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

Abstract

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.

Fenoldopam—but not dopamine—selectively increases gastric mucosal oxygenation in dogs

“…However, because we did not measure regional blood flow, it remains unclear if this was caused by an increase in total gastric perfusion or by an intramural redistribution of blood flow toward the gastric mucosa (31). The effects of fenoldopam were abolished by DA 1 -receptor blockade, implying that other vasodilatory mechanisms [e.g., ␣ 1 -antagonism as described for fenoldopam (12)(13)(14)] are negligible. Because DA 1 -receptors are more densely allocated in vessels of the gastrointestinal mucosa compared with vessels of the other layers (31), we speculate that this might facilitate the redistribution of blood flow toward the mucosa.…”

“…In contrast to dopamine, it blocks rather than activates ␣ 1 -adrenoceptors (12,13). Furthermore, fenoldopam's receptor profile is merely independent of the dose applied.…”

“…Stimulation of ␣ 1 -adrenoceptors in the splanchnic region causes mesenteric vasoconstriction (9) counteracting the desired, dopamine receptorinduced mesenteric vasodilation. Whereas dopamine may stimulate ␣ 1 -receptors even at low doses (10,11), fenoldopam acts antagonistically on those receptors (12)(13)(14) and may thus provide another vasodilatory pathway. We therefore hypothesized that fenoldopam is superior to dopamine in increasing gastric mucosal oxygenation.…”

Dopamine under α1-blockade, but not dopamine alone or fenoldopam, increases depressed gastric mucosal oxygenation*

“…Thus, we speculated that combining dopamine with a selective ␣ 1 -receptor antagonist unmasks the beneficial effects of DA 1 -stimulation on gastrointestinal mucosal oxygenation. In contrast, fenoldopam acts antagonistically on ␣ 1 -receptors (22)(23)(24) and may thus provide another vasodilatory pathway. We therefore hypothesized that dopamine under ␣ 1 -blockade and fenoldopam are superior to dopamine alone in increasing gastric mucosal oxygenation.…”

In vivo venodilator action of fenoldopam, a dopamine D1‐receptor agonist

“…infusion of fenoldopam (1–30 μg kg −1 min −1 ) into pithed rabbits dose‐dependently decreased MAP, and increased HR at the highest dose. Fenoldopam has been shown to possess antagonistic activity at α 1 ‐adrenoceptors in perfused rat kidneys in situ (Martin & Broadley, 1995). Moreover, fenoldopam at 5 but not 2 μg kg −1 min −1 inhibited by 14% the renal arterial constrictor effect of the α 1 ‐adrenoceptor agonist phenylephrine (Kohli et al ., 1988).…”