creatinine was unchanged at 79 J.Lmol/liter. In the second, it had increased from 76 to 130 J.LmOI/Iiter. Thus, renal artery occlusion occurred in four of nine patients at various times up to 24 months of therapy. In contrast, plasma flow was consistently increased via the contralateral, unaffected kidney during enalapril treatment, from an initial mean of 298 ± 21 ml per minute to 437 ± 48 (p <0.01) (Figure 1). Overall effective renal plasma flow therefore increased, and the percentage increase was significantly related to the concurrent decrease in plasma angiotensin II (r = -0.66; p <0.05). The decrease in glomerular filtration rate also correlated inversely with the increase in total effective renal plasma flow (r = -0.83; p <0.05). Calculated renal vascular resistance thus was reduced in the contralateral kidney by enalapril, from 90,000 ± 14,600 (SEM) dynes • second • em - 5 to 46,500 ± 6,600 (p <0.01 ). Renal vascular resistance could not be computed on the affected side, as we had no measure of renal arterial pressure distal to the stenosis. Before enalapril therapy, renal venous plasma renin concentration was higher on the affected side than on the contralateral side in every patient (respective means 82.4 ± 22.1 versus 52.0 ± 11.3 mU/Iiter). Treatment with
56
August 20, 1984
The American Journal of Medicine
enalapril for three months increased these values greatly on both sides to respective means of 1,906 ± 476 and 1,209 ± 367 mU/Iiter. Although the average renal venous renin ratio increased during enalapril therapy from 1.61:1 to 1.88:1, the change was inconsistent and not statistically significant. Both before and during enalapril treatment, the affected kidney was solely responsible for renin secretion, the renin value being consistently and significantly higher in renal venous plasma than in peripheral venous, and hence in arterial, plasma. By contrast, renin secretion from the unaffected kidney was suppressed both before and during enalapril treatment, with no significant difference in renin concentration in peripheral venous and in renal venous plasma on that side. The renin secretion rate was increased on average more than 10-fold by long-term enalapril therapy from 431 ± 138 to 4,330 ± 2,124 J.LU per minute (p <0.02). However, as shown by the measurements of renal venous renin concentration, the long plasma half-life of renin, combined with the limited ability of the contralateral kidney to extract renin from the circulation, meant that, despite the very large increases in circulating renin concentration, the renal venous renin ratio remained little changed. Serum potassium increased significantly, but in no patient was this marked (Table 1). There was no change in serum sodium. There were no measurable long-term changes in total body potassium. Total exchangeable sodium, however, was reduced during therapy in nine patients and unchanged in the 1Oth, falling from a mean of 101 percent to 96 percent of predicted normal values. The mean reduction was 140 mmol and was highly significant (p <0.001) (Figure 5). The decrease in exchangeable sodium was not significantly correlated with the increase in serum creatinine concentration. Group 2. Supine and erect blood pressure level, during previous antihypertensive treatment and immediately before enalapril was given, were 190/104 ± 15/5 mm Hg and 179/1 08 ± 11/4 mm Hg, respectively (Figure 6). After three months, four patients were receiving 10 mg, three patients 20 mg, and three patients 40 mg of enalapril daily. The blood pressures of seven patients were well controlled with enalapril alone. Three required additional
CONVERTING ENZVME INHIBITION-HODSMAN ET AL
Placebo 3500 NaE mMol 3000
2500
2000
Previous therapy
Enalapr!l
~hs
~
~ ~ ::st1·
200
Enalapr!l 3 months
180 BP mmHg 140 120 100
~
80
t
p<0.001 Figure 5. Exchangeable sodium (NaE) in patients of Group 1 before and at the third month of enalapril therapy.
I
t
p < 0.01 Serum creatinine
132
:!:
17
133
:!:
23
)JMOI/1
therapy. In one patient with overall renal impairment, furosemide (500 mg daily) together with atenolol (50 mg daily) was continued for control of symptomatic tachycardia. One patient continued to receive chlorthalidone (25 mg daily), and also atenolol (1 00 mg daily) because of angina. One patient needed atenolol alone (50 mg daily) for control of symptomatic tachycardia. In this group of 10 patients, after three months of enalapril therapy, supine and erect blood pressure levels had fallen to 142/84 ± 5/8 mm Hg and 129/85 ± 7/5 mm Hg (p <0.01 ), respectively (Figure 6). Corresponding seated measurements in the outpatient clinic were 150/87 ± 5/3 mm Hg four hours after dosing. There were no changes in mean serum sodium or potassium and no deterioration in mean or individual overall renal function (serum creatinine 132 ± 17 J.t-mol/liter during previous therapy, 133 ± 23 J.t-mol/liter after three months of enalapril therapy). In particular, renal function did not deteriorate in the five patients with bilateral renal artery lesions. In thest;l, none of whom received concurrent diuretic therapy, the blood pressure level fell from 204/110 ± 2117 mm Hg to 154/88 ± 2/3 mm Hg by the third month, whereas serum creatinine was unchanged (142 ± 34 versus 145 ± 35 J.t-mol/liter). Side-Effects. The drug was well tolerated by all 20 patients, and problems were minor. In one· man, previously impaired sexual function improved. In four patients (one also receiving a large dose of loop diuretic), symptomatic tachycardia developed in the supine and standing positions; in two cases, the tachycardia resolved slowly and spontaneously without additional therapy, but in two other
Figure 6. Patients of Group 2. Comparison of supine (open columns) and erect (solid columns) blood pressure levels and of serum creatinine during previous therapy and at third month of enalapril therapy. Means ± SEM shown.
