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Hemodynamic and endocrine changes associated with captopril in diuretic-resistant hypertensive patients
Hemodynamic and Endocrine Changes Associated with Captopril in Diuretic-Resistant Hypertensive Patients
TOSHIRO FUJITA, M.D. KATSUYUKI ANDO, M.D. HIROSHI NODA, M.D. YUJI SATO, Ph.D. NOBUKI YAMASHITA, M.D. KAMEJIRO YAMASHITA, M.D. Ibaraki, Japan
From the Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukaba, Ibaraki, Japan. Requests for reprints should be addressed to Dr. Toshiro Fuji& Department of Internal Medicine, University of Tsukaba, Sakura-mura, Ibaraki-ken 305, Japan. Manuscript accepted January 26. 1982.
To evaluate the therapeutic efficacy of oral angiotensin-converting enzyme inhibition with tow-dose (average 30 mg/day) captoprii in diuretic-resistant hypertension, its lone_term cardioc&cuietory action was determined by dye-dilution method and venous-occlusion forearm piethysmography in 11 uncontrolled patients taking a thiazide diuretic. Significant declines in mean blood pressure (average 12.4 f 1.4 percent) and systemic vascular resistance (28.7 f 3.2 percent) accompanied an increase in cardiac &put (24.8 f 4.1 percent). Forearm vascular resistance (18.0 f 2.7 percent) decreased considerably, but the decrease in limb vascular resistance did not parallel the fail in systemic vascular resfstance in magnitude (p
September 1982
The American Journal of Medklne
Volume 73
341
CAPTOPRIL
IN DIURETIC-RESISTANT
TABLE I
HYPERTENSION-FUJITA
ET AL.
Clinical Characteristics of Patients Studied (mean f S.E.M.) Electrocardiographic Blood Pressure inOutpatient Clinic (mmHg)
Patient 1 2 3 4 5 6 7 a 9 10 11
Sex/Age
Before l’hiazide
AfterThiaride
F, 36 M,51 F, 45 M,57 M,55 M,47 M,52 M,50 M,34 M,56 M,51 48.5 f 3.3
160/100 162/115 1751106 190/126 150/110 165197 1701116 182iioa 1641106 iao/io4 1701112 170/109f 312
140190 125194 152194 165/119 1441106 140192 1661114 160192 1461108 1621102 162/110 153/102f 513
In uncontrolled hypertensive patients taking a thiazide diuretic, systemic vascular resistance is frequently elevated with reduced cardiac output, and thus the elimination of circulating angiotensin II with captopril would be expected to reduce systemic vascular resistance, leading to the fall in blood pressure. Since a reduction of systemic vascular resistance with captopril causes an improvement in cardiac output in patients with heart failure and low cardiac output [ 1 l-161, important hemodynamic effects can occur with the use of captopril in hypertensive patients taking a thiazide diuretic with elevated plasma renin activity. We have correlated the hemodynamic changes observed with alterations in plasma renin activity and aldosterone levels as well as with the degree of blood pressure control. Moreover, inhibition of the converting enzyme can cause redistribution of regional blood flow in favor of the brain, heart, and kidneys in situations in which the renin-angiotensin system is stimulated [ 171. Recently, Faxon et al. [ 18,191 have demonstrated that, in contrast to the actions of generally available vasodilator drugs, essentially no limb vasodilation occurred in either arteries or veins following administration of teprotide and captopril to patients with chronic congestive heart failure. Accordingly, in the present study, we have investigated the long-term systemic and peripheral hemodynamic effects as well as the interplay of several hormonal factors during treatment with captopril.
METHODS Patients. Twenty-five patients with “essential” hypertension were studied. informed consent was obtained from each patient. The diagnosis was based on history, and results of physical examination, appropriate laboratory tests, and intravenous pyeiography. Renal arteriography and renal vein blood sampling for measurement of plasma renin activity were performed when indicated.
