Life Sciences, Vol . 21, pp . 237- 244, Printed Ia The ü.S .A .

1977 .

Pergamoa Preae

SIIPPRESSION OF RENIN SECRETION BY PROPRANOLOL IN SALT-DEPLETED DOGS John C .H . Yua,

Gerald Kelly

aad Frederic C . Bartter Hypertension-Endocrine Breach, National Heart, Luag, and Blood Institute, National Institutes of Health, Betheada, MD 20014 (Received is final form June 17, 1977) Summary d,l-propranolol was infused into salt-depleted, conscious dogs at two dosages : 1 mg/kg followed by 0 .60 - 0.67 mg/kg/hr, and 5 mg/kg followed by 1.57 - L76 mg/kg/hr . At both dosages, propranolol decreased plasma resin activity (PRA), plasma aldostarone concentration, and heart rate PRA significantly. Resin substrate concentration remained unchanged. was suppressed with the higher dosage but not with the lower dosage, to values found with dietary salt loading . Mean arterial blood presaure (MABP) remained unchanged with the low-dose infusions, but decreased significantly with the high-dose infusions . The data suggest that the mechaaiem(s) for the increase is PRA with low-salt diets is sensitive to propranolol and that the effect of propraaolol on MABP is dependent on the salt intake and on the done administered . It is well established that salt depletion raises resin secretion is man as well as is experimental animals (see 1 for review) . The mechanism(a) for the increase is resin secretion, however, is still unlmowa. Recently we demon strated that infusion of propranalol cauaea suppression of resin secretion in anesthetized as well as conscious dogs (2) . The present aeries of experiments was done to determine whether infusion of propranolol can suppress the elevated resin secretion induced by low-salt diets to the entent that they are lowered by salt loading . Methode Sin female mongrel dogs (body weight, 17-25 kg) were placed is metabolic cages on constant diets . IIrine was collected daily and urinary sodium and potassium were determined . During the first weak of study, the dogs were maintained on a diet containing 60 mSq/day of sodium . Then they ware placed on operating tables for the recording of blood pressure and collection of blood samples . (Since these dogs had bees trained previously, they usually lay quietly without showing any excitement .) Aa hour later, arterial blood samples were collected through indwelling arterial catheters in a femoral artery for determination of plasma resin activity (PRA), resin substrate concentration (RS), plasma aldosterone concentration, and electrolytes . The animals. were then maintained on a diet containing 4 mEq/day of sodium for thret~eeke . During the first two days, each dog received an injection of Thiamerid~ (Wyeth) (125 mg per day, I .M .) . After one week on the 4~mEq sodium diet, the dogs again were placed on operating tables . Aa hour later, as arterial blood sample was taken and saline (1 .0 ml/kg) was then injected 237

238

Propranolol In Salt-Depleted Doge

Vol . 21, No . 2, 1977

through a catheter in a femoral vain ; this was followed by a Blow infusion (0 .194 ml/min) of saline - these ware the amounts of saline to be given with Arterial blood samples were then obtained every 30 propraaolol, vide infra. minutes for 90 miautae during the infusion of saline, and also 60 minutes after the infusion had been stopped. On the second weak of the 4-mEq sodium diet, the dogs were again placed on the operating tables . An hour later, an arterial blood sample was obtained . This was followed by the injection (1 mg/kg) and infusion (0 .60 - 0.67 mg/kg/ hr) of d,l-propraaolol (Ayeret) . Arterial blood samples were than taken every 30 minutes for 90 minutes during the infusion of propranolol sad also 60 minutae after thn infusion had bean stopped . On the third week of the 4-mEq sodium diet, the same procedures were repeated except that the doses of propraaolol given by injection and infusion were increased to 5 mg/kg and 1 .57 - 1.76 mg/kg/hr ., rnepectively . The animals were than maiatatinad on a diet coataiaing 180 mEq/day of sodium for 4 weeks. Oa the last day of the 180 mEq sodium diet, the procedures dose on the 60ymEq sodium diet were repeated . Arterial blood pressure was measured with Statham transducers (P 23 IA) and recorded on a Brush 440 recorder . Heart rata was obtained from arterial blood pressure recordings . Saline and propranolol were infused through Tygoa catheters (Surprenant, 0 D 2 .5 mm) is the femoral veine with Harvard infusion pumps (modal 901) . Plasma sodium and potassium concentrations ware datarmiaed on a flame photometer (Instrumentation Laboratory Inc., Model 143) . Pissas aldosterone concentration was measured by radioimmuaoassay (3) . Plasma renia activity (PRA) wee determined by radioi~unoassay for aagiotansin I as daecribed is as earlier paper (4) . Plasma tanin substrate coaceatration (RS) was determined ae daecribed elsewhere (2) . 1251 Aagiotanain I etaadard was purchased from Squibb and Soae Company . angiotensia I was purchased from New England Nuclear . d,l Propraaolol was purchased from Ayeret Pharmaceutical Company . Angioteaein I antibody was kindly supplied by Dr . Fred Ratz of the University of Colorado . Statistical analysis was done with the uea of 3tudeat'e paired "t" test . Reeulta Plasma sodium and potassium concentration appeared to be related to sodium intake . Aa iacresee in sodium intake caused an iacreeae in plasma sodium concentration and a decrease is plasma potassium concentration (Table I) . Plasma tame activity and plasma aldosteroae concentration showed as inverse relationehip to sodium intake, as increase in sodium intake leading to a decrease is both . Plasma main substrata concentration showed no relationship to sodium intake . Mean arterial blood pressure also showed ao significant change with changes in sodium intake . There was a slightly lower heart rate with the highsodium intake as comparsd to that with the low-sodium intake . Thn difference was not, however, statistically significant . Infusion of propranolol (1 mg/kg followed by 0.60 - 0.67 ag/kg/hr) in salt-depleted dogs caused a marked decrease is heart rata without significant change in mesa arterial blood pressure (Figure 1) . Lnfusion of propranolol at this dosage also caused marked decreases is plass~a resin activity, sad plasma aldoeterone concentration. Mean PRA was 32 .2 + 6.5

Vol . 21, No . 2, 1977

Propraaolol In Salt-Depleted Doga

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Propraaolol Ia Salt-Depleted Doge

Vol . 21, No . 2, 1977

PROPRANOLa tmq/kq .E0-0.87mq/kq/hr 0 ~0 PRA

nq/ml/hr

MISE N-8

20 0 6.0

PLASMA K mEq/L

4 .6 4.0 3.6 3A

MABP mmHq

740 730 720 750

H.R . b/min

t30 110 80 70

* P