patients, both in Group 2, the addition of a beta blocker was required. In one patient receiving enalapril alone, Raynaud's phenomenon developed. In another woman, also receiving enalapril alone, preexisting Raynaud's phenomenon worsened distinctly. In four patients of Group 1, complete occlusion of previously stenosed renal arteries developed during the first two years of enalapril treatment even though all remained asymptomatic with good blood pressure control, and their overall renal function did not deteriorate seriously. There were no instances of druginduced proteinuria; indeed, significant proteinuria in seven subjects before the start of enalapril therapy was markedly reduced in three and resolved completely in four. There were no instances of taste disturbance, skin rash, glycosuria, or hematologic disorder. COMMENTS In the present study, we have shown that the administration of enalapril in the range of 10 to 40 mg daily produces a distinct reduction in plasma converting enzyme activity and in angiotensin II levels, which are greater at six hours than at 24 hours, and are sustained during continued treatment. Plasma active renin concentration and blood angiotensin I levels rise, but there is no evidence that the
August 20, 1984
The American Journal of Medicine
57
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
converting enzyme inhibition is being overcome during prolonged therapy. The proportionately greater increase in active renin concentration than in angiotensin I between the sixth day and third month of treatment (Figure 1) probably reflects the decrease in renin substrate that occurs during converting enzyme inhibition [20]. Mean plasma aldosterone was not high before treatment, and the reduction with enalapril was not statistically significant. In none of the 10 patients of Group 1 was the pretreatment plasma renin or angiotensin II level particularly high. Thus, although the decrease in arterial pressure six hours after the first dose of enalapril was (as previously found with captopril (1 ,2, 16] proportional to the concurrent decrease in plasma angiotensin II, in no case was there profound hypotension [21]. A highly significant reduction in arterial pressure, without marked postural effect, was seen at the sixth day of therapy. At three months, although mean plasma angiotensin II concentration was no different from that at six days, a further highly significant decrease in blood pressure had taken place; possible mechanisms in this slow decrease in pressure have been discussed by us elsewhere [22-24]. Despite the distinct, but minor, variations in angiotensin II over 24 hours, blood pressure control remained good throughout the day. Blood pressure reduction by enalapril was similarly impressive in the more severely hypertensive and more complicated patients of Group 2, and additional therapy was largely unnecessary. Effective renal plasma flow was found to be consistently increased via the unaffected kidney during enalapril treatment. Thus, renal vascular resistance was also lowered pn that side. These findings are in accordance with those of Mimran et al [25], using captopril in essential hypertension, and with our own studies of captopril in cardiac failure [26]. By contrast, renal plasma flow was significantly reduced through the kidney distal to the renal artery stenosis; we could not calculate vascular resistance on that side as we had no measure of renal arterial perfusion pressure. By the third month of treatment, occlusion of the affected artery had occurred in one man; by two years, this complication had also occurred in three other patients, although it was not associated with symptoms or with a sharp deterioration in overall renal function and was revealed only by routine renography. There has been concern that the use of converting enzyme inhibitors in renovascular hypertension might enhance the risk of renal arterial occlusion. Experimental studies have emphasised the importance of angiotensin II in maintaining vascular tone and hence renal arterial pressure:;rlistal to a stenosis [27,28]; this mechanism would be lost during converting enzyme inhibition. However, the condition in many patients progresses to renal artery occlusion irrespective of treatment, as was shown by the presence of this complication in six of 20 patients before the start of the present trial. More-
58
August 20, 1984
The American Journal of Medicine
over, a decrease in blood pressure, however achieved, may increase the risk. The occurrence of renal artery thrombosis has been said not to be unduly frequent with the use of captopril [29]. However, it could easily be overlooked and probably would have gone unnoticed in the present series if we had not performed repeated isotope renography. In the patients of Group 1, we saw a significant reduction in overall creatinine clearance with associated increases in serum creatinine and urea. Perhaps surprisingly, the more severely hypertensive patients of Group 2 did not show an increase in serum creatinine or urea with enalapril treatment. However, patients in Group 2 were in the malignant phase, and one had been in recent cardiac failure when the drug was introduced; improvement in renal function would be expected with control of blood pressure in these circumstances. There are several reports of deterioration of renal function with converting enzyme inhibition, particularly in patients with bilateral renal artery stenosis or with stenosis of the artery to a sole remaining kidney [30-33]; diuretics have been given also in many of these accounts. We did not observe worsening of renal function in any of our five patients with bilateral renal artery lesions, although we emphasize that diuretics were not used concurrently with enalapril in any of them. The strikingly consistent decrease in exchangeable sodium with long-term enalapril therapy contrasts with our earlier study of captopril in renovascular hypertension in which, however, patients were included with the hyponatremic syndrome and marked sodium depletion that was corrected with treatment [1 ,2, 16]. In the present study, sodium loss took place despite the decrease in arterial pressure and, hence, in diminution of pressure-natriuresis. The decrease in plasma aldosterone seems too minor and inconsistent to provide a full explanation. Perhaps more plausible is the elimination by converting enzyme inhibition of direct actions of angiotensin II upon the kidneys [1 ,2,22,33,34]. The decrease in exchangeable sodium with enalapril alone underlines the absence of an indication for concomitant diuretic treatment in these circumstances; indeed such a combination might have adverse effects. The slight but significant increase in serum potassium is well known with converting enzyme inhibition. In the present series it probably resulted in part from loss of sodium in the absence of an increase in aldosterone. Although enalapril treatment increased renin secretion on average more than 10-fold and mean renal venous plasma renin concentrations more than 20-fold, the ratio of renin in venous plasma between the affected and unaffected kidneys was not altered. This is in accordance with theoretic concepts and experimental findings we have presented previously [10]. Because of the long plasma half-life of renin, it is difficult to increase the renal venous
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
renin ratio much above 1.5:1 by increasing the unilateral renin secretion rate alone. Ratios substantially higher than this can be achieved only by reducing renal blood flow on the affected side or by removing renin from the circulation by the contralateral kidney. In the present series, neither before nor during long-term enalapril treatment was the contralateral kidney removing renin from the circulation significantly, because renin concentrations in renal venous plasma on that side were similar to those in peripheral venous and hence in arterial plasma. The slight reductions in plasma flow induced by enalapril via the affected kidney (Figure 1) were not of sufficient magnitude to alter the renal venous renin ratio consistently. The only substantial individual increase in ratio we observed with enalapril, from 2.4:1 to 4.5:1, was in the man whose already tenuous renal artery was occluded by the third month. Thus, in patients of Group 1 as a whole, despite the great increases in the renin secretion rate and in the plasma renin concentration, renal venous renin ratio remained unaltered. Lyons et al [35] have reported that 30 minutes after the oral administration of 25 mg of captopril, renal venous ratios of plasma renin activity might be markedly increased
in patients with unilateral renal artery stenosis. Their findings are clearly different from ours, although the study design also was quite distinct. It is uncertain to what extent acute changes in renal blood flow affected their results. All but one of their 26 patients were receiving diuretics at the time of captopril administration, and all but three were also being given agents that would tend to suppress renin release, for example, guanethidine, methyldopa, clonidine, and various beta-blockers. Side-effects of enalapril treatment in the present series were trivial. Several patients commented on a sense of well-being during enalapril therapy, and this was an important factor in limiting their enthusiasm for surgical intervention. Enalapril thus appears to be an effective and well-tolerated agent given once daily to hypertensive patients with associated renovascular disease. ACKNOWLEDGMENT
We are grateful to Merck Sharp and Dohme Limited for financial support for these studies. The editors of the British Medical Journal and the Journal of Hypertension kindly allowed us to reproduce material that appeared previously in those journals.
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5. 6. 7. 8. 9.
10. 11.
Atkinson AB, Brown JJ, Cumming AMM, et al: Captopril in renovascular hypertension: long-term use in predicting surgical outcome. Br Med J 1982; 284: 689-693. Atkinson AB, Brown JJ, Cumming AMM, et al: Captopril in the management of hypertension with renal artery stenosis: its long-term effect as a predictor of surgical outcome. Am J Cardiol 1982; 49: 1460-1466. Staessen J, Bulpitt C, Fagard R, Lijnen P, Amery A: Long-term converting-enzyme inhibition as a guide to surgical curability of hypertension associated with renovascular disease. Am J Cardiol1983; 51: 1317-1322. Atkinson AB, Cumming AMM, Brown JJ, et al: Captopril treatment: inter-dose variations in renin, angiotensins I and II, aldosterone and blood pressure. Br J Clin Pharmacol1983; 13: 855-858. Hodsman GP, Robertson JIS: Captopril: 5 years on. Br Med J 1983, 287: 851-852. Hodsman GP, Brown JJ, Cumming AMM, et al: Enalapril in the treatment of hypertension with renal artery stenosis. Br Med J (in press). Hodsman GP, Brown JJ, Cumming AMM, et al: Enalapril in the treatment of hypertension with renal artery stenosis. J Hypertension 1983; 1 (suppl1): 109-117. Mackay A, Eadie AS, Cumming AMM, Graham AG, Adams FG, Horton PW: Assessment of total and divided renal plasma flow by 123 1-hippuran renography. Kidney lnt 1981; 19: 49-57. Millar JA, Leckie BJ, Semple PF, et al: Active and inactive renin in human plasma: renal arteriovenous differences and relationships with angiotensin and renin substrate. Circ Res 1978; 120-127. 43 (suppl Brown JJ, Lever AF, Robertson JIS: Renal hypertension: diagnosis and treatment. In: Black D, Jones NF, eds. Renal disease, 4th ed. Oxford: Blackwell, 1979; 731-765. McAreavey D, Cumming AMM, Sood VP, Leckie BJ, Morton JJ,
n
12.
13. 14. 15. 16.
17. 18. 19. 20. 21.
Murray GD, Robertson JIS: The effect of oral prazosin on blood pressure and plasma concentrations of renin and angiotensin II in man. Clin Sci 1981; 61 (suppl 7): 457-460. Agabiti-Rosei E, Brown JJ, Cumming AMM, et al: Is the "sodium index" a useful way of expressing clinical plasma renin, angiotensin and aldosterone values? Clin Endocrinol 1978; 8: 141-147. Waite MA: Measurement of concentrations of angiotensin I in human blood by radioimmunoassay. Clin Sci Mol Med 1973; 45: 51-64. Fraser R, GuestS, Young J: Comparison of double isotope derivative and radioimmunological estimation of plasma aldosterone concentration. Clin Sci Mol Med 1973; 45: 411-415. Cushman OW, Cheung HS: Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacal 1971; 20: 1637. Atkinson AB, Morton JJ, Brown JJ, et al: Captopril in clinical hypertension. Changes in components of the renin-angiotensin system and in body composition in relation to fall in blood pressure with a note on measurement of angiotensin II during converting enzyme inhibition. Br Heart J 1980; 44: 290-296. Wright BM, Dore CF: A random-zero sphygmomanometer. Lancet 1970; 1: 337-338. Davies DL, Robertson JWK: Simultaneous measurements of total exchangeable potassium and sodium using 43 K and 24 Na. Metabolism 1973; 22: 133-137. Boddy K, King PC, Tothill P, Strong JA: Measurement of total body potassium with a shadow shield whole-body counter: calibration and errors. Phys Med Bioi 1971, 16: 275-282. Rasmussen S, Nielsen MD, Giese J: Captopril combined with thiazide lowers renin substrate concentration: implications for methodology in renin assays. Clin Sci 1981; 60: 591-593. Hodsman GP, Isles GC, Murray GO, Usherwood TP, Webb OJ, Robertson JIS: Factors related to first dose hypotensive effect
August 20, 1984
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CONVERTING ENZVME INHIBITION-HODSMAN ET AL
22. 23.
24.
25. 26. 27.
60
of captopril: prediction and treatment. Br Med J 1983; 286: 832-834. Brown JJ, Casals-Stenzel J, Cumming AMM, et al: Angiotensin II, aldosterone and arterial pressure: a quantitative approach. Hypertension 1979; 1: 159-179. Bean BL, Brown JJ, Casals-Stenzel J, et al: The relation of arterial pressure and plasma angiotensin II in the conscious dog. A change produced by prolonged infusion of angiotensin II. Circ Res 1979; 44: 452-458. Atkinson AB, Brown JJ, Fraser R, et al: Antagonists and inhibitors of the renin-angiotensin-aldosterone system in the treatment of hypertension. In: Robertson JIS, Pickering G, eds. The therapeutics of hypertension. London: Academic Press (Royal Society of Medicine International Congress and Sym· posium Series No. 26), 1980; 29-61. Mimran A, Brunner HR, Turini GA, Waeber B, Brunner D: Effect of captopril on renal vascular tone in patients with essential hypertension. Clin Sci 1979; 57 (suppl 5): 421-423. Cleland JGF, Gillan G, East BW, et al: Renal and metabolic ef· fects of converting enzyme inhibition in heart failure. Clin Sci 1983; 65: 60P. Selig SE, Anderson WP, Korner PI, easley DJ: The role of angi· otensin II in the development of hypertension and in the main· tenance of glomerular filtration rate during 48 hours of renal artery stenosis in conscious dogs. Hypertension 1983; 1: 153158.
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28.
29. 30. 31.
32. 33.
34. 35.
Anderson WP, Korner PI, Johnston Cl: Acute angiotensin II mediated restoration of distal renal artery pressure in renal artery stenosis and its relationship to the development of sustained "one-kidney" hypertension in conscious dogs. Hypertension 1979; 1: 292-298. Hollenberg N: Renal artery thrombosis caused by antihyperten· sive treatment. Br Med J 1983; 286: 893. Farrow PR, Wilkinson R: Reversible renal failure during treatment with captopril. Br Med J 1979; 1: 1680. Hrick DE, Browning PJ, Kopelman R, Goorno WE, Madias NE, Dzau VJ: Captopril induced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal artery stenosis in a solitary kidney. N Engl J Med 1983; 373-376. Silas JH, Klenka Z, Solomon SA; Bone JM: Captopril induced reversible renal failure: a marker of renal artery stenosis affecting a solitary kidney. Br Med J 1983; 1: 1702-1703. Aldigier J-C, Plouin P·F, Guyene TT, Thibonnier M, Corvol P, Menard J: Comparison of hormonal and renal effects of cap· topril in severe essential and renovascular hypertension. Am J Cardiol 1982; 49: 1447-1452. Hollenberg NK: Renal response to angiotensin-converting en· zyme inhibition. Am J Cardiol 1982; 49: 1425-1429. Lyons OF, Streck WF, Kem DC, et al: Captopril stimulation of differential renins in renovascular hypertension. Hypertension 1983; 5: 615-622.
G. P. HODSMAN, M.R.C.P.
J. J. BROWN, F.R.S.E., F.R.C.P. A. D. B. A.
M. M. CUMMING, R.G.N. L. DAVIES, F.R.C.P. W. EAST, Ph.D. F. LEVER, F.R.S.E., F.R.C.P. J. J. MORTON, Ph.D. G. D. MURRAY, Ph.D. J. I. S. ROBERTSON, F.R.S.E., F.R.C.P. Glasgow, United Kingdom
From the Medical Research Council Blood Pressure Unit, and the University Department of Medicine, Western Infirmary; the Scottish Universities' Research and Reactor Centre, East Kilbride; and the Department of Statistics, University of Glasgow, Glasgow, United Kingdom. Requests for reprints should be addressed to J.I.S. Robertson, MRC Blood Pressure Unit, Western Infirmary, Glasgow, G11 6NT, United Kingdom.
52
August 20, 1984
The converting enzyme inhibitor enalapril, in single daily doses of 10 to 40 mg, was given to 20 hypertensive patients with renal artery stenosis. The decrease in blood pressure six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II, and to the concurrent decrease in angiotensin II. Blood pressure decreased further with continued treatment; the long-term decrease was not significantly related to pretreatment plasma renin or angiotensin II levels. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low, and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, decreased further. The increase in active renin during long-term treatment was proportionately greater than the increase in angiotensin I; this probably reflects the diminution in renin substrate that occurs with converting enzyme inhibition. Long-term enalapril treatment increased renin secretion by more than 10-fold, and renal venous and peripheral plasma renin concentration by more than 20-fold; however, the mean renal venous renin ratio was not changed. Enalapril caused a reduction in effective renal plasma flow via the affected kidney but a marked and consistent increase on the contralateral side, where renal vascular resistance decreased. The overall increase in effective renal plasma flow was significantly related to the decrease in angiotensin II. Overall glomerular filtration rate was lowered, and serum creatinine and urea increased. Enalapril alone caused a longterm reduction in exchangeable sodium, with slight but distinct increases in serum potassium. In five patients with bilateral renal artery lesions, enalapril given alone for three months did not cause renal function to deteriorate. Enalapril was well tolerated and provided effective long-term control of hypertension; only two of the 20 patients studied required concomitant diuretic treatment. We have previously reported on [1 ,2] the use of the orally active converting en~yme inhibitor captopril in the preoperative treatment of hypertension associated with unilateral renal artery stenosis. Long-term captopril therapy effectively controlled hypertension in the majority of such patients. Moreover, it showed promise as a predictor of the blood pressure response to surgery; this latter aspect has since been confirmed [3]. We have also observed that the administration of oral captopril in a dose of 150 mg three times daily resulted in sustained suppression of peripheral plasma angiotensin II concentration throughout 24 hours [4]; however, the efficacy, in this respect, of the lower doses of captopril currently rec-
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CONVERTING ENZYME INHIBITION-HODSMAN ET AL
ommended [5] remains to be established. We present herein data on the long-term use of oral enalapril, given in a single daily dose, in 20 patients with hypertension and renal artery stenosis. Some aspects of this work have already been reported [6,7].
500
Enalapril
400
PATIENTS AND METHODS
All patients gave informed consent to the study, which was approved by the hospital's ethical supervisory committee. Two distinct study protocols were followed, in two separate groups. Group 1 consisted of 10 patients with unilateral renal artery stenosis and good overall renal function. All previous antihypertensive therapy was discontinued so that detailed measurement of blood pressure, serum and body electrolytes, and components of the renin-angiotensin system could be made during the administration of a placebo and then during long-term enalapril therapy. Group 2 comprised 10 patients with unilateral or bilateral renal artery disease in whom severe or resistant hypertension necessitated the continuation of previous antihypertensive therapy up to the time that enalapril was introduced. Group 1. Of these 10 patients (aged 37 to 56 years; two women), nine had unilateral renal artery stenosis, and one had unilateral occlusion. On renal arteriography, nine had roentgenologic evidence of atheromatous stenosis and one of fibromuscular hyperplasia. Isotope renography [8) showed reduced renal plasma flow on the affected side in all patients (Figure 1). Bilateral renal vein renin measurements [9) were also performed in all but one patient, a man with unilateral renal artery occlusion, and showed higher values on the stenotic side. In seven patients, additional divided ureteric catheter studies were performed [1 OJ that confirmed the diagnosis; these studies were not performed in the patient with renal artery occlusion on arteriography, and the procedure was technically unsatisfactory in two others. All patients had normal serum electrolyte values and normal or near-normal overall renal function (mean serum creatinine 103 ± 8 SEM JLmol/liter). Seven of the 10 had previously had poor blood pressure control with the combination of a beta blocker and diuretic, together with either hydralazine (three patients), prazosin (one patient), minoxidil (one patient), or methyldopa (one patient). One patient had received a diuretic alone with poor response, and two patients had not received any previous antihypertensive therapy. Three patients had proteinuria of 0.3 to 1.3 g per 24 hours. Mean outpatient blood pressure during previous treatment was 183/109 ± 10/3 (SEM) mm Hg. All treatment was stopped at least 14 days before enalapril therapy was started in all but one subject who received prazosin alone [11] until two days before enalapril was given. The patients were admitted to the hospital and ate a normal ward diet; previous studies have shown that in these circumstances, plasma renin, angiotensin II, and aldosterone values are similar to those obtained during strictly controlled sodium and potassium intake [12]. A matching placebo was given at 10 A.M. each day for five days before the active drug was administered; thereafter, enalapril was given at 10 A.M. every day. Two patients received a placebo for only two days before the administration of enalapril was begun because of se-
Untreated
ERPF
ml/min 300
200
100 50
I~I
Stenotic sJde
Mean ± SEM
Figure 1. Effective renal plasma flow (ERPF; means ± SEM) via the post-stenotic and unaffected kidneys in Group 1 patients before and at the third month of enalapril therapy.
verely elevated blood pressure. The patients began a regimen of 10 mg enalapril daily, which was continued for each of the six days of inpatient stay. After discharge, the enalapril dose was adjusted in all 10 patients until supine and erect blood pressure measurements were below 140 mm Hg systolic and 90 mm Hg diastolic (phase V) four hours after the morning dose was given, or until a maximal dose of 40 mg daily was reached. No drugs other than enalapril were given in this study. After three months of treatment with enalapril, the patients were readmitted and studied under circumstances identical to those at the start of therapy. Peripheral venous blood was taken for measurement of plasma active renin concentration [9) (normal range 10 to 50 mU/Iiter), blood angiotensin I [13] (normal range 3 to 18 pmol/ liter), plasma aldosterone [14) (normal range less than 500 pmol/liter; less than 18 ng/dl), plasma converting enzyme activity, [15] and plasma angiotensin II [16) (normal range 5 to 35 pmol/liter) after 30 minutes of recumbency, before the first dose of enalapril was given, and six and 24 hours later. Supine and erect pulse rate and blood pressure readings (after two minutes standing) were recorded after blood sampling by the same observer (G.P.H.). The Hawksley random-zero sphygmomanometer [17) was employed, and phase V was taken as diastolic. These measurements were repeated under identical conditions after six days and after 12 weeks of treatment. Measurements were made of exchangeable sodium [18) and total body potassium [19) before and at the
August 20, 1984
The American Journal of Medicine
53
CONVERTING ENZVME INHIBITION-HODSMAN ET AL
Placebo
~
160 .
BP mmHg
,00 140
ACE )JMOI/ml/h
1.0 0.5
120 100 80
"~ 0
All
pg/ml
~j 25 20 15 10
5 AI pg/ml
.. 200 300 100
~
0
Active renin )JU/ml
, ~ 750 500 250
1~ j 0
AI do. ng/dl
1st day
6th day
3 months
~ 0. 0- o·· EnalaPrll
~• ..
•
I
1""'
•
•
•
~!..::_!
.---~
..
~!··
0·
___.--I . ~----~
I
I
Figure 2. Patients of Group 1. Measurements made six hours after dosing on the final day of placebo therapy, on the first day of enalapril therapy, on the sixth day of enalapril therapy, and at the third month of enalapril therapy. BP = blood pressure; ACE = plasma converting enzyme activity; AI = blood angiotensin I concentration; All = plasma angiotensin II concentration; A/do. = plasma aldosterone concentration. Statistical comparisons with placebo values. **=p
<0.01.
third month of enalapril treatment. Creatinine clearances were measured using 24-hour urine collections during the initial placebo phase and again at the third month of enalapril treatment alone. Effective renal plasma flow was measured separately [8] for the two kidneys before treatment and again during longterm enalapril therapy, except in one man with unilateral renal artery occlusion initially, in whom this test was not repeated. The investigation was carried out at the third month of enalapril therapy in seven of the remaining nine patients; this was not possible in two others in whom the repeated investigations were made at 20 and 24 months, respectively. Renal vascular resistance was calculated from the renal blood flow and mean systemic arterial pressure. The renal venous renin measurement was repeated at the third month of enalapril treatment in eight of the 10 patients. Net renin secretion rates for single kidneys were calculated from the effective renal plasma flow and the venoarterial difference in plasma renin concentration across the kidney. Group 2. These 10 patients (aged 15 to 61 years; five female) were more seriously ill and therefore unsuitable for study according to the foregoing protocol. On arteriography, five had unilateral renal artery occlusion. Five had arteria-
54
August 20, 1984
The American Journal of Medicine
graphic evidence of bilateral renal artery disease. Eight had very high blood pressure levels (four were in the malignant phase with bilateral retinal hemorrhages, exudates, and papilledema). One had cardiac failure and recent hypertensive encephalopathy. Three had overall renal impairment (mean ± SEM serum creatinine for the whole group was 132 ± 17 JLmol/liter). Four had proteinuria of 0.7 to 4.2 g per 24 hours. Preceding therapy in the patients of Group 2 included various combinations of diuretics, beta-blocking agents, prazosin, hydralazine, and nifedipine. All were studied as inpatients initially and were readmitted for assessment three months later. A supine blood pressure reading immediately before enalapril was introduced was 190/104 ± 15/5 (SEM) mm Hg. Enalapril was given in a starting dose of 10 mg and increased to a maximum of 40 mg daily, with lower dosage in those with renal impairment. Over 12 weeks, therapy was adjusted, and other drugs were withdrawn whenever possible. Blood pressure was measured as for the patients in Group 1. · The statistical comparisons are based on paired t tests, with biochemical measurements transformed to a logarithmic scale. The correlation coefficients quoted are product-moment correlations, again with biochemical measurements analyzed on a logarithmic scale. Mean arterial pressure (diastolic plus one-third pulse pressure) was taken for correlations involving blood pressure. RESULTS
Group 1. At three months, six patients were receiving 10 mg of enalapril daily, one was receiving 20 mg, and three were receiving 40 mg. In Figure 2, blood pressure and various biochemical measurements obtained six hours after the daily dose of enalapril on the first and sixth days of therapy, and at three months, are compared with those obtained on the final day of placebo therapy at the comparable time after dosing. Six hours after the initial dose of enalapril, there were marked decreases in plasma converting enzyme activity and in angiotensin II, with converse increases in blood levels of angiotensin I and in plasma active renin concentration. The small decrease in mean plasma aldosterone was not significant. A highly significant reduction in blood pressure accompanied the decrease in plasma angiotensin II, and these changes were significantly correlated(r = 0.67; p <0.05); the decrease in blood pressure at six hours also correlated with the plasma concentrations (before enalapril therapy) of active renin (r = 0.76; p <0.05) and angiotensin II (r = 0.70; p <0.05). With continued enalapril treatment, suppression of plasma converting enzyme activity and angiotensin II, similar to that observed on the first day, was seen at six days and at three months, six hours after dosing. Active renin concentration increased progressively from the first to the sixth day and from the sixth day to the third month of treatment. The mean blood concentration of angiotensin I also increased further from the first to the sixth day of enalapril treatment, but there was no further increase
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
3 months enalaprll
Placebo 160 180 140 120 100 80
ACE
)JMOI/ml/h
1.5~
1.0 0.5
0
AI I
pg/ml
AI
pg/ml
29
30 20 15 10 5 300 200 100 0
Active renin )JU/ml
~
~
from last dose
~
24hr
tto
! ...... ......
...... ......
I. . . ......
tt
0
3 months
180 160
BP mmHg
~··
140
120 100
......... ~'!-..._1·
+
I
p<0,001
~
I
----!--!
·---- tt ~
500
250 0
... I
16th day
6hr
80
woo~ 750
Enalapril
Placebo
I .......
,"'"'
..... , tt
Figure 3. Patients of Group 1. Comparison of values obtained after three months of continuous enalapril therapy alone with those obtained on the final day of placebo therapy. Measurements during enalapril therapy were determined 24 hours and six hours after the preceding dose. Daggers show comparisons with values obtained during placebo therapy: t=p <0.05; tt=p <0.01. Asterisks show comparisons with 24-hour values: *=p <0.05; **=p <0.01. Other abbreviations as for Figure 1.
thereafter. The slight decrease in mean plasma aldosterone remained insignificant. Blood pressure remained controlled at six days and at three months. However, during long-term treatment, the decrease in blood pressure was less closely related than on the first day to either the pretreatment plasma renin or angiotensin II concentrations or to the long-term decrease in plasma angiotensin II (respective correlation coefficients 0.44, 0.42 and 0.56, none significant). In Figure 3, measurements made on the last day of placebo therapy are compared with those at the third month of enalapril treatment, 24 hours after the preceding dose and again six hours after the morning dose of drug. At the third month of active treatment, continued enalapril effect was evident 24 hours after the last dose of the drug, with a marked increase in active renin and angiotensin I, and a converse reduction of converting enzyme activity and angiotensin II. Blood pressure also remained significantly reduced 24 hours after dosing in comparison with pretreatment values. Nevertheless, following the morning dose of enalapril at the third month, significant further reductions in plasma converting enzyme activity and angio-
t
p
Heart rate/ min
100 90
~
80
70
Figure 4. Patients of Group 1. Comparison of supine (open columns) and erect (solid columns) blood pressure levels and pulse rate before and during enalapril therapy. Means (±SEM) of measurements made two, six, and 24 hours after dosing.
tensin II occurred, wherever mean values for active renin and angiotensin I increased. The small additional lowering of arterial pressure six hours after dosing was not statistically significant. Figure 4 shows systolic and diastolic blood pressures and heart rates, with the patients lying and standing, during placebo therapy, and at the sixth day and third month of enalapril treatment. Values are means of measurements made two, six, and 24 hours after dosing. A significant decrease in blood pressure had occurred by the sixth day of enalapril therapy, and a further highly significant decrease by three months without a marked postural component or change in mean heart rate. Good blood pressure control was maintained after the patient's discharge from the ward (seated clinic values 142/82 ± 6/3 mm Hg four hours after dosing). Creatinine clearance decreased by the third month from an initial mean (±SEM) of 105 ± 12 ml per minute to 88 ± 8 (p <0.02). This change was reflected in a significant increase in both serum creatinine and urea (Table I). The increase in serum creatinine was related to the decrease in arterial pressure (r = -0.68; p <0.05). Renal plasma flow changed in different directions in the affected and unaffected kidneys (Figure 1). On the side supplied by the narrowed renal artery, enalapril treatment was associated with a significant reduction in effective renal plasma flow, from a mean of 162 ± 41 (SEM) ml per
August 20, 1984
The American Journal of Medicine
55
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
TABLE I
Measurements (means ± SEM) in Patients after Six Days of Enalapril Therapy and after Three Months of Enalapril Therapy Alone Enalapril Serum Sodium (mmol/liter) Potassium (mmol/liter) Creatinine (ttmol/liter) Urea (mmollliter)
Placebo 140.8 ± 3.8 ± 103 ± 5.1 ±
0.7 0.10 8 0.4
Six Days 140.6 ± 0.5 4.0 ± 0.08
117 ± 9 5.2 ± 0.4
Three Months 140.4 ± 4.3 ± 127 ± 6.2 ±
0.7 0.07** 10*** 0.5*
*p <0.05, **p <0.01' ***p <0.001.
minute to 102 ± 41 (p <0.05). In one man, with a previously tightly stenosed artery supplying a shrunken kidney, renography indicated that renal circulation to the affected side had ceased by the third month; arteriography confirmed occlusion of the diseased renal artery. This patient's overall renal function had not deteriorated seriously, the increase in serum creatinine over three months, from 118 to 127 J.Lmol/liter, being less than the average for Group 1 at that time. In another patient, renal plasma flow was reduced from 103 ml per minute on the affected side before treatment to 19 ml per minute after three months of treatment; serum creatinine had increased conCO!'Jlitantly from 145 to 184 J.Lmol/liter. Further renography at 12 months showed that circulation to the affected kidney had ceased, serum creatinine then being 199 J.Lmol/liter. Renal artery occlusion was detected by renography in two other patients, respectively, at 20 and 24 months of enalapril therapy. In the first of these, serum creatinine was unchanged at 79 J.Lmol/liter. In the second, it had increased from 76 to 130 J.LmOI/Iiter. Thus, renal artery occlusion occurred in four of nine patients at various times up to 24 months of therapy. In contrast, plasma flow was consistently increased via the contralateral, unaffected kidney during enalapril treatment, from an initial mean of 298 ± 21 ml per minute to 437 ± 48 (p <0.01) (Figure 1). Overall effective renal plasma flow therefore increased, and the percentage increase was significantly related to the concurrent decrease in plasma angiotensin II (r = -0.66; p <0.05). The decrease in glomerular filtration rate also correlated inversely with the increase in total effective renal plasma flow (r = -0.83; p <0.05). Calculated renal vascular resistance thus was reduced in the contralateral kidney by enalapril, from 90,000 ± 14,600 (SEM) dynes • second • em - 5 to 46,500 ± 6,600 (p <0.01 ). Renal vascular resistance could not be computed on the affected side, as we had no measure of renal arterial pressure distal to the stenosis. Before enalapril therapy, renal venous plasma renin concentration was higher on the affected side than on the contralateral side in every patient (respective means 82.4 ± 22.1 versus 52.0 ± 11.3 mU/Iiter). Treatment with
56
August 20, 1984
The American Journal of Medicine
enalapril for three months increased these values greatly on both sides to respective means of 1,906 ± 476 and 1,209 ± 367 mU/Iiter. Although the average renal venous renin ratio increased during enalapril therapy from 1.61:1 to 1.88:1, the change was inconsistent and not statistically significant. Both before and during enalapril treatment, the affected kidney was solely responsible for renin secretion, the renin value being consistently and significantly higher in renal venous plasma than in peripheral venous, and hence in arterial, plasma. By contrast, renin secretion from the unaffected kidney was suppressed both before and during enalapril treatment, with no significant difference in renin concentration in peripheral venous and in renal venous plasma on that side. The renin secretion rate was increased on average more than 10-fold by long-term enalapril therapy from 431 ± 138 to 4,330 ± 2,124 J.LU per minute (p <0.02). However, as shown by the measurements of renal venous renin concentration, the long plasma half-life of renin, combined with the limited ability of the contralateral kidney to extract renin from the circulation, meant that, despite the very large increases in circulating renin concentration, the renal venous renin ratio remained little changed. Serum potassium increased significantly, but in no patient was this marked (Table 1). There was no change in serum sodium. There were no measurable long-term changes in total body potassium. Total exchangeable sodium, however, was reduced during therapy in nine patients and unchanged in the 1Oth, falling from a mean of 101 percent to 96 percent of predicted normal values. The mean reduction was 140 mmol and was highly significant (p <0.001) (Figure 5). The decrease in exchangeable sodium was not significantly correlated with the increase in serum creatinine concentration. Group 2. Supine and erect blood pressure level, during previous antihypertensive treatment and immediately before enalapril was given, were 190/104 ± 15/5 mm Hg and 179/1 08 ± 11/4 mm Hg, respectively (Figure 6). After three months, four patients were receiving 10 mg, three patients 20 mg, and three patients 40 mg of enalapril daily. The blood pressures of seven patients were well controlled with enalapril alone. Three required additional
CONVERTING ENZVME INHIBITION-HODSMAN ET AL
Placebo 3500 NaE mMol 3000
2500
2000
Previous therapy
Enalapr!l
~hs
~
~ ~ ::st1·
200
Enalapr!l 3 months
180 BP mmHg
~
80
t
p<0.001 Figure 5. Exchangeable sodium (NaE) in patients of Group 1 before and at the third month of enalapril therapy.
I
t
p < 0.01 Serum creatinine
132
:!:
17
133
:!:
23
)JMOI/1
therapy. In one patient with overall renal impairment, furosemide (500 mg daily) together with atenolol (50 mg daily) was continued for control of symptomatic tachycardia. One patient continued to receive chlorthalidone (25 mg daily), and also atenolol (1 00 mg daily) because of angina. One patient needed atenolol alone (50 mg daily) for control of symptomatic tachycardia. In this group of 10 patients, after three months of enalapril therapy, supine and erect blood pressure levels had fallen to 142/84 ± 5/8 mm Hg and 129/85 ± 7/5 mm Hg (p <0.01 ), respectively (Figure 6). Corresponding seated measurements in the outpatient clinic were 150/87 ± 5/3 mm Hg four hours after dosing. There were no changes in mean serum sodium or potassium and no deterioration in mean or individual overall renal function (serum creatinine 132 ± 17 J.t-mol/liter during previous therapy, 133 ± 23 J.t-mol/liter after three months of enalapril therapy). In particular, renal function did not deteriorate in the five patients with bilateral renal artery lesions. In thest;l, none of whom received concurrent diuretic therapy, the blood pressure level fell from 204/110 ± 2117 mm Hg to 154/88 ± 2/3 mm Hg by the third month, whereas serum creatinine was unchanged (142 ± 34 versus 145 ± 35 J.t-mol/liter). Side-Effects. The drug was well tolerated by all 20 patients, and problems were minor. In one· man, previously impaired sexual function improved. In four patients (one also receiving a large dose of loop diuretic), symptomatic tachycardia developed in the supine and standing positions; in two cases, the tachycardia resolved slowly and spontaneously without additional therapy, but in two other
Figure 6. Patients of Group 2. Comparison of supine (open columns) and erect (solid columns) blood pressure levels and of serum creatinine during previous therapy and at third month of enalapril therapy. Means ± SEM shown.