342
September 1982
The American Journal of Medicine
LeflVentricular Hypertrophy -
Crealinine
Clearance (milmin) 98.2 90.4 80.3 75.4 92.2 104.6 74.4 102.4 84.2 86.4 80.2 88.1 f 3.2
All patients had been untreated. They began a regimen of 4 to 6 mg per day of trichiorthiazide, and were followed up on an outpatient basis for about two months. in 14 of 25 patients, diastolic pressure was decreased below 90 mm Hg after two-month treatment with the diuretic. Conversely, 11 of 25 patients had a diastolic pressure above 90 mm Hg despite ceiling doses of the diuretic. “Diuretic-resistant” hypertension was diagnosed in these 11 patients, and they were followed up for the next study. Eleven patients were studied in the Captopril Protocol. diuretic-treated state. Systemic and forearm hemodynamic measurements were repeated until three similar determinations 15 minutes apart demonstrated homeostasis. Patients were followed up on an outpatient basis at weekly intervals, and the initial dosage of captopril (5 mg, three times daily) was increased at each visit until control of blood pressure was obtained (up to a dosage of 45 mg/day). On the fourth week of captopril treatment, the patients took their morning dose of captoprii (5 to 15 mg) in the laboratory, and the hemodynamic data were obtained about 60 to 75 minutes later. Systemic Hemodynamics. Systemic blood pressure was measured by sphygmomanometer. Cardiac output was determined by dye-dilution (indocyanine green). Total systemic vascular resistance was calculated as the ratio of mean blood pressure to cardiac output, expressed in dynes/sec/cmT5. Peripheral Hemodynamks. Forearm piethysmography was carried out using the mercury-filled rubber strain gauge placed around the midforearm. Patients were studied in the supine position with the forearm elevated so that venous pressure in the arm approached zero; the hand was isolated from the forearm by inflation of a wrist cuff to suprasystolic pressures. Forearm venous occlusion was rapidly achieved by inflation of a sphygmomanometer cuff wrapped around the upper arm and attached to a container of compressed air with a special pressure gauge preset at 40 mm Hg. Forearm blood flow was calculated from the change in forearm circumference during acute venous occlusion and was expressed as ml/100 ml tissue/min. Forearm vascular resistance was calculated as the ratio of mean blood pressure to forearm blood flow expressed in units of mm Hg/mi/lOO ml tissueimin. Ail values for forearm blood flow and forearm vascular resistance were
Volume 73
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TABLE ii
IN DIURETIC-RESISTANT
HYPERTENSION-FUJITA
ET AL.
Responses of Plasma Renin Activity, Aidesterone, and Norepinephrfne Concentrations to Captoprii (mean f S.E.M.) Plasma Renin Activity (nglmllhr) Before After
Patient
1 3.70 1.69 8.08 2 4.36 1.74 2.72 3 9.41 4 5.18 5 4.62 8.23 3.54 6 2.26 7 4.50 7.06 8 4.41 12.50 9.41 9 4.85 10 4.68 3.60 11 8.53 3.45 Mean f S.E.M. 3.70 f 0.38 7.08 f 0.92
Aldosterone (Wd)) Afler Before 10.5 8.1 5.4 4.4 9.1 5.6 6.6 6.0 4.9 5.8 12.3 11.2 15.2 10.6 8.0 7.2 12.4 9.6 13.7 11.0 8.8 6.8 9.8 f 1.0 7.8 f 0.8
Norepinqhrine Wm)) Before After 102 279 185 89 309 278 290 120 85 341 242 211f29
82 184 94 98 462 121 246 127 125 124 198 169f33 NS
obtained by averaging at least six individual determinations
nephrine concentration did not correlate with alterations
that were within 5 percent
in systemic vascular resistance. Plasma aidosterone concentration decreased in ail patients (p
Hormonal Factors.
of each other.
Before and after captoprii
blood for hormonal determinations
treatment,
was drawn with the patient
in the supine position, and the plasma was frozen at -7OOC. Plasma renin activity was determined of angiotensin
by radioimmunoassay
I generated during incubation of plasma at pH
6.5 and 37’C (normal range 0.4 to 2.2 ng/mi/hour). Plasma aidosterone concentration was quantitated by the radioimmunoassay technique, using a commercial kit (CEA-IRESOFUN).Plasma norepinephrine was measured by the method of Schwedt [20], using high-pressure liquid chromatography combined with automatic fiuorimetric detector. The statistical methods used were regression analysis and two-tailed Student t test for paired data. Ail data are expressed as mean values f standard error of the mean.
RESULTS
/ Pretreatment
The clinical characteristics of the patients studied are presented in Table I. After treatment with a diuretic,
declines in both systolic (10 percent) and diastolic (6 percent) pressures were statistically significant (both p
PRA
(ng/ml/hr)
2 lu
ai b
d ae -50’
I
y=-5.52x-8.29
.
Figure 1. Relationship between the pretreatment plasma renin activity (PRA) and percent decrease in systemic vascular resistance (SW) after captopril in 11 patients with hypertension refractory to a diuretic.
September 1982
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Volume 73
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CAPTOPRIL
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HYPERTENSION-FLlJITA
ET AL.
SVR
P
:: 60-
50-
s
TH
-
.”
. .
TH
TH+CP
HR
-
TH+CP
8
MBP
\pco’ool
3OOOr
P
4.5
L
TH
-
TH+CP
2.0 L
TH
-
TH+CP
Ffgure 2. Changes in cardi~irculatory dynamics producs by low-dose captopril (CP) (mean daily dose 30 mg) in 17 hypertensive patients treated with a thiaride on heart rate (HR), mean blood pressure (MBP), systemic vascular resistance (SW?), and cardiac index (Cl). 7li = during the treatment with a thiazide. TH i- CP values were obtained four weeks after oral captopril administration.
Systemic vascular resistance fell substantially, from the elevated resting level of 1,909 f 163 to 1,330 f 86 dynes/set/cm-5 after captopril treatment. Cardiac index improved 25 percent from a mean value of 2.9 f 0.1 to 3.6 f 0.1 liter/min/m* after treatment, while stroke volume index increased 23 percent from 40.5 f 2.1 to 49.7 f 2.7 ml/beat/m*; increments in both indexes were significant (p X0.001). Heart rate did not significantly change. In all patients, the magnitude of the decrease in mean blood pressure resulting from converting enzyme inhibition was related to the concurrent changes in systemic vascular resistance (r = 0.759, p
September 1982
IPCO.01
_J
I
Comparative percent change in systemic vasCuiar resistance @VP) and foreamI vascular resistance (FVR) four weeks after captopril administration.
SVR
344
I
F&ure 3.
r
500
FVR
The American Journal of Yedtclne
did not change significantly after captopril treatment (1.5 1 f 0.12 ml/100 ml tissue/min; N.S.) despite improved cardiac output. Calculated forearm vascular resistance diminished from an average value of 88.3 f 7.8 to 73.5 f 6.0 units after captopril treatment (p <0.005). Figure 3 compares the changes in systemic and forearm vascular resistances after captopril treatment. The reduction in systemic vascular resistance (29 f 3 percent) was significantly greater (p
Volume 73
CAPTOPRIL IN DIURETIC-RESISTANT
studies with teprotide and captopril in hypertension [6,7], for systemic vascular resistance in heart failure [11,12,21], and in normal man [22]. From the hemodynamic responses demonstrated in our patients with diuretic-resistant hypertension, captopril appears most efficacious in the subset of diuretic-treated patients whose cardiac dysfunction is hemodynamically characterized by marked elevation of systemic vascular resistance with moderately reduced cardiac output. Almost all patients in this study showed a substantial decrease in systemic vascular resistance, and there was also a concomitant increase in cardiac output and stroke volume. According to the effect of captopril on cardiac function, short-term administration for up to several days in patients with hypertension usually had no significant effect on heart rate, stroke volume, or cardiac output [23,24]. In patients with high-renin hypertension, however, cardiac output is increased by short-term administration of captopril [25]. During longer-term administration, moreover, cardiac output and stroke volume increased slightly [24,26]. Based on the correlation between the changes in systemic vascular resistance and those in cardiac output in our study and in previous studies of heart failure [ 12,2 11,the increase in stroke volume may be mainly due to the reduction in afterload and hence better ventricular emptying, although an increase in myocardial contractility due to coronary artery vasodilation may contribute to this effect. Coronary artery vasodilation, with the increase in coronary blood flow during converting enzyme inhibition, has been documented previously by Gavras et al. [ 171. Furthermore, improvement in cardiac function has been observed in patients with heart failure treated with captopril [lo151. Therefore, long-term blockade of the renin system, when routinely available, might prove preferable, since it would be expected to counteract some of the undesirable effects of sodium depletion due to diuretics alone, such as decreased cardiac output and increased peripheral resistance. The rise in plasma renin activity following captopril administration is compatible with the negative feedback control of renal renin release and serves to confirm angiotensin blockade in these patients. In addition, we found a simultaneous reduction in aldosterone levels, as might be expected following angiotensin inhibition. Furthermore, aldosterone has cardiovascular actions of its own [27,28]. These findings taken together support the view that the renin-angiotensin-aldosterone system possibly participates not only in the maintenance of blood pressure but also in abnormal cardiovascular homeostasis in diuretic-resistant hypertensive patients. Plasma norepinephrine concentrations did not sig-
September
HYPERTENSION-FUJITA
ET AL.
nificantly change, as in previous experience with captopril and teprotide [ 12,13,19]; reflex tachycardia was absent despite a reduction in blood pressure after therapy, suggesting that substantial adrenergic stimulation did not occur. The absence of reflex tachycardia could be explained on the basis not only that the antagonists of angiotensin II abolish the positive chronotropic effect of angiotensin on the heart, which could occur either directly or by interaction with the sympathetic nervous system [29], but also that reduced circulating angiotensin II decreases catecholamine release
[131. Because converting enzyme participates also in the degradation of the vasodilator bradykinin to inactivate peptides, it is possible that the cardiovascular effects of captopril are due not only to the elimination or decrease in the level of circulating (or local tissue) angiotensin II, but also to cumulation of bradykinin and/or prostaglandin E [30-321. Bradykinin (admittedly in high dosage), however, increases cardiac output because it markedly increases heart rate, while its effects on stroke volume are inconsistent-that is, the hemodynamic pattern of response to bradykinin is the opposite of the one observed in the present and previous studies ]331. Although cardiac output increased 25 percent following captopril therapy, no increase in forearm blood flow was detected in this study. These findings are consistent with the experience of Faxon et al. [ 191 with captopril, in patients with severe congestive heart failure. These data indicate that converting enzyme inhibitor does not significantly increase regional flow to the limb circuit in patients with congestive heart failure nor in hypertensive patients treated with a diuretic. Regional redistribution of blood flow has been verified in sodium-depleted dogs given teprotide [ 151 and in spontaneously hypertensive rats given captopril [34], and flow to the renal, cerebral, and myocardial vasculature increased at the expense of cutaneous and skeletal muscular flow. Possible mechanisms for this phenomenon of regional redistribution of flow after converting enzyme inhibition include differences in tissue concentrations of converting enzyme or in local affinity of angiotensin II receptors. Moreover, converting enzyme inhibition may influence the tissue concentrations of bradykinin and prostaglandins. Recent experimental evidence suggests that the vasculature of different organs may display various degrees of sensitivity to the action of vasoconstrictive factors [35-371. The renal and coronary vessels were found to exhibit the greatest increase in local resistance after administration of exogenous angiotensin, while the muscular and cutaneous vessels exhibit greater constriction than the coronary vessels after adrenergic
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ET AL.
