Renal vasodilatation by dopexamine and fenoldopam due to α1‐adrenoceptor blockade

The renal vascular responses of the rat isolated perfused kidney to the dopamine D,‐receptor agonists, dopexamine and fenoldopam, were examined. Both kidneys were perfused in situ at constant flow rate (11ml min−1) 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 × 10−9 m). Dose‐related vasodilator responses to bolus doses of dopexamine and fenoldopam were obtained. However, these were not antagonized by the D1‐receptor antagonist, SCH 23390, indicating that D1‐receptors were not involved. Bolus doses of the α1‐adrenoceptor antagonist, prazosin, caused similar dose‐related vasodilator responses indicating the possibility that α1‐adrenoceptor blocking properties of dopexamine and fenoldopam were responsible for the vasodilatation. α‐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, 10−5 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. This study has demonstrated that renal vasodilator responses to the D1‐receptor agonists, dopexamine and fenoldopam, are due to a brief antagonism of the α‐adrenoceptor‐mediated vasoconstriction induced by noradrenaline. This presumably masks any direct D1‐receptor‐mediated vasodilatation.