patients, both in Group 2, the addition of a beta blocker was required. In one patient receiving enalapril alone, Raynaud's phenomenon developed. In another woman, also receiving enalapril alone, preexisting Raynaud's phenomenon worsened distinctly. In four patients of Group 1, complete occlusion of previously stenosed renal arteries developed during the first two years of enalapril treatment even though all remained asymptomatic with good blood pressure control, and their overall renal function did not deteriorate seriously. There were no instances of druginduced proteinuria; indeed, significant proteinuria in seven subjects before the start of enalapril therapy was markedly reduced in three and resolved completely in four. There were no instances of taste disturbance, skin rash, glycosuria, or hematologic disorder. COMMENTS In the present study, we have shown that the administration of enalapril in the range of 10 to 40 mg daily produces a distinct reduction in plasma converting enzyme activity and in angiotensin II levels, which are greater at six hours than at 24 hours, and are sustained during continued treatment. Plasma active renin concentration and blood angiotensin I levels rise, but there is no evidence that the
August 20, 1984
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57
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
converting enzyme inhibition is being overcome during prolonged therapy. The proportionately greater increase in active renin concentration than in angiotensin I between the sixth day and third month of treatment (Figure 1) probably reflects the decrease in renin substrate that occurs during converting enzyme inhibition [20]. Mean plasma aldosterone was not high before treatment, and the reduction with enalapril was not statistically significant. In none of the 10 patients of Group 1 was the pretreatment plasma renin or angiotensin II level particularly high. Thus, although the decrease in arterial pressure six hours after the first dose of enalapril was (as previously found with captopril (1 ,2, 16] proportional to the concurrent decrease in plasma angiotensin II, in no case was there profound hypotension [21]. A highly significant reduction in arterial pressure, without marked postural effect, was seen at the sixth day of therapy. At three months, although mean plasma angiotensin II concentration was no different from that at six days, a further highly significant decrease in blood pressure had taken place; possible mechanisms in this slow decrease in pressure have been discussed by us elsewhere [22-24]. Despite the distinct, but minor, variations in angiotensin II over 24 hours, blood pressure control remained good throughout the day. Blood pressure reduction by enalapril was similarly impressive in the more severely hypertensive and more complicated patients of Group 2, and additional therapy was largely unnecessary. Effective renal plasma flow was found to be consistently increased via the unaffected kidney during enalapril treatment. Thus, renal vascular resistance was also lowered pn that side. These findings are in accordance with those of Mimran et al [25], using captopril in essential hypertension, and with our own studies of captopril in cardiac failure [26]. By contrast, renal plasma flow was significantly reduced through the kidney distal to the renal artery stenosis; we could not calculate vascular resistance on that side as we had no measure of renal arterial perfusion pressure. By the third month of treatment, occlusion of the affected artery had occurred in one man; by two years, this complication had also occurred in three other patients, although it was not associated with symptoms or with a sharp deterioration in overall renal function and was revealed only by routine renography. There has been concern that the use of converting enzyme inhibitors in renovascular hypertension might enhance the risk of renal arterial occlusion. Experimental studies have emphasised the importance of angiotensin II in maintaining vascular tone and hence renal arterial pressure:;rlistal to a stenosis [27,28]; this mechanism would be lost during converting enzyme inhibition. However, the condition in many patients progresses to renal artery occlusion irrespective of treatment, as was shown by the presence of this complication in six of 20 patients before the start of the present trial. More-
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over, a decrease in blood pressure, however achieved, may increase the risk. The occurrence of renal artery thrombosis has been said not to be unduly frequent with the use of captopril [29]. However, it could easily be overlooked and probably would have gone unnoticed in the present series if we had not performed repeated isotope renography. In the patients of Group 1, we saw a significant reduction in overall creatinine clearance with associated increases in serum creatinine and urea. Perhaps surprisingly, the more severely hypertensive patients of Group 2 did not show an increase in serum creatinine or urea with enalapril treatment. However, patients in Group 2 were in the malignant phase, and one had been in recent cardiac failure when the drug was introduced; improvement in renal function would be expected with control of blood pressure in these circumstances. There are several reports of deterioration of renal function with converting enzyme inhibition, particularly in patients with bilateral renal artery stenosis or with stenosis of the artery to a sole remaining kidney [30-33]; diuretics have been given also in many of these accounts. We did not observe worsening of renal function in any of our five patients with bilateral renal artery lesions, although we emphasize that diuretics were not used concurrently with enalapril in any of them. The strikingly consistent decrease in exchangeable sodium with long-term enalapril therapy contrasts with our earlier study of captopril in renovascular hypertension in which, however, patients were included with the hyponatremic syndrome and marked sodium depletion that was corrected with treatment [1 ,2, 16]. In the present study, sodium loss took place despite the decrease in arterial pressure and, hence, in diminution of pressure-natriuresis. The decrease in plasma aldosterone seems too minor and inconsistent to provide a full explanation. Perhaps more plausible is the elimination by converting enzyme inhibition of direct actions of angiotensin II upon the kidneys [1 ,2,22,33,34]. The decrease in exchangeable sodium with enalapril alone underlines the absence of an indication for concomitant diuretic treatment in these circumstances; indeed such a combination might have adverse effects. The slight but significant increase in serum potassium is well known with converting enzyme inhibition. In the present series it probably resulted in part from loss of sodium in the absence of an increase in aldosterone. Although enalapril treatment increased renin secretion on average more than 10-fold and mean renal venous plasma renin concentrations more than 20-fold, the ratio of renin in venous plasma between the affected and unaffected kidneys was not altered. This is in accordance with theoretic concepts and experimental findings we have presented previously [10]. Because of the long plasma half-life of renin, it is difficult to increase the renal venous
CONVERTING ENZYME INHIBITION-HODSMAN ET AL
renin ratio much above 1.5:1 by increasing the unilateral renin secretion rate alone. Ratios substantially higher than this can be achieved only by reducing renal blood flow on the affected side or by removing renin from the circulation by the contralateral kidney. In the present series, neither before nor during long-term enalapril treatment was the contralateral kidney removing renin from the circulation significantly, because renin concentrations in renal venous plasma on that side were similar to those in peripheral venous and hence in arterial plasma. The slight reductions in plasma flow induced by enalapril via the affected kidney (Figure 1) were not of sufficient magnitude to alter the renal venous renin ratio consistently. The only substantial individual increase in ratio we observed with enalapril, from 2.4:1 to 4.5:1, was in the man whose already tenuous renal artery was occluded by the third month. Thus, in patients of Group 1 as a whole, despite the great increases in the renin secretion rate and in the plasma renin concentration, renal venous renin ratio remained unaltered. Lyons et al [35] have reported that 30 minutes after the oral administration of 25 mg of captopril, renal venous ratios of plasma renin activity might be markedly increased
in patients with unilateral renal artery stenosis. Their findings are clearly different from ours, although the study design also was quite distinct. It is uncertain to what extent acute changes in renal blood flow affected their results. All but one of their 26 patients were receiving diuretics at the time of captopril administration, and all but three were also being given agents that would tend to suppress renin release, for example, guanethidine, methyldopa, clonidine, and various beta-blockers. Side-effects of enalapril treatment in the present series were trivial. Several patients commented on a sense of well-being during enalapril therapy, and this was an important factor in limiting their enthusiasm for surgical intervention. Enalapril thus appears to be an effective and well-tolerated agent given once daily to hypertensive patients with associated renovascular disease. ACKNOWLEDGMENT
We are grateful to Merck Sharp and Dohme Limited for financial support for these studies. The editors of the British Medical Journal and the Journal of Hypertension kindly allowed us to reproduce material that appeared previously in those journals.
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