The role of renal hemodynamics in the antihypertensive effect of captopril

The role of renal hemodynamics in the antihypertensive effect of captopril To evaluate the role of regional hemodynamics in mediating the long-term depressor effect of the converting enzyme inhibitor, captopril, at a low dose (37.5 mgday), for 2 weeks, its systemic, renal, and forearm circulatory actions were determined in 12 patients with mild to moderate essential hypertension. After administration of captopril, there was a significant decline in mean blood pressure (average -12.1 + 1.9%) accompanied by a decrease in systemic vascular resistance (-9.1 +_ 3.3%), but cardiac output did not change. Although forearm vascular resistance was not altered, renal vascular resistance decreased considerably (-17.1 + 5.0%). Moreover, there was a highly significant (r = 0.891) correlation between the changes in mean blood pressure and renal vascular resistance. Plasma renin activity increased after therapy as plasma aldosterone decreased, while plasma norepinephrine slightly increased. The change in renal vascular resistance significantly (r = -0.617) correlated with the pretreatment level of plasma renin activity. These findings suggest that suppression of the renin-angiotensin system in essential hypertension induces selective vasodilation in the renal vasculature, which may play an important role in the long-term antihypertensive effect of the converting enzyme inhibitor. This renal vasodilator action appears to be the feature that distinguishes the converting enzyme inhibitor from conventional vasodilator drugs. (AM HEART J 111:347, 1986.)

Katsuyuki Ando, M.D., Toshiro Fujita, M.D., Yasushi Ito, M.D., Hiroshi and Kamejiro Yamashita, M.D. Ibaruki, Japan

Angiotensin-converting enzyme inhibitor, which eliminates circulating angiotensin II, lowers blood pressure in hypertensive patients.‘s2 We have previously reported that long-term administration of the converting enzyme inhibitor, captopril, in diureticresistant hypertensive patients, improved cardiocirculatory function through selective vasodilation.3 Similarly, it was demonstrated that essentially no limb vasodilation occurred following converting enzyme inhibition in patients with congestive heart failure.4*5 Angiotensin inhibition induced renal vasodilation without decreasing splanchnic6 or limb7 vascular resistance. Similar changes in regional blood flow by converting enzyme inhibition have been reported in animal studies.*-lo Conversely, the renal vessels exhibited the greatest increase in local resistance after administration of exogenous angiotensin 11,11,12although the skeletal muscle vascular beds remained relatively unafIected by angiotensin II.12 From the Department University of Tsukuba. Received accepted

for publication July 22, 1985.

of Internal April

Medicine, 1, 1985;

Reprint requests: Toshiro Fujita, M.D., Institute of Clinical Medicine, University 305, Japan.

Institute revision

of Clinical received

Department of Tsukuba,

June

of Internal Niihari-gun,

Medicine, 24, 1985; Medicine, Ibaraki

Noda, M.D.,

The kidney is engaged in long-term regulation of arterial blood pressure13-15 and the hemodynamic change in the kidney plays an important role in sustaining hypertension. Thus, angiotensin might play a role in the maintenance of high blood pressure resulting from renal vasoconstriction, and it can be expected that the hemodynamic changes induced by angiotensin inhibition may be beneficial in lowering blood pressure over a long-term period. Accordingly, in the present study, we have investigated the long-term effect of captopril on renal hemodynamics and its relationship to the decrease in blood pressure after converting enzyme inhibition in patients with mild to moderate essential hypertension. METHODS Patients. Twelve patients (eight men and four women) with mild to moderate 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 pyelography. Renal arteriography and renal vein blood sampling for measurement of plasma renin activity (PRA) were performed when indicated. Captopril protocol. All antihypertensive medications were discontinued for at least 2 weeks prior to the study. Systemic and forearm hemodynamic measurements were repeated until three similar determinations, 15 minutes

347

348

Ando

et al.

Table

1. Clinical and laboratory findings

American

Afttv Mean BP (mm Hgl Systolic BP (mm Hg) Diastolic BP (mm Hg) CI ( IJmin/m2) HR (bpm) SI (ml/mi) SVR (dynes .sec cm-’ m’) FBF (ml/100 ml tissue/min) FVR (units) RPF (ml/min/1.73 m’) RRF (ml/min/1.73 m’) RVR (units) PRA (ng/ml/hrJ Plasma aldosterone (pg/ml) Plasma norepinephrine (pg/ml) Plasma epinephrine (pg/ml)

118 15:i 101

104 134 88 3.64 69 53.7 2318 2.62 40.9 479.7 818.1 10.7 3.25 83 288 54

* 2 _t 4 + 2

:I.72 + 0.17 7 1 It_ .3 Xl.6 25Sl

i 2.9 * 130

3.06 + 0.33 44.0 t 5.8 418.7

_; 19.1

748.5

i 40.1

1:i.1

+ 0.9

1.78 I21

i t

0.29 PFj

226 i 16 60 t 6

+ i t t 2 i k _t 2 + i + _t 2 _t i

p Value* 2 3 2 0.16 3 2.9 124 0.17 2.9 28.9 57.0 0.8 0.68 14 33 8

Values are given as mean 2 SEM. Before = before treatment with captopril; after = 2 weeks after captopril administration. Ahhreviations: BP = blood pressure; Cl = cardiac index; HR = heart rate; SI = stroke index; SVR = systemic vascular Now: FVR = forearm vascular resistance: RPF = renal plasma How; RRF = renal blood flow; RVR = renal vascular activity. *Paired t test

apart, demonstrated homeostasis;were renal hemodynamics then measured. On an outpatient basis, patients received 37.5mg/day of captopril for 2 weeks.On day 15of captopril treatment, the patients were given 12.5 mg of captopril in the morning in the laboratory, and their hemodynamic data were obtained approximately 60 to 75 minutes later. Systemic hemodynamics. Systemic blood pressurewas measured by sphygmomanometer. Cardiac output was determined by the dye dilution method (indocyanine green).3,‘6Measurements were made after patients had rested in the supine position for at least 30 minutes. Systemic vascular resistance(SVR) wascalculated as the ratio of mean blood pressure to cardiac output and corrected for body surface area, expressed in dynes set . cm+ . m2. Forearm hemodynamics. Forearm blood flow (FBF) was measured by plethysmography, as previously described.3FBF was calculated from the change in forearm circumference during acute venous occlusionwith 40 mm Hg pressureand was expressedas milliliters per 100 ml tissue per minute. Forearm vascular resistance(FVR) wascalculated asthe ratio of meanblood pressureto FBF, expressedin units of mm Hg . (ml/100 ml tissue)-’ . min. Renal hemodynamics. Renal blood flow was determined by the single injection clearance of ‘3110doparaaminohippurate (Is11-PAH)17on the basis of the model proposed by Sapirstein et al.ls 13’1-PAH,60 &i/1.73 m2, was injected intravenously and 5 ml of heparinized blood wasthen drawn at 5,10,15,20,30,40,50, and 60 minutes after injection. Renal plasma flow was calculated as proposedby Sapirstein et al.‘* This value wascorrected for hematocrit and body surface area. Renal vascular resistance (RVR) was calculated as the ratio of mean blood

February, 199 Heart Journi


<0.05 CO.05 <0.05 NS

resistance; resistance;

FBF = forearm PRA = plasma

blood renin

pressureto renal blood flow, expressedin units of X103 dynes . set . cm+ . (1.73 m2). Hormonal factors. Before and after captopril treatment, blood for hormonal determinations wasdrawn with the patients in the supine position, and the plasma was frozen at -40’ C. PRA wasdetermined by radioimmunoassayof angiotensinI.19Plasmaaldosteroneconcentration was quantitated by the radioimmunoassay technique, with the use of a commercial kit (CEA-IRE-SORIN).3 Plasma norepinephrine and epinephrine were measured by the radioenzymatic method of Peuler and Johnson,20 as previously reported.16 Statistics. Numeric results are expressedas mean + standard error of the mean. Statistical analysisof the data was performed by meansof paired and unpaired t tests and regressionanalysis according to standard procedures. Difference at a 5% level (p < 0.05) wasconsideredsignificant. RESULTS

Twelve patients were 44 + 3 years of age (range 21 to 57 years). The basal PRA was 1.78 + 0.29 ng/ml/hr (0.45 to 3.25 ng/ml/hr) (Table I). After captopril treatment, PRA increased (p < 0.05) and plasma aldosterone concentration decreased (p < 0.05). Plasma norepinephrine was slightly (p < 0.05) elevated, but plasma epinephrine was unchanged. Mean blood pressure decreased signi&antly (-12.1 +- 1.9%; p < O.OOl), from 118 + 2 mm Hg to 104 k 2 mm Hg, with converting enzyme inhibition (Table I, Fig. 1). Declines in both systolic (-11.9 + 2.2%; p < 0.001) and diastolic (-12.3 f 1.9%;

Volume

111

Renal hemodynamics

Number 2

140r mmHg

Mean

BP

beats’m’n lOOr

mllmin/

HR

1.73m2

jq~~

and captopril

RVR

units

25

1500

349

r 1

0:’

Before

After

N.S.

Before n-e/m2

5-

“1

PCO.01

After

Before

l/m2

/

SVR

After

Before

After

2. Changes in renal hemodynamics, produced by captopril in 12 hypertensive patients, of renal blood flow (RBF) and renal vascular resistance(RVR). Fig.

Pt0.02

\ E-I

\

200(

--$ Before

+ After

(

1. Changesin cardiocirculatory dynamics, produced by captopril in 12 hypertensive patients, of mean blood pressure (BP), heart rate (HR), cardiac index (CI), and systemicvascular resistance(SVR). Before = before treatment with captopril; After = 2 weeks after captopril administration. Fig.

p < 0,001) blood pressure were statistically significant. The change in mean blood pressure did not significantly correlate with pretreatment PRA (r = -0.547; 0.05 < p < 0.1). SVR fell substantially @ < O.OZ), from 2551 + 130 dynes . set . cmW5 . m2 to 2318 f 124 dynes . set . crnb5 . m2 (Table I, Fig. 1). However, cardiac output and stroke volume were not altered and heart rate was unchanged. The decrease in blood pressure with captopril did not appear to be simply the result of reduced SVR, since there was no significant (r = 0.320) correlation between the changes in mean blood pressure and SVR. The decrease in SVR did not correspond to pretreatment PRA (r = -0.327). FBF and FVR did not change after the administration of captopril (Table I). Renal blood flow increased slightly after captopril, but the change was not significant (Table I, Fig. 2). On the other hand, RVR decreased significantly (p < O.Ol), from 13.1 + 0.9 units to 10.7 +- 0.8 units (Table I, Fig. 2). The decline in RVR correlated negatively (r = -0.617; p < 0.05) with pretreatment PRA, although there

was no significant (r = -0.091) correlation between the pretreatment levels of RVR and PRA. Fig. 3 compares the changes in SVR, RVR, and FVR after The reduction in RVR angiotensin inhibition. (-17.1 -+ 5.0%) was significantly (p < 0.05) greater than that in FVR (1.2 +_ 7.0%). The change in SVR (-9.1 f 3.3%) showed the intermediate value among three parameters. The change in RVR correlated significantly (r = 0.891; p < 0.01) with that in mean blood pressure (Fig. 4), although the change in FVR did not. In addition, a few patients who did not show decreased RVR with captopril had little or no decrease in blood pressure. DISCUSSION Change in SVR. In the present study, the blood pressure-lowering effect of captopril in patients with essential hypertension was associated with substantial reductions of SVR and RVR but not with arteriolar dilatation in the forearm. This finding was similar to those of previous studies,3-10 suggesting regional selectivity in the vasodilator action of the converting enzyme inhibitor. Moreover, the antihypertensive mechanism in long-term therapy might not only be the result of the reduced SVR, in contrast to the actions of generally available vasodilator drugs, since the change in mean blood pressure did not correlate with that in SVR. However, in our previous study of long-term captopril treatment,3 there was significant correlation between the decreases in mean blood pressure and SVR. The seeming discrepancy in results can be explained by the fact that the patients in the previous study3 received diuretics throughout the experiment and had considerably higher PRA than those in the present study. Thus, diuretic-treated

350

Ando et al.

American

February, 1966 Heart Journal

%ARVR : f .-v) :

0

a

ii T-10 0 I4 G ae -20 4. Relationship between changes in renal vascular resistance(% AR VR) and mean blood pressure(% Ah4ean BP) after captopril in 12 hypertensive patients. Fig.

SVR Fig.

RVR

FVR

3. Comparative percentagechangesin systemicvas-

cular resistance (SVR), renal vascular resistance (RVR), and forearm vascular resistance (FVR), 2 weeks after captopril administration. *p < 0.05 (paired t test); **p < 0.01.

patients must have greater plasma angiotensin concentrations, and then reveal more pronounced systemic vasoconstriction by angiotensin, which may be a major factor in the maintenance of high blood pressure. This speculation is supported by a significantly greater decrease in SVR and FVR in the previous study3 than that in the present one, in spite of the similar dosages of captopril. FVR. The change in FVR with captopril was not significant. Similarly, some investigators reported that the alteration in limb resistance after angiotensin inhibition was insignificant, despite the considerable decrease in SVR,5s%10 or that it did not parallel the change in SVR.4 In contrast, subjects with the enhanced renin-angiotensin system, diuretic-treated hypertensive patientq3 or sodium-depleted normal subjects21 exhibited a significant decrease in FVR by converting enzyme inhibition. Thus, it is suggested that the renin-angiotensin system may play only a minor role in the maintenance of limb vascular tone, so that its influence may become obvious when stimulated. On the other hand, the sympathetic nervous system may be more involved in the maintenance of limb vascular tone.22 One alternate possibility that may explain unchanged FVR could be that the enhanced sympathetic nervous system, which may be the result of reflexive

neurogenic stimulation by blood pressure reduction, offset the effect of angiotensin inhibition, since plasma norepinephrine slightly but significantly increased after administration of captopril in the present study. The identical result concerning plasma norepinephrine was reported in the study by Faxon et al.,5 which showed similar hemodynamic changes. Change in RVR and its role in the antihypertensive effect of captopril. RVR was markedly decreased

after converting enzyme inhibition. Moreover, there was a highly significant (r = 0.891) correlation between the decreases in mean blood pressure and RVR. In addition, patients without reduced RVR had poor blood pressure response to captopril. Thus it is suggested that the specific vasodilation in the kidney may play an important role in the long-term antihypertensive action of angiotensin inhibition. Renal vasodilation may have an effect on the reduction in SVR because of its large supply of blood flow (about 20% of cardiac output). Moreover, selective renal vasodilation may prevent fluid retention against systemic vasodilation. In addition to the regional selectivity of vasodilation, intrarenal selectivity may also be critical in increased sodium excretion after converting enzyme inhibition, since angiotensin II constricts predominantly the efferent arterioles,23 with an increase in peritubular capillary absorption of fluid from the renal tubules. Several investigators reported that extracellular fluid volume24g 25 and plasma volume26~ 27 did not increase after long-term captopril treatment. Moreover, the converting enzyme inhibitor produced negative sodium balance in a substantial number of

Volume Number

111 2

hypertensive patientsz8 and in renal hypertensive rats.2s In contrast, conventional vasodilators often cause sodium and water retention, and the volume expansion with antihypertensive drugs is usually responsible for most instances of secondary resistance to therapy. 30,31It was demonstrated that there was no tendency for “escape” from the antihypertensive action of captopril during a period of several months.’ Following the initial fall in arterial blood pressure in the Goldblatt malignant hypertensive rats, blood pressure continued to decrease slowly and progressively for the remainder of the period of captopril administration,2s which may be accompanied by natriuresis. Therefore, increased sodium excretion, which may be the result of selective arteriolar dilatation in the kidney, may be an important factor for a long-term antihypertensive effect of the converting enzyme inhibitor. In the present study, basal PRA did not significantly correlate with the blood pressure response to captopril (r = -0.547; 0.05 < p < 0.1). This correlation was observed shortly after a single dose of captopri125,32-34However, such a correlation was weak and variable after long-term treatment.‘, 3,25,26,33.34It may have been the result of the change in volume status by long-term therapy with captopril. Alternatively, it is well known that kininase II is identical to converting enzyme. In hypertensive patients, plasma bradykinin concentrations were reported to be elevated 20 minutes after the administration of converting enzyme inhibitor.35 In addition, it was demonstrated that the administration of captopril increased urinary prostaglandin and its metabolite3’jv31 and that indomethacin treatment inhibited a captopril-induced fall in blood pressure.36 Therefore, it is possible that kinins and prostaglandins may participate in the natriuretic and antihypertensive effects of captopril. On the other hand, the decrease in RVR significantly correlated with that of mean blood pressure as well as basal PRA. Thus the change in RVR, rather than that in SVR, may contribute to the long-term blood pressure-lowering effect of the converting enzyme inhibitor; the antihypertensive effect might be mediated by natriuresis. In addition to renal vasodilation, the suppression of aldosterone by angiotensin inhibition could increase sodium excretion. Conclusions. The present study showed that converting enzyme inhibitor normalized blood pressure by reordering blood flow in favor of the kidney at the expense of skeletal muscle flow. The selective vasodilation in the kidney may be important, especially in long-term treatment; these findings suggest that suppression of the renin-angiotensin-aldosterone

Renal

hemodynamics

and captopril

351

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