Atypical antagonism of D1-receptor-mediated vasodilator response in the perfused kidney by SCH23390.
Vasodilator responses to dopexamine, fenoldopam and dopamine, which are known to have agonist activity at D1-dopamine receptors, were examined in the rat isolated perfused kidney preparation. Perfusion pressure was raised by perfusing with the thromboxane TxA2 analogue, U46619, and vasodilator responses were observed as dose-related falls in perfusion pressure. Propranolol (10(-6) M) and prazosin (10(-6) M) were present throughout to eliminate beta 2 and alpha 1-adrenoceptor-mediated responses, respectively. The vasodilator responses were antagonized by SCH23390 (10(-9) M), indicating that they were mediated via D1-receptors. The displacements of the dose-response curves for fenoldopam, dopexamine and dopamine were, however, non-parallel with significant depression of the maxima to 30.2, 37.9 and 34.3%, respectively. In the presence of SCH23390 (10(-8) M) and prazosin (10(-6) M), dopexamine, isoprenaline and noradrenaline produced dose-related renal vasodilation. This was antagonized by propranolol indicating a role for beta-adrenoceptors. In the case of dopexamine, the maximum response was depressed in the presence of propranolol. The reason for the atypical blockade of vasodilator responses by SCH23390 was investigated. One possibility was the appearance of transient vasoconstrictor responses at higher doses of fenoldopam, dopexamine and dopamine, usually preceding the vasodilatation. The possibility was therefore considered that the vasoconstriction may have opposed the usual vasodilation at high doses and thus limited the size of the maximum vasodilation in the presence of SCH23390. The vasoconstriction by fenoldopam was not antagonized by S-sulpiride, the D2-receptor antagonist but was blocked by mianserin and therefore attributed to 5-HT2 receptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018818:Fenoldopam / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001552:Benzazepines; D017447:Receptors, Dopamine D1; D014665:Vasodilator Agents; C046318:dopexamine; D018818:Fenoldopam; D007545:Isoproterenol; D004298:Dopamine