VASODILATATION ELICITED BY 5-HT1A RECEPTOR AGONISTS IN CONSTANT-PRESSURE-PERFUSED RAT-KIDNEY IS MEDIATED BY BLOCKADE OF ALPHA-1A-ADRENOCEPTORS

The vasodilator mechanism of the putative serotonin1A (5-HT) receptor agonist, urapidil, 5-methyl-urapidil, ipsapirone, flesinoxan and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was investigated in constant-pressure perfused rat kidneys. The compounds (10(-12) - 10(-7) mol bolus injection) neither enhanced basal flow nor evoked vasodilatation in kidneys preconstricted by 27 mM KCl, 1.5 mM BaCl2 or 10(-6) M prostaglandin (PG)F2-alpha, but evoked a dose-dependent, reversible and spiroxatrine-resistant increase in vasodilatation of organs preconstricted by 6 x 10(-7) M noradrenaline. 5-Carboxamidotryptamine and sumatriptan did not reverse the vasoconstriction induced by all stimuli or that induced by noradrenaline in the presence of 5-HT2 plus 5-HT3 receptor blockade. No correlation for the vasorelaxant drugs was found between their - log ED50 in rat kidney and pK(i) values at 5-HT1A binding sites in pig cortex as determined in radioligand experiments. The relaxation in rat kidney induced by 5-HT1A receptor agonists and alpha-1A-adrenoceptor-selective antagonists (WB 4101 and (+)-niguldipine) was significantly correlated with pK(i) values at alpha-1A binding sites in rat cortex and the pA2 values derived from contraction studies for competitive antagonism at alpha-1-adrenoceptors in prostatic portions of the rat vas deferens, but differed from pK(i) values for alpha-1B binding sites in rat cortex. Thus, the vasodilator effect of the 5-HT1A receptor agonists urapidil, 5-methyl-urapidil, ipsapirone, flesinoxan and 8-OH-DPAT in the noradrenaline-perfused rat kidney appears to be mediated by their concomitant alpha-1A-adrenoceptor blockade. No evidence for a vasodilator effect mediated through 5-HT1A receptors was found under our experimental conditions.