Search

The effects of the D1/D2 dopamine receptor agonist SK & F 85174, an N-allyl derivative of fenoldopam, on blood pressure and regional hemodynamics were studied in anesthetized normotensive rats. SK & F 85174 reduced blood pressure and enhanced blood flow in the renal, superior mesenteric and the hindquarters vascular beds. Calculated vascular resistances were reduced. The nonselective dopamine receptor antagonist RS-sulpiride abolished, while SCH 23390 (D1 antagonist), domperidone (D2 antagonist) and hexamethonium (ganglion blocker) each partly blocked the hypotensive effect. SCH 23390 antagonized the vasodilator effect more in the renal and superior mesenteric vascular beds, whereas domperidone antagonized the response more in the hindquarters vascular bed. RS-sulpiride antagonized vasodilatation in the three vascular beds. Hexamethonium abolished vasodilatation in the hindquarters vascular bed only. These results indicate that the hypotensive effect of SK & F 85174 is due to stimulation of both postsynaptic D1 and neuronal D2 receptors. The vasodilator effect in the renal and superior mesenteric vascular beds is mediated by D1 receptor stimulation, the vasodilator response in the hindquarters vascular bed is due to neuronal D2 receptor stimulation.

The effects of systemic administration of the selective dopamine1 receptor agonist fenoldopam and the selective dopamine2 receptor agonist quinpirole on blood pressure and regional haemodynamics were investigated in anaesthetized normotensive Wistar rats. Both compounds produced dose-dependent reductions in blood pressure. Mesenteric and renal blood flow were enhanced by fenoldopam, but reduced by quinpirole. Hindquarter blood flow was not modified by fenoldopam, but was increased by quinpirole. The calculated vascular resistances were reduced by both compounds in the three vascular beds. The effects of fenoldopam were antagonized by SCH 23390 but SCH 23390 did not affect those of quinpirole. The effects of quinpirole, but not those of fenoldopam, were antagonized by domperidone. Hexamethonium abolished the effects of quinpirole without affecting those of fenoldopam. These results indicate that the hypotensive effects of fenoldopam and quinpirole are due to stimulation of postsynaptic dopamine1 and neuronal dopamine2 receptors, respectively, resulting in differential regional haemodynamic effects.

The effect of fenoldopam, a selective DA1-agonist, on the plasma aldosterone response to metoclopramide was studied in six hypertensive patients included in a multicentre double-blind placebo controlled cross-over study of the antihypertensive effects of fenoldopam. Fenoldopam significantly increased baseline plasma renin activity (PRA); baseline plasma aldosterone levels rose slightly. Baseline PRL and the PRL response to metoclopramide were not altered by fenoldopam. After metoclopramide, a significant increase of plasma aldosterone was observed during treatment with fenoldopam, as well as in the placebo-period. The peak values were not significantly different and occurred at 15 min during both treatment periods. These results indicate that fenoldopam does not reduce metoclopramide-induced aldