Hypotensive and renal effects of Captopril

zyxwvuts zyxwvut zyxwvu Europ~ariJournal qf’C1inic.d Investigation ( I98 1 ) 11, 409-4 13 Hypotensive and renal effects of Captopril A. C. PESSINA, A. GATTA, A. SEMPLICINI, G . P. ROSSI, E. CASIGLIA, L. MILANI, P. AMODIO, C. MERKEL, A. PAGNAN & C. DAL PALU, Istituto di Medicina Clinica, Universitri di Padova, Italy Received 12 August I980 and in revised form 8 July 1981 Abstract. The effects of Captopril on blood pressure and renal function were evaluated in ten patients with different degrees of hypertension. In seven, blood pressure was reduced after 7 weeks of therapy; in three it remained practically unchanged. No correlation was found between the standing plasma renin activity before treatment and the hypotensive response. Plasma renin activity increased significantly from the median value of 5.4 (range 1-16.7) to 9.5 (range 2.6-19.8) ng ml-’ h-’ (P<O.O5) and urine aldosterone significantly fell from 13 (range 2.3-52.5) to 7.4 (range 1 . 6 1 4 ) pg 24 h - ’ (P<O.OI) during therapy. Renal plasma flow decreased from 534 (range 300-616) to 471 (range 333-606) ml min-I, but the difference was not significant, and glomerular filtration rate fell significantly form 122 (range 64-143) to 88 (range 71-1 16) ml min-’ (P<O.O5). N o urinary excretion of alpha?-macroglobulin was observed during Captopril. 24 h proteinuria, albumin and transferrin clearance, alanine-amino transferase, gammaglutamyl transferase and alpha glucosidase excretion rate and malatedehydrogenase clearance remained unaltered throughout the treatment. This indicates that neither glomerular permeability nor renal tubular function were affected by the drug. function for proteinuria and initial signs of glomerular or tubular damage. zyxwvutsrq Key words. Captopril, coverting enzyme inhibitor, hypertension, plasma renin activity, proteinuria. Introduction Patients and Methods Ten hypertensive patients (eight males and two females, aged 24-55, median 43), eight with essential hypertension, one with unilateral pyelonephritis and one with unilateral renal artery stenosis were studied, after each one of them gave their consent. The degree of hypertension was severe in two cases, moderate in two, mild in four and borderline in another two (Table I). Only in three cases were serum creatinine and blood urea nitrogen above normal levels. None of them had been receiving antihypertensive drugs for a t least 2 weeks prior to the study or put on sodium restricted diet. The following protocol was adopted: 2 weeks of placebo consisting of tablets identical in shape and colour to the active drug, and 7 weeks of administration of CaptopriP (D-3-mercapto2-methylpropanoyl-~-proline; SQ 14225, Squibb). The starting dose was 25 mg three times daily and it was incremented once a week during the first 3 weeks of ‘dose ranging’ in those cases where the hypotensive response was considered unsatisfactory (i.e. supine diastolic pressure higher than 95 mmHg). The maximum daily dose used was 500 mg. At the end of the first 3 weeks the dosage reached was thereafter maintained during the 4 weeks of ‘full treatment’ without further increase, even if the blood pressure was considered not to be well controlled. During the ‘full treatment’ period the daily dose given was from 150 to 500 mg (median 300 mg). Blood pressure and heart rate were taken each week, after 30 min recumbency and 5 min standing during the study. BloJd pressure was measured with a Riva-Rocci sphygmomanometer (using phase IV of Korotkoff sounds for diastolic pressure). Plasma renin activity (PRA) after 1 h active orthostatism, and 24 h urine aldosterone excretion rate were determined at the end of the placebo period and after the ‘full treatment’ period using the Angiotensin I radioimmunoassay (RENCKT Sorin, Saluggia, Italy) and the aldosterone radioimmunoassay (ALDOK, Sorin Italy). The normal values, when the patients are on a hospital diet zyxwvutsrq In the last few years Captopril, the Angiotensin 1 converting enzyme inhibitor, has been successfully employed in the treatment of essential and renovascular hypertension [IH].Proteinuria is one of the side effects reported to date [5-81. As it is known that Captopril induces a significant increase in plasma renin activity [9] and concentration [ 101and that renin induces proteinuria in rats and rabbits [11-18], we decided to study the effect of Captopril on blood pressure and plasma renin and to monitor renal zyxwvutsrq Correspondence: Dr A. C. Pessina, Clinica Medica 1 I , Policlinico Universitario. Via Giustiniani 2, 35 100 Padova. Italy. 00 14-2972/8 I /1000-04091602.00 # ( ‘ 1981 Blackwell Scientific Publications 409 zyxwvutsrq zyxwvutsrqp zyxwvutsrq zyxw A. C. PESSINA et al. 410 containing 15&200 mmol of sodium per day, are 1-55 ng ml-' h-', and 5-20 pg 24 h-I, respectively. Before and after Captopril administration glomerular filtration rate (GFR) and renal plasma flow (RPF) were also measured. The first as iothalamate and the second as iodohippurate clearance without bladder catheterization, after oral hydration, when urine output was stable, roughly 10 ml min-I. After a priming i.v. injection of 15 pCi '3'I-iodohippurate (Sorin, Italy) and of 20 pCi l*SI-iothalamate(Amersham, England), 40 pCi '311-iodohippurateand 30 pCi '*SI-iothalamate in 100 ml normal saline solution were infused in 100 min. Three 30 min clearance periods were measured. At the end of each urine collection 2 ml of blood were drawn. Only the mean of the last two clearance periods was used for the analysis of the results. For each clearance period, 1 ml plasma and 1 ml undiluted urine were counted up to 40,000 counts in a two channel automatic well-type scintillation counter (PriasPackard PGD autogamma). In order to detect early changes in glomerular capillary permeability, daily proteinuria, albumin, transferrin and alpha*-macroglobulin clearances and alanine-amino-transferase (ALT) excretion rate, known to be sensitive indicators of an increase of glomerular capillary permeability [ 19, 201, were measured before and during Captopril administration. Similarly, in order to verify tubular functional and anatomical derangement, malate-dehydrogenase (MDH) clearance indicating functional tubular damage [21] and alphaglucosidase (AGL) and gammaglutamyl-transferase (GGT) excretion rate indicating anatomical tubular damage [22, 231 were determined in some of the patients. All the results were divided by the glomerular filtration rate in order to obtain normalized values. Therefore clearances lose their original dimension (ml min-I) and are expressed as fraction of GFR, while excretion rate acquires the ' dimension ofamount per volume of G F R (i.e. mU dlof GFR). G G T was measured with the 'Monotest GGT novo' (no. 125938, Boehringer, Italy) using a Zeiss PM Spectrophotometer at 405 nm wavelength. AGL was measured at 400 nm wavelength according to the method of Ceriotti & Guarnieri [24]. MDH was measured on both plasma and urine with the Combination test MDH (no. 124940, Boehringer, Italy) at 340 nm wavelength. All urine enzyme measurements were obtained on samples previously centrifuged (2500 g for 10 min) and dialysed against normal saline solution using 18/32 Visking tubings. Daily proteinuria was determined with the biuret method [25]. Albumin, transferrin and alpha*-macroglobulin were measured in serum and in 25-fold concentrated urine by immunoelectrophoresis on agar [26]. Urine was concentrated by ultrafiltration in a 200 ml U F cell (Amicon Corp., Lexington, Massachussets, U.S.A.) using a Diaflo membrane U M 10. Quantitation was obtained by comparison of the area enclosed by the precipitates of proteins in unknown samples to the area of a reference solution [27]. The amount of specific antiserum (Boehringer, Italy) added to the agar was such that we could measure a urine protein concentration as little as 2 mg I - [ . Normal values for urinary enzymes and protein clearances were obtained from twenty-one healthy subjects aged 22-56 years, and are reported in the Tables. The median values and the range were used to express the results. Statistics were performed by means of one-tailed Wilcoxon test for paired data and Spearman rank correlation coefficient. zyxwvutsrqpo zy zy Results After 7 weeks of treatment with Captopril at a daily dosage ranging from 150 to 500 mg, systolic and Table 1. Supine and standing blood pressure (BP) and heart rate (HR) at the end of the placebo period and of 7 weeks of treatment with Captopril. EH =essential hypertension; UP = unilateral pyelonephritis; RVH = renovascular hypertension. Placebo Diagnosis No. I EH No. 2 U P No. 3 EH No. 4 EH No. 5 RVH No. 6 EH No. 7 EH No. 8 EH No. 9 EH No. 1 0 E H Median Captopril SupineBP H R (mmHg) (beats min-') Standing BP H R (mmHg) (beats min-I) Supine BP H R (mmHg) (beats min-l) Standing BP H R Dose (mmHg) (beats min-I) (mgd a y - ' ) 175/135 165/90 140/100 185/135 145/95 140/105 76 76 72 80 68 68 80 177/140 170/130 I 50/80 212/118 170/120 I75/95 I35/95 190/135 140/100 130/90 72 80 112 78 80 70 88 72 80 80 125/85 120/85 130/90 200/110 145/100 130/80 145/95 160/120 152/100 lSO/l05 76 75 104 72 72 76 68 72 90 76 I30/85 145/105 140/95 200/ I 1 5 l50/l05 140/85 I40/95 l60/l14 I SO/ 100 l55/l05 82 84 I10 78 76 80 76 80 94 84 200 so0 200 400 250 I50 450 500 300 300 163/103 76 I70/109 80 145*/98 76 148*/103 81 300 lSO/lOO 160/80 205/105 165/115 76 76 108 *P< 0.05 I,. placebo RENAL EFFECTS OF CAPTOPRIL zy zy 41 1 Table 2. Renal plasma flow (RPF). glomerular filtration rate (GFR) and filtration fraction ( F F ) during the placebo period and after 7 weeks of treatment with Captopril Placebo Captopril RPF GFR (mI min-l) (mi m i n - 0 FF No. I No. 2 No. 3 No. 4 No. 5 No. 6 No. 7 No. 8 No. 9 No. 10 562 588 616 300 612 495 509 546 398 522 134 123 I08 64 I43 87 120 I42 93 127 0.24 0.21 0.19 0.2I 0.23 0.17 0.24 0.26 0.23 0.24 Median Range 534 300-616 I22 64-143 0.23 47 1 0.17-0.26 333-606 RPF (mI min-I) GFR (mI min-I) FF 415 529 447 333 47I 516 92 88 82 71 109 109 0.22 0.17 0.19 0.2I 0.24 0.19 - - - 587 339 606 I I6 0.20 0.24 0.15 zyxwvutsrqpon zyxwvutsrqp zyx zyxwvuts zyxwv 79 88 0.20 0.15-0.24 88* 71-1 16 *P< 0.05 I , . placebo. diastolic pressure fell. However only the decrease of the systolic pressure was significant, both in the supine and standing posture (Table 1). The blood pressure was actually normalized by the treatment (i.e. supine diastolic pressure 6 9 5 mmHg) in four patients, it was reduced in three and it remained almost unchanged in the other three. Of these one had moderate and two mild hypertension. Heart rate was practically unaffected by the treatment. Pretreatment standing PRA was normal in nine patients and high in one. No correlation was found between pretreatment PRA values and the fall in blood pressure after 7 weeks of treatment. At the end of the dose ranging period, PRA increased to a variable extent in all cases: from a median value of 5.4 (range 1-16.7) to 10.6 (1.7-19.5) ng ml-' h - ' (P<0.05). No further increase was observed at the end of the full treatment period when it was 9.5 (2.55-19.8) ng ml-' h- I . Urinary aldosterone excretion rate was normal in all cases before the treatment, and fell at the end of the 3 weeksofdoserangingfrom 13 (2.3-52.5)pg24h-I to 7 (2.3-20.8) ( P <0.01) even though remaining within the normal values. No significant further decrease was observed after the following 4 weeks of full treatment when it was 7.4 ( 1 , 6 1 4 ) pg 24 h-I. R P F and G F R , measured during the placebo period, were normal in seven patients and reduced in three (Table 2). At the end of the full treatment period mean G F R was significantly lower than that measured during the placebo (P< 0.05), while mean R P F did not change significantly. No correlation was found between the fall in R P F and the fall in blood pressure. Mean daily proteinuria was normal and urine alphaz-macroglobulin was undetectable either before. during and at the end of the treatment in every case zyxw Table 3. Effects of Captopril on glomerular permeability. 24 h proteinuria, clearance of albumin and transferrin, and excretion rate of alanine-aminotransferase (ALT) per dl of glomerular filtration rate (median and range). Normal values: proteinuria < 2.45 mg 24 h - l ; normalized albumin clearance <4.1 x lo-' d1-l of G F R ; normalized transferrin clearance < 3.2x lo-' dl-' of G F R ; normalized ALT excretion rate < 5.0mU dl I of GFR. Proteinuria (mg 24 h - ' ) Placebo period After 3 weeks of dose ranging After 4 weeks o f full treatment 1.1 (0'1-3) 1.2(W) 1.0 (0.1-2.9) 2,5(1.5-6.4)x 1.8(0.3-5.5)x Normalized albumin clearance (dl-l of G F R ) 2.1 ( 1 , 2 4 9 ) ~ Normalized transferrin clearance 3.3 (0.7-60.1) x lo-' (dl-' of G F R ) Normalized ALT excretion rate (mU d l - ' of G F R ) 1.0 (0-1.7) 1.2(0.6-5.5)~low4 1.5 (0.8-6.1)x lo-' 1.7(0.3-6.5) 2.0 (0.8-2.4) 412 zyxwvutsrq zyxwvutsrqp zyxwvutsr zyxwvutsrq A. C. PESSINA et al. zyxwvutsrq Table 4. Effects of Captopril on the renal tubule. Clearance of malate dehydrogenase (MDH) and excretion rate of alpha-glucosidase (AGL) and gammaglutamyl transferase (GGT) per dl of glomerular filtration rate (median and range). Normal values: normalized MDH clearance i78 x I0W2dl-' of GFR; normalized AGL excretion rate < 2.0 mU dl-' of GFR; normalized GGT excretion rate 5.142.0 mU dl-' of GFR. No. of observations Placebo period Normalized MDH clearance (dl-' of GFR) 5 Normalized AGL excretion rate ( m u dl-l of GFR) 5 Normalized GGT excretion rate ( m u d1-I of GFR) 6 After 3 weeks of After 4 weeks of dose ranging full treatment I4 (0-66) x lo-' 0 (c21) x 9 ( 4 1 5 ) x lo-' 2.2 (1 ,(t3.9) 3.2 ( 2 4 3 . 8 ) 2.6 (0.3-2.9) 13.3 (7.7-28. I ) 19.8 (4.8-36.6) 20.2 ( I 5.5-27.0) (Table 3). Median normalized albumin clearance remained within normal levels throughout the study. Median normalized transferrin clearance was above normal during the placebo period due to one patient with very high transferrin excretion rate. However, after the treatment, median values were normal. Median normalized ALT excretion rate was normal and remained unaltered during the study (Table 3). Normalized GGT and AGL excretion rates were normal during the placebo period in all cases. After the 3 weeks of dose ranging and at the end of the full treatment both were practically unchanged (Table 4). Normalized MDH excretion rate was normal in every case during the study (Table 4). Discussion The results obtained in the present study confirm the experience of other authors [4,9] on the variabledegree of effectiveness of Captopril in lowering blood pressure. The degree of the hypotensive response did not seem to depend on the severity of the hypertension or on the dosage used. Contrary to the acute blood pressure lowering effect [28], the medium-term hypotensive effect was not correlated to the pretreatment PRA. These results would suggest that in this condition Captopril lowers blood pressure by mechanisms other than that of decreasing circulating Angiotensin 11. However, renin levels do only within certain limits reflect the role of the renin-angiotensin system in the control of arterial pressure, as pointed out by Brunner et al. [29]. Whatever the mechanism of the hypotensive action of Captopril might be, its effects on renal function (the aim of the present study) consisted in a moderate reduction of RPF and a significant fall of G F R with a consequent decrease of FF. The most likely explanation for the reduction of RPF is the fall of the blood pressure. It was in fact greater in the patients who displayed a good hypotensive response than in those who did not respond. The fact that no significant correlation could be found between these two para- meters is to be attributed to the small number of cases studied. The greater fall in G F R than in RPF, with a consequent decrease in FF, indicates the loss of autoregulation. This is due to the lack of constriction of the efferent arterioles of the glomeruli, possibly secondary to the inhibition of the formation of Angiotensin 11, which is known to exert a prominent constrictor effect on these vessels [ 16, 171. A decrease in FF was also found by Mimran et al. [30] who, however, noted an increase in RPF and a fall in G F R after the acute oral administration of Captopril. In contrast with these findings, Hollenberg et al. [3I ] observed an increase in endogenous creatinine clearance averaging 33%. One reason for this discrepancy could be that they obtained a smaller fall in blood pressure than that obtained in our good responders, so that the reduced serum concentration of Angiotensin I1 and the consequent vasodilation might have masked the effect of the reduced perfusion pressure on GFR. In fact, Angiotensin I1 has recently been demonstrated to play an important role in the control of G F R through its effect on afferent and efferent arterioles [32]. All the indices of glomerular capillary permeability were unaltered after 3 and 7 weeks of therapy. This might be due to the fact that PRA did not reach in any of our patients the high levels which are known to provoke proteinuria in other species [ll-181. No data are available on the renin levels in the patients who had proteinuria during Captopril treatment. Still the possibility exists that the proteinuric effect of renin could depend not by renin itself but be mediated by Angiotensin I1 formation. In fact, it has been shown that renin-induced proteinuria in the rat is secondary to an increase in FF due to efferent arteriolar constriction produced by Angiotensin I1 [ 16, 171. On the contrary, in our patients FF actually decreased as a consequence of the inhibition of Angiotensin I1 formation. All the indices of functional and anatomical damage of the renal tubules were also unchanged after 7 weeks of treatment. In conclusion, it is unlikely that the proteinuria reported by others after 3 weeks to 7 months of zyx zyxwvuts zyxwvutsrqp RENAL EFFECTS OF CAPTOPRIL treatment with Captopril [5-8] is due to either intrarenal haemodynamic changes or to a direct toxic effect of renin. The late onset of proteinuria makes it more likely that some immunological mechanism is involved. 413 16 Pessina A.C. & Peart W.S. (1972) Renin induced proteinuria and 17 the effects of adrenalectomy. I . Haemodynamic changes in relation to function. Proc R0.v Soc Lond B 180,43-60. Pessina A.C.. Hulme B. & Peart W.S. (1972) Renin induced proteinuria and the effects of adrenalectomy. 11. Morphology in relation to function. Proc Rqv Soc Lond B 180, 61-71. Brandt J.L. & Gruhn J.G. (1948) Effect of renin o n proteinuria and PAH clearance at low plasma levels. Ant J Physiol 153, 458464. C0henA.M. & Wa1kerG.W. (1967)Theuseofrenalclearanceof enzymes as an indicator of selective permeability of the renal glomerulus. J Lab Clin Med 4, 571-579. Hardwicke J. (1970) Proteinuria. Sci Busis Med Ann Rivs 1, 2 1 1-229. Harrison J.F.. Lunt G.S.. Scott P. & Blainey J.D. (1968) Urinary lisozyme, ribonuclease and low molecular-weight protein in renal disease. Luncer i, 371-375. Bonini P.A. & Ceriotti G . (1970) Human urinary alpha-glucosidase as an index of kidney tubular damage. Clin Cl7im Acra 27, 415419. Thiele K.G. ( I 973) Gamma-glutamyltranspeptidase Activitit im Urin bei gesunden und nierenkranken. Klin Wschr 51, 339-345. Ceriotti C. & Guarnieri G.F. (1974) Physiological background for a possible utilization of urinary enzyme in clinical diagnosis. Proceedings of rhe 6th Inrernarional Sj~niposiim7 on Clinic,ul Enzymology (ed. by A. Burlina). pp. 255-270. Piccin. Padova. Tidstrom B. (1963) Quantitative determination of protein in normal urine. Srand J Clin Lab Inresr 15, 167- 172. Laurel1 C.B. (1972) Electrophoretic and electroimmunochcmical analysis of protein. ScandJ Clin Lab Inrexi 29, Suppl 124.21 -23. Weeke B. (1973) Rocket immunoelectrophoresis. Quanriiuriw Immitnoe/er/rophore.sis (ed. by N . H. Axelsen. J. Krcrll and B. Weeke). pp. 3 7 4 6 . Universitetsforlaget. Oslo. Case D.B.. Laragh J.H., Sealey J.E.. Sullivan P.A. & McKinstry D.N. (1978) Clinical experiences with blockage of the reninangiotensin-aldosterone system by an oral converting enzyme inhibitor (SQ 14225, Captopril) in hypertensive patients. Progr Caru'iotusc Dis 21, 195-206. Brunner H.R.. Wauters J.P.. McKinstry D.N.. Waeber N.. Turini G . & Gavras H. (1978) Inappropriate rcnin secretion unmasked by Captopril (SQ 14225) in hypertension o f chronic renal Failure. Lancer ii. 704707. Mimran A,. Brunner H.R., Turini G.A.. Waeber H. & Brunncr D. (1979) Effect of Captopril on renal vascular tone in patients with essential hypertension. Clin Sci 5 7 , 4 2 1 ~ 4 2 3 s . Hollenberg N.K., Swartz S.L., Passan D.R. & Williams G.H. ( 1979) Increased glornerular filtration rate after converting enzyme inhibition in essential hypertension. N Engl J M r d 301. 9-12. Hollenberg N.K.. Williams G.H.. Burger B.. lshikawa I . & Adams D.F. (1976) Blockade and stimulation of renal. adrenal and vascular Angiotensin 11 receptors with I-sar-8-ala-angioten5in 11 in normal man. ./ C/in It7tV.Sl 57, 3 9 4 6 . zyxwvutsrqpo zyxwvutsrqponm 18 References I Case D.B.. Wallace J.M. & Keim H.J. (1976) Estimating renin participation in hypertension: superiority of converting enzyme inhibitor over saralasin. Am J Med 61, 79G796. 2 Case D.B., Wallace J.M. & Keim H.J. (1977) Possible role of renin in hypertension as suggested by renin-sodium profiling and inhibition of converting enzyme. N Engl J Met/ 2%. 641-646. 3 Williams G.H. & Hollenberg N.K. (1977) Accentuated vascular and endocrine response to SQ 20881 in hypertension. N Engl J Med 297, 184-188. 4 Bravo E.L. & Tarazi R.C. (1979) Converting enzyme inhibition with an orally active compound in hypertensive man. Hyperrension I, 39-46. 5 Prins E.J.L., Hoorntje S.J., Weening J.J. & Donker Ab.J.M. (1979) Nephrotic syndrome in patient on Captopril. Luncer ii, 306307. 6 Case D.B., Atlas S.A., Mouradian J.A.. Fishman R.A.. Sherman R.L. & Laragh J.H. (1980) Proteinuria during long-term Captopril therapy. J Am Med Ass 244, 246349. 7 Hoorntje S.J., Kallenberg C.G.M., Weening J.J.. Donker Ab.J.M., The T.H. & Hoedemaker P.J. (1980) Immune-complex glomerulopathy in patients treated with Captopril. Lancer i, 1212-1214. 8 Kinkaid-Smith P.. Whitworth J.A.. Walter N.M.A. & Dowling J.P. (1980) Immune-complex glomerulopathy and Captopril. Luncet ii, 37. 9 Gavras H.. Brunner H.R., Turini G.A.. Kershaw G.R., Tufft C.P.. Cuttelod S., Gavras I.. Vukovich R.A. & McKinstry D.N. (1978) Antihypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ 14225 in man. N Engl J Med 298, 991-995. 10 Johnston C.I.. Millar J.A., McGrath B.P. & Matthews P.G. (1979) Long-term effects of Captopril (SQ 14225) on blood pressure and hormone levels in essential hypertension. LUt7Cel ii, 493-496. 11 Pickering G.W. & Prinzmetal M. (1940) The effect of renin on urine formation. J Physiol98, 314-335. 12 Lippman R.W., Ureen H.J. & Oliver J. (1951a) Mechanism of proteinuria. J E.rp Med 93, 325-336. 13 Lippnian R.W., Ureen H.J. & Oliver J . (1951b) Mechanism of proteinuria. J ESP M i d 93, 605-614. 14 Sellers A.L.. Smith S.. Marmorston J. & Goodman H.C. (1952) Studies on the mechanism of experimental proteinuria. J E.r, Med 96,643-65 I . 15 Deodhar S.D., Cuppage F.E. & Gableman E. (1964) Studies on the mechanism of experimental proteinuria induced by rcnin. J E.vp Med 120, 677-690. 19 20 21 22 23 24 25 26 zyxwvutsrqpo zyxwvutsrqpon zyxw zyxwvutsrq zyxwvutsrqpo 27 28 29 30 31 32