stimulation [35]. Since during captopril administration, the renin-angiotensin system was suppressed but substantial adrenergic stimulation did not occur despite a reduction in blood pressure, the converting enzyme inhibitor might be expected to cause more pronounced vasodilation resulting from elimination of angiotensin II, possibly because of the relative contribution of the adrenergic factors just mentioned to the observed changes. In summary, captopril in very low dose (average 30
mg/day) normalizes blood pressure without any side effects, associated with ventricular afterload reduction and resultant increase in cardiac output, and the reordering of regional blood flow, suggesting that it may be a useful adjunct to the therapy of severe hypertensive patients treated with a diuretic. Therefore, captopril and a diuretic probably should be used in combinations at low dosage to minimize not only humoral and hemodynamic compensatory mechanisms but also perceptible side effects.
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Fujita T, Henry WL. Barber FC, et al.: Factors influencing blood pressure in salt-sensitive patients with hypertension. Am J Med 1980; 69: 334-344. Carey RM, Douglas JG, Schweikert JR, et al.: The syndrome of essential hypertension and suppressed plasma renin activity; normalization of blood pressure with spironolactone. Arch Intern Med 1972; 130: 849-854. Vaughan ED, Carey RM, Peach MJ, et al.: The renin response to diuretic therapy. A limitation of antihypertensive potential. Circ Res 1978; 42: 376-381. Gavras H, Waeber B, Kershaw GR, et al.: Role of reactive hyperreninemia in blood pressure changes induced by sodium depletion in patients with refractory hypertension. Hypertension 1981; 3: 441-447. Brunner HR, Gavras H, Waeber B, et al.: Oral angiotensinconverting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med 1979; 90: 19-23. Gavras H, Brunner HR, Turini GA, et al.: Antihypertensive effect of the oral angiotensin converting enzyme inhibitor Xl 14225 in man. N Engl J Med 1978; 298: 991-995. Fujita T, Yamashita N, Yamashita K: Effects of angiotensinconverting enzyme inhibition on blood pressure and plasma renin activity in essential hypertension. Am Heart J 1981; 101: 259-368. Atkinson AB, Brown JJ, Leber AF, et al.: Combined treatment of severe intractable hypertension with captopril and diuretic. Lancet 1980; II: 105-108. White NJ, Rajagopalan B, Yahaya H, et al.: Captopril and furosemide in severe drug-resistant hypertension. Lancet 1980; II: 108-l 10. Koffer H, Vlasses PH. Ferguson RK: Captopril in diuretictreated hypertensive patients. JAMA 1980; 244: 25322535. Gavras H, Flessas A, Ryan TJ, et al.: Angiotensin II inhibitor: treatment of congestive heart failure in a high renin hypertension. JAMA 1977; 238: 880-882. Gavras H, Faxon DP, Berkoben J, et al.: Angiotensin converting enzyme inhibition in patients with congestive heart failure. Circulation 1978; 58: 770-778. Curtiss C, Cohn JN, Urobel T, et al.: Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 1978; 58: 763-769. Davis R, Ribner HS, Keung E, et al.: Treatment of chronic congestive heart failure with captopril, oral inhibitor of angiotensin converting enzyme. N Engl J Med 1979; 301: 117-121. Turini GA, Brunner HR, Gribic M, et al.: Improvement in chronic congestive heart failure by oral captopril. Lancet 1979; I: 1213-1215. Awan NA, Evenson MK, Needham KE, et al.: Efficacy of oral angiotensin-converting enzyme inhibition with captopril
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therapy in severe chronic normotensive congestive heart failure. Am Heart J 1981; 101: 22-31. Gavras H, Liang C-S, Brunner HR: Redistribution of regional blood flow after inhibition of the angiotensin converting enzyme. Circ Res 1978; 43 (Suppl I): l-59-l-63. Faxon DP, Creager MA. Halperin JL, et al.: Central and peripheral hemodynamic effects of angiotensin inhibition in patients with refractory congestive heart failure. Circulation 1980; 61: 925-930. Faxon DP. Halperin JL, Creager MA, et al.: Angiotensin inhibition in severe heart failure: acute central and limb hemcdynamic effects of captopril with observations on sustained oral therapy. Am Heart J 1981; 101: 548-556. Schwedt G: Separation and fluorimetric determination of adrenaline and noradrenaline. Combination of a highpressure liquid chromatography with an automatic analysis system. J Chromatogr 1977; 143: 463-471. Curtis C. Cohn JN, Vrobel I, et al.: Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 1978; 58: 763-770. Niarchos AP, Pickering TG, Case DB, et al.: Role of the renin-angiotensin system in blood pressure regulation: the cardiovascular effects of converting enzyme inhibition in normotensive subjects. Circ Res 1979; 45: 829-837. Turini GA, Brunner HR. Waeber B, et al.: Long term cardiac responses of hypertensive patients treated by an inhibitor of angiotensin converting enzyme. Clin Res 1979; 27: 319A. Fagard R, Amery A, Lijnen P, et al.: Haemodynamic effects of captopril in hypertensive patients: comparison with saralasin. Clin Sci 1979; 57: 131A-134s. Niarchos AP, Pickering TG, Wallace JM, et al.: Hemodynamic effects of the converting enzyme inhibitory teprotide in normal- and high-renin hypertension. Clin Pharmacol Ther 1980; 28: 592-610. Fagard R, Amery A, Reybrouck T. et al.: Acute and chronic systemic and pulmonary hemodynamic effects of angiotensin converting enzyme inhibition with captopril in hypertensive patients. Am J Cardiol 1980; 46: 295300. Ballard K. Lefer A, Sayers G: Effect of aldosterone and plasma extracts on a heart-lung preparation. Am J Physiol 1960; 199: 221-225. Tanz RD: Studies on the inotropic action of aldosterone on isolated cardiac tissue preparations: including the effects of pH, ouabain and SC 8109. J Pharmacol Exp Ther 1962; 135: 71-78. Kairallah PA, Davila D, Papanicolaou N, et al.: Effects of angiotensin infusion on catecholamine uptake and reactivity in blood vessels. Circ Res 1971; 28-29 (suppl II): 11-96. Williams GH, Hollenberg NK: Accentuated vascular and endocrine response to SQ 20881 in hypertension. N Engl J
CAPTOPRIL IN DIURETIC-RESISTANT
31.
32.
33.
34.
Med 1977; 297: 184-188. Swantz SL, Williams GH, Hollenberg NK, et al.: Converting enzyme inhibition in essential hypertension. The hypotensive response does not reflect only redoced angiotensin II formation. Hypertension 1979; 1: 106-l 11. Fujita T, Yamashita N, Yamashita K: Effect of indomethacin on antihypertensive action of captopril in hypertensive patients. Clin Exp Hypertens 1981; 3: 939-952. DeFreita FM, Faraco EZ, DeAzevedo DF: General circulatory alterations induced by intravenous infusion of synthetic bradykinin in man. Circulation 1964; 29: 66-70. Koike H, Ito K, Miyamoto M, Nishino N: Effects of long-term
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35.
36.
37.
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blockade of angiotensin converting enzyme with captopril (SQ 14225) on hemodynamics and circulating blood volume in SHR. Hypertension 1980; 2: 299-303. Mark AL, Abboud FM, Schmid PG, et al.: Differences in direct effects of adrenergic stimuli on coronary, cutaneous and muscular vessels. J Clin Invest 1972; 51: 279-281. Freeman RH. Davis JD, Vitale SJ, et al.: lntrarenal role of angiotensin II: homeostatic regulation of renal blood flow in the dog. Circ Res 1973; 32: 692-698. Barbour JA, Bailie MD: Effect of the synthetic peptide SQ 20881 on distribution of blood flow in the rat. Proc Sot Exp Biol Med 1973; 143: 400-403.
The American Journal of Medlclna
Volume 73
347
TOSHIRO FUJITA, M.D. KATSUYUKI ANDO, M.D. HIROSHI NODA, M.D. YUJI SATO, Ph.D. NOBUKI YAMASHITA, M.D. KAMEJIRO YAMASHITA, M.D. Ibaraki, Japan
From the Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukaba, Ibaraki, Japan. Requests for reprints should be addressed to Dr. Toshiro Fuji& Department of Internal Medicine, University of Tsukaba, Sakura-mura, Ibaraki-ken 305, Japan. Manuscript accepted January 26. 1982.
To evaluate the therapeutic efficacy of oral angiotensin-converting enzyme inhibition with tow-dose (average 30 mg/day) captoprii in diuretic-resistant hypertension, its lone_term cardioc&cuietory action was determined by dye-dilution method and venous-occlusion forearm piethysmography in 11 uncontrolled patients taking a thiazide diuretic. Significant declines in mean blood pressure (average 12.4 f 1.4 percent) and systemic vascular resistance (28.7 f 3.2 percent) accompanied an increase in cardiac &put (24.8 f 4.1 percent). Forearm vascular resistance (18.0 f 2.7 percent) decreased considerably, but the decrease in limb vascular resistance did not parallel the fail in systemic vascular resfstance in magnitude (p
September 1982
The American Journal of Medklne
Volume 73
341
CAPTOPRIL
IN DIURETIC-RESISTANT
TABLE I
HYPERTENSION-FUJITA
ET AL.
Clinical Characteristics of Patients Studied (mean f S.E.M.) Electrocardiographic Blood Pressure inOutpatient Clinic (mmHg)
Patient 1 2 3 4 5 6 7 a 9 10 11
Sex/Age
Before l’hiazide
AfterThiaride
F, 36 M,51 F, 45 M,57 M,55 M,47 M,52 M,50 M,34 M,56 M,51 48.5 f 3.3
160/100 162/115 1751106 190/126 150/110 165197 1701116 182iioa 1641106 iao/io4 1701112 170/109f 312
140190 125194 152194 165/119 1441106 140192 1661114 160192 1461108 1621102 162/110 153/102f 513
In uncontrolled hypertensive patients taking a thiazide diuretic, systemic vascular resistance is frequently elevated with reduced cardiac output, and thus the elimination of circulating angiotensin II with captopril would be expected to reduce systemic vascular resistance, leading to the fall in blood pressure. Since a reduction of systemic vascular resistance with captopril causes an improvement in cardiac output in patients with heart failure and low cardiac output [ 1 l-161, important hemodynamic effects can occur with the use of captopril in hypertensive patients taking a thiazide diuretic with elevated plasma renin activity. We have correlated the hemodynamic changes observed with alterations in plasma renin activity and aldosterone levels as well as with the degree of blood pressure control. Moreover, inhibition of the converting enzyme can cause redistribution of regional blood flow in favor of the brain, heart, and kidneys in situations in which the renin-angiotensin system is stimulated [ 171. Recently, Faxon et al. [ 18,191 have demonstrated that, in contrast to the actions of generally available vasodilator drugs, essentially no limb vasodilation occurred in either arteries or veins following administration of teprotide and captopril to patients with chronic congestive heart failure. Accordingly, in the present study, we have investigated the long-term systemic and peripheral hemodynamic effects as well as the interplay of several hormonal factors during treatment with captopril.
METHODS Patients. Twenty-five patients with “essential” hypertension were studied. informed consent was obtained from each patient. The diagnosis was based on history, and results of physical examination, appropriate laboratory tests, and intravenous pyeiography. Renal arteriography and renal vein blood sampling for measurement of plasma renin activity were performed when indicated.
342
September 1982
The American Journal of Medicine
LeflVentricular Hypertrophy -
Crealinine
Clearance (milmin) 98.2 90.4 80.3 75.4 92.2 104.6 74.4 102.4 84.2 86.4 80.2 88.1 f 3.2
All patients had been untreated. They began a regimen of 4 to 6 mg per day of trichiorthiazide, and were followed up on an outpatient basis for about two months. in 14 of 25 patients, diastolic pressure was decreased below 90 mm Hg after two-month treatment with the diuretic. Conversely, 11 of 25 patients had a diastolic pressure above 90 mm Hg despite ceiling doses of the diuretic. “Diuretic-resistant” hypertension was diagnosed in these 11 patients, and they were followed up for the next study. Eleven patients were studied in the Captopril Protocol. diuretic-treated state. Systemic and forearm hemodynamic measurements were repeated until three similar determinations 15 minutes apart demonstrated homeostasis. Patients were followed up on an outpatient basis at weekly intervals, and the initial dosage of captopril (5 mg, three times daily) was increased at each visit until control of blood pressure was obtained (up to a dosage of 45 mg/day). On the fourth week of captopril treatment, the patients took their morning dose of captoprii (5 to 15 mg) in the laboratory, and the hemodynamic data were obtained about 60 to 75 minutes later. Systemic Hemodynamics. Systemic blood pressure was measured by sphygmomanometer. Cardiac output was determined by dye-dilution (indocyanine green). Total systemic vascular resistance was calculated as the ratio of mean blood pressure to cardiac output, expressed in dynes/sec/cmT5. Peripheral Hemodynamks. Forearm piethysmography was carried out using the mercury-filled rubber strain gauge placed around the midforearm. Patients were studied in the supine position with the forearm elevated so that venous pressure in the arm approached zero; the hand was isolated from the forearm by inflation of a wrist cuff to suprasystolic pressures. Forearm venous occlusion was rapidly achieved by inflation of a sphygmomanometer cuff wrapped around the upper arm and attached to a container of compressed air with a special pressure gauge preset at 40 mm Hg. Forearm blood flow was calculated from the change in forearm circumference during acute venous occlusion and was expressed as ml/100 ml tissue/min. Forearm vascular resistance was calculated as the ratio of mean blood pressure to forearm blood flow expressed in units of mm Hg/mi/lOO ml tissueimin. Ail values for forearm blood flow and forearm vascular resistance were
Volume 73
CAPTOPRIL
TABLE ii
IN DIURETIC-RESISTANT
HYPERTENSION-FUJITA
ET AL.
Responses of Plasma Renin Activity, Aidesterone, and Norepinephrfne Concentrations to Captoprii (mean f S.E.M.) Plasma Renin Activity (nglmllhr) Before After
Patient
1 3.70 1.69 8.08 2 4.36 1.74 2.72 3 9.41 4 5.18 5 4.62 8.23 3.54 6 2.26 7 4.50 7.06 8 4.41 12.50 9.41 9 4.85 10 4.68 3.60 11 8.53 3.45 Mean f S.E.M. 3.70 f 0.38 7.08 f 0.92
Aldosterone (Wd)) Afler Before 10.5 8.1 5.4 4.4 9.1 5.6 6.6 6.0 4.9 5.8 12.3 11.2 15.2 10.6 8.0 7.2 12.4 9.6 13.7 11.0 8.8 6.8 9.8 f 1.0 7.8 f 0.8
Norepinqhrine Wm)) Before After 102 279 185 89 309 278 290 120 85 341 242 211f29
82 184 94 98 462 121 246 127 125 124 198 169f33 NS
obtained by averaging at least six individual determinations
nephrine concentration did not correlate with alterations
that were within 5 percent
in systemic vascular resistance. Plasma aidosterone concentration decreased in ail patients (p
Hormonal Factors.
of each other.
Before and after captoprii
blood for hormonal determinations
treatment,
was drawn with the patient
in the supine position, and the plasma was frozen at -7OOC. Plasma renin activity was determined of angiotensin
by radioimmunoassay
I generated during incubation of plasma at pH
6.5 and 37’C (normal range 0.4 to 2.2 ng/mi/hour). Plasma aidosterone concentration was quantitated by the radioimmunoassay technique, using a commercial kit (CEA-IRESOFUN).Plasma norepinephrine was measured by the method of Schwedt [20], using high-pressure liquid chromatography combined with automatic fiuorimetric detector. The statistical methods used were regression analysis and two-tailed Student t test for paired data. Ail data are expressed as mean values f standard error of the mean.
RESULTS
/ Pretreatment
The clinical characteristics of the patients studied are presented in Table I. After treatment with a diuretic,
declines in both systolic (10 percent) and diastolic (6 percent) pressures were statistically significant (both p
PRA
(ng/ml/hr)
2 lu
ai b
d ae -50’
I
y=-5.52x-8.29
.
Figure 1. Relationship between the pretreatment plasma renin activity (PRA) and percent decrease in systemic vascular resistance (SW) after captopril in 11 patients with hypertension refractory to a diuretic.
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SVR
P
:: 60-
50-
s
TH
-
.”
. .
TH
TH+CP
HR
-
TH+CP
8
MBP
\pco’ool
3OOOr
P
4.5
L
TH
-
TH+CP
2.0 L
TH
-
TH+CP
Ffgure 2. Changes in cardi~irculatory dynamics producs by low-dose captopril (CP) (mean daily dose 30 mg) in 17 hypertensive patients treated with a thiaride on heart rate (HR), mean blood pressure (MBP), systemic vascular resistance (SW?), and cardiac index (Cl). 7li = during the treatment with a thiazide. TH i- CP values were obtained four weeks after oral captopril administration.
Systemic vascular resistance fell substantially, from the elevated resting level of 1,909 f 163 to 1,330 f 86 dynes/set/cm-5 after captopril treatment. Cardiac index improved 25 percent from a mean value of 2.9 f 0.1 to 3.6 f 0.1 liter/min/m* after treatment, while stroke volume index increased 23 percent from 40.5 f 2.1 to 49.7 f 2.7 ml/beat/m*; increments in both indexes were significant (p X0.001). Heart rate did not significantly change. In all patients, the magnitude of the decrease in mean blood pressure resulting from converting enzyme inhibition was related to the concurrent changes in systemic vascular resistance (r = 0.759, p
September 1982
IPCO.01
_J
I
Comparative percent change in systemic vasCuiar resistance @VP) and foreamI vascular resistance (FVR) four weeks after captopril administration.
SVR
344
I
F&ure 3.
r
500
FVR
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did not change significantly after captopril treatment (1.5 1 f 0.12 ml/100 ml tissue/min; N.S.) despite improved cardiac output. Calculated forearm vascular resistance diminished from an average value of 88.3 f 7.8 to 73.5 f 6.0 units after captopril treatment (p <0.005). Figure 3 compares the changes in systemic and forearm vascular resistances after captopril treatment. The reduction in systemic vascular resistance (29 f 3 percent) was significantly greater (p
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studies with teprotide and captopril in hypertension [6,7], for systemic vascular resistance in heart failure [11,12,21], and in normal man [22]. From the hemodynamic responses demonstrated in our patients with diuretic-resistant hypertension, captopril appears most efficacious in the subset of diuretic-treated patients whose cardiac dysfunction is hemodynamically characterized by marked elevation of systemic vascular resistance with moderately reduced cardiac output. Almost all patients in this study showed a substantial decrease in systemic vascular resistance, and there was also a concomitant increase in cardiac output and stroke volume. According to the effect of captopril on cardiac function, short-term administration for up to several days in patients with hypertension usually had no significant effect on heart rate, stroke volume, or cardiac output [23,24]. In patients with high-renin hypertension, however, cardiac output is increased by short-term administration of captopril [25]. During longer-term administration, moreover, cardiac output and stroke volume increased slightly [24,26]. Based on the correlation between the changes in systemic vascular resistance and those in cardiac output in our study and in previous studies of heart failure [ 12,2 11,the increase in stroke volume may be mainly due to the reduction in afterload and hence better ventricular emptying, although an increase in myocardial contractility due to coronary artery vasodilation may contribute to this effect. Coronary artery vasodilation, with the increase in coronary blood flow during converting enzyme inhibition, has been documented previously by Gavras et al. [ 171. Furthermore, improvement in cardiac function has been observed in patients with heart failure treated with captopril [lo151. Therefore, long-term blockade of the renin system, when routinely available, might prove preferable, since it would be expected to counteract some of the undesirable effects of sodium depletion due to diuretics alone, such as decreased cardiac output and increased peripheral resistance. The rise in plasma renin activity following captopril administration is compatible with the negative feedback control of renal renin release and serves to confirm angiotensin blockade in these patients. In addition, we found a simultaneous reduction in aldosterone levels, as might be expected following angiotensin inhibition. Furthermore, aldosterone has cardiovascular actions of its own [27,28]. These findings taken together support the view that the renin-angiotensin-aldosterone system possibly participates not only in the maintenance of blood pressure but also in abnormal cardiovascular homeostasis in diuretic-resistant hypertensive patients. Plasma norepinephrine concentrations did not sig-
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nificantly change, as in previous experience with captopril and teprotide [ 12,13,19]; reflex tachycardia was absent despite a reduction in blood pressure after therapy, suggesting that substantial adrenergic stimulation did not occur. The absence of reflex tachycardia could be explained on the basis not only that the antagonists of angiotensin II abolish the positive chronotropic effect of angiotensin on the heart, which could occur either directly or by interaction with the sympathetic nervous system [29], but also that reduced circulating angiotensin II decreases catecholamine release
[131. Because converting enzyme participates also in the degradation of the vasodilator bradykinin to inactivate peptides, it is possible that the cardiovascular effects of captopril are due not only to the elimination or decrease in the level of circulating (or local tissue) angiotensin II, but also to cumulation of bradykinin and/or prostaglandin E [30-321. Bradykinin (admittedly in high dosage), however, increases cardiac output because it markedly increases heart rate, while its effects on stroke volume are inconsistent-that is, the hemodynamic pattern of response to bradykinin is the opposite of the one observed in the present and previous studies ]331. Although cardiac output increased 25 percent following captopril therapy, no increase in forearm blood flow was detected in this study. These findings are consistent with the experience of Faxon et al. [ 191 with captopril, in patients with severe congestive heart failure. These data indicate that converting enzyme inhibitor does not significantly increase regional flow to the limb circuit in patients with congestive heart failure nor in hypertensive patients treated with a diuretic. Regional redistribution of blood flow has been verified in sodium-depleted dogs given teprotide [ 151 and in spontaneously hypertensive rats given captopril [34], and flow to the renal, cerebral, and myocardial vasculature increased at the expense of cutaneous and skeletal muscular flow. Possible mechanisms for this phenomenon of regional redistribution of flow after converting enzyme inhibition include differences in tissue concentrations of converting enzyme or in local affinity of angiotensin II receptors. Moreover, converting enzyme inhibition may influence the tissue concentrations of bradykinin and prostaglandins. Recent experimental evidence suggests that the vasculature of different organs may display various degrees of sensitivity to the action of vasoconstrictive factors [35-371. The renal and coronary vessels were found to exhibit the greatest increase in local resistance after administration of exogenous angiotensin, while the muscular and cutaneous vessels exhibit greater constriction than the coronary vessels after adrenergic
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stimulation [35]. Since during captopril administration, the renin-angiotensin system was suppressed but substantial adrenergic stimulation did not occur despite a reduction in blood pressure, the converting enzyme inhibitor might be expected to cause more pronounced vasodilation resulting from elimination of angiotensin II, possibly because of the relative contribution of the adrenergic factors just mentioned to the observed changes. In summary, captopril in very low dose (average 30
mg/day) normalizes blood pressure without any side effects, associated with ventricular afterload reduction and resultant increase in cardiac output, and the reordering of regional blood flow, suggesting that it may be a useful adjunct to the therapy of severe hypertensive patients treated with a diuretic. Therefore, captopril and a diuretic probably should be used in combinations at low dosage to minimize not only humoral and hemodynamic compensatory mechanisms but also perceptible side effects.
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