SYMPATHOINHIBITORY EFFECTS OF LOSARTAN IN SPONTANEOUSLY HYPERTENSIVE RATS

Nonselective inhibition of endogenous angiotensin II (AII) by AI-conve rting enzyme inhibitors (ACEI) results in sympathoinhibitory effects. We wished to examine the influence of selective inhibition of endogeno us AII by losartan, a nonpeptide AT1-receptor antagonist, on the sympa thetic system. Cardiac, systemic, and regional vascular (kidney, mesen tery, hindlimb) responses to selective alpha1- and alpha2-adrenoceptor agonists and to electrical stimulation of the spinal cord were invest igated in pithed spontaneously hypertensive rats (SHR) by pulsed Doppl er technique. Losartan (10 mg/kg) was administered orally, either as a single dose or for 8 successive days. Under both conditions, AII syst emic pressor, regional vasoconstrictor, and tachycardic responses were completely abolished by losartan. At the vascular level, losartan did not affect postsynaptic alpha1-adrenoceptor-mediated systemic pressor and regional vasoconstrictor responses, but reduced postsynaptic alph a2-adrenoceptor-mediated renal vasoconstriction. Losartan significantl y decreased the systemic pressor and regional vasoconstrictor response s elicited by spinal cord stimulation. This sympathoinhibitory effect was not homogeneously distributed, preferentially affecting the kidney . At the cardiac level, spinal cord stimulation induced a strong tachy cardia which remained unaffected by losartan. Thus in SHR, losartan ex erts sympathoinhibitory effects against the vascular but not the cardi ac responses to spinal cord stimulation. Because the vascular response s to postjunctional alpha1- and alpha2-adrenoceptor stimulation, excep t in the kidney, simultaneously remain poorly affected, the sympathoin hibitory effects of losartan mainly develop prejunctionally through AT 1-receptors blockade.