ATYPICAL ANTAGONISM OF D-1-RECEPTOR-MEDIATED VASODILATOR RESPONSES INTHE PERFUSED KIDNEY BY SCH23390

Vasodilator responses to dopexamine, fenoldopam and dopamine, which ar e known to have agonist activity at D-1-dopamine receptors, were exami ned in the rat isolated perfused kidney preparation. Perfusion pressur e was raised by perfusing with the thromboxane TxA(2) analogue, U46619 , and vasodilator responses were observed as dose-related falls in per fusion pressure. Propranolol (10(-6) M) and prazosin (10(-6) M) were p resent thoughout to eliminate beta(2) and alpha(1)-adrenoceptor-mediat ed responses, respectively. The vasodilator responses were antagonized by SCH23390 (10(-9) M), indicating that they were mediated via D-1-re ceptors. 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 vasodilatat ion. This was antagonized by propranolol indicating a role for beta-ad renoceptors. In the case of dopexamine, the maximum response was depre ssed in the presence of propranolol. The reason for the atypical block ade of vasodilator responses by SCH23390 was investigated, One possibi lity was the appearance of transient vasoconstrictor responses at high er doses of fenoldopam, dopexamine and dopamine, usually preceding the vasodilatation. The possibility was therefore considered that the vas oconstriction may have opposed the usual vasodilatation 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 D-2-receptor antagonist but was blocked by mianserin and therefore attributed to 5-HT2 receptor stimulation. In the presen ce of mianserin, however, the maximum vasodilator response to fenoldop am (in the presence of SCH23390) was not restored. Thus, the 5-HT rece ptor-mediated vasoconstriction could not explain the atypical antagoni sm. It was proposed that the depression of maximum response was due to the use of single bolus doses of agonists which in the presence of a high affinity antagonist, such as SCH23390, do not reach equilibrium.