SYMPATHOINHIBITORY EFFECTS OF SR 47336, A NEW ANGIOTENSIN-II ANTAGONIST IN THE PITHED SHR

In vivo studies have previously shown that exogenous angiotensin II (A II) reinforces sympathetic nervous system activity. Conversely, non se lective inhibition of endogenous AII by angiotensin I converting enzym e inhibitors (ACEIs) results in sympathoinhibitory effects. The aim of the present study was to examine the influence of selective inhibitio n of endogenous AII by SR 47436, a non peptide AT1-receptor antagonist , on the sympathetic nervous system. Cardiac, systemic and regional va scular (kidney, mesentery, hindlimb) responses to selective alpha1- an d alpha2-adrenoceptor agonists and to electrical stimulation of the sp inal cord were investigated in the pithed spontaneously hypertensive r at (SHR). Male adulte SHRs were orally treated by SR 47436 (10 mg/kg/d ay for 8 days) or by distilled water. Two hours later, they were anest hetized with pentobarbital (50 mg/kg, i.p.), pithed and artificially v entilated. Blood pressure. heart rate, cardiac output and regional (ki dney, mesentery and hindlimb) blood flows (pulsed Doppler technique) w ere measured. Corresponding vascular resistances were calculated. Thre e hours after SR 47436 - at the time of the drug's maximal effects - o r distilled water administration, cardiac, systemic pressor and region al vasoconstrictor responses (a) to increasing i.v. doses of All, (b) to increasing frequencies of electrical stimulation of the spinal cord , and (c) to increasing i.v. doses of cirazoline, a selective alpha1-a drenoceptor agonist, and of UK-14,304, a selective alpha2-adrenoceptor agonist, were investigated.AII systemic pressor, regional vasoconstri ctor and tachycardic responses were completely abolished by SR 47436. SR 47436 significantly reduced the systemic pressor responses elicited by spinal cord stimulation, cirazoline and UK-14,304. This sympathoin hibitory effect of SR 47436 was not homogeneously distributed in the d ifferent investigated vascular beds. In the mesentery, SR 47436 did no t exert any sympathoinhibitory effect. In the kidney, only postsynapti C alpha2-adrenoceptor mediated-vasoconstrictor responses were signific antly decreased by SR 47436. In the hindlimb, SR 47436 only reduced th e vasoconstrictor responses elicited by spinal cord stimulation. At th e cardiac level, spinal cord stimulation induced a strong tachycardia which was reduced by SR 47436. These results demonstrate that in SHRs, SR 47436 exerts sympathoinhibitory effects at the cardiac and vascula r levels. These sympathoinhibitory effects develop mainly prejunctiona lly at the cardiac and muscular levels and postjunctionally in the kid ney.