Atypical antagonism of D 1-receptor-mediated vasodilator responses in the perfused kidney by SCH23390

Abstract

Vasodilator responses to dopexamine, fenoldopam and dopamine, which are known to have agonist activity at D 1-dopamine receptors, were examined in the rat isolated perfused kidney preparation. Perfusion pressure was raised by perfusing with the thromboxane TxA 2 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 thoughout to eliminate gb 2 and α 1-adrenoceptor-mediated responses, respectively. The vasodilator responses were antagonized by SCH23390 (10 −9 m), indicating that they were mediated via D 1-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 vasodilatation. This was antagonized by propranolol indicating a role for β-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 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-HT 2 receptor stimulation. In the presence of mianserin, however, the maximum vasodilator response to fenoldopam (in the presence of SCH23390) was not restored. Thus, the 5-HT receptor-mediated vasoconstriction could not explain the atypical antagonism. 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.