Sympathoinhibitory Effects of Losartan in Spontaneously Hypertensive Rats

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Abstract
Nonselective inhibition of endogenous angiotensin II (AII) by AI-converting enzyme inhibitors (ACEI) results in sympathoinhibitory effects. We wished to examine the influence of selective inhibition of endogenous AII by losartan, a nonpeptide AT1-receptor antagonist, on the sympathetic system. Cardiac, systemic, and regional vascular (kidney, mesentery, hindlimb) responses to selective alpha 1- and alpha 2-adrenoceptor agonists and to electrical stimulation of the spinal cord were investigated in pithed spontaneously hypertensive rats (SHR) by pulsed Doppler technique. Losartan (10 mg/kg) was administered orally, either as a single dose or for 8 successive days. Under both conditions, AII systemic pressor, regional vasoconstrictor, and tachycardic responses were completely abolished by losartan. At the vascular level, losartan did not affect postsynaptic alpha 1-adrenoceptor-mediated systemic pressor and regional vasconstrictor responses, but reduced postsynaptic alpha 2-adrenoceptor-mediated renal vasoconstriction. Losartan significantly decreased the systemic pressor and regional vasoconstrictor responses 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 tachycardia which remained unaffected by losartan. Thus in SHR, losartan exerts sympathoinhibitory effects against the vascular but not the cardiac responses to spinal cord stimulation. Because the vascular responses to postjunctional alpha 1- and alpha 2-adrenoceptor stimulation, except in the kidney, simultaneously remain poorly affected, the sympathoinhibitory effects of losartan mainly develop prejunctionally through AT1-receptors blockade.

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