1 The renal vascular responses of the rat isolated perfused kidney to the dopamine D,-receptor agonists, dopexamine and fenoldopam, were examined. 2 Both kidneys were perfused in situ at constant flow rate (11 ml min-') with Krebs-bicarbonate solution at 37°C. The perfusion pressure was monitored and to enable vasodilator responses to be measured, the resting perfusion pressure was raised by infusing noradrenaline (6 x 10-9 M).3 Dose-related vasodilator responses to bolus doses of dopexamine and fenoldopam were obtained. However, these were not antagonized by the D,-receptor antagonist, SCH 23390, indicating that DI-receptors were not involved.4 Bolus doses of the a,-adrenoceptor antagonist, prazosin, caused similar dose-related vasodilator responses indicating the possibility that a,-adrenoceptor blocking properties of dopexamine and fenoldopam were responsible for the vasodilatation. 5 a-Adrenoceptor blockade by dopexamine and fenoldopam was confirmed by the parallel displacement of dose-response curves for the vasopressor responses to noradrenaline. pA2 values were determined by Schild analysis for dopexamine, fenoldopam and prazosin antagonism of noradrenaline in the presence of neuronal (cocaine, 10-M) and extraneuronal uptake blockade (metanephrine, 10-5 M). The values were 6.23, 6.02 and 8.91, respectively. Schild plot slopes of unity were obtained for dopexamine and fenoldopam indicating competitive antagonism. A slope of greater than unity for prazosin may be explained by the lack of equilibrium conditions associated with bolus doses of noradrenaline, the responses of which are affected more by the high affinity antagonist, prazosin, than the two lower affinity antagonists. 6 This study has demonstrated that renal vasodilator responses to the D,-receptor agonists, dopexamine and fenoldopam, are due to a brief antagonism of the a-adrenoceptor-mediated vasoconstriction induced by noradrenaline. This presumably masks any direct D,-receptor-mediated vasodilatation.

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1 Rats received intravenous infusions of dopexamine, an agonist with selectivity for D1-dopamine receptors and P2-adrenoceptors (240 ,g kg-' h-1), isoprenaline, a P,-and P2-adrenoceptor agonist (40 fig kg- and paced left atrium (increase in tension) showed significant reductions in sensitivity to isoprenaline following isoprenaline infusion. The EC5 values were significantly increased from 5.6 to 17.7 nM in right atria and from 7.4 to 27.1 nM in left atria. The maximum rate increase of right atria was also significantly less after isoprenaline infusion compared with controls (164.0 and 251.9 beats min-', respectively) but the maximum tension responses of left atria were not significantly different. After infusion with dopexamine, however, there was no change in sensitivity of the left or right atria to PI-adrenoceptor stimulation by isoprenaline.3 P2-Adrenoceptor-mediated relaxation responses to isoprenaline of the pulmonary artery, constricted with noradrenaline (6 x 108 M), showed no significant difference in maximum response or ECm in tissue from isoprenaline-or dopexamine-infused rats compared with vehicle-infused controls. P2-Adrenoceptormediated vasodilator responses were also examined in the kidney perfused with the thromboxane A2 analogue, U46619 (7.1 x 10-8 M) to raise perfusion pressure. As with the pulmonary artery, there was no significant difference in ED50 or maximum response to isoprenaline in kidneys from isoprenalineinfused animals compared with vehicle controls.4 The DI-receptor-mediated vasodilator responses to dopamine of the kidney perfused with U46619 were reduced after infusion of rats with dopexamine. The maximum fall in perfusion pressure (16.0 mmHg) and ED50 value (5.2 rig) were significantly different from those after vehicle infusion (31.5 mmHg; 1.5 pg). 5 These results show that functional responses mediated via P1-adrenoceptors and DI-receptors are reduced by intravenous infusions of isoprenaline and dopexamine, respectively. In contrast, the P2-adrenoceptor-mediated vasodilator responses of the pulmonary artery and kidney are not reduced by these agonists. Thus, under identical conditions, there appears to be selective down-regulation of peripheral P,-and D,-receptors, but not of P2-adrenoceptors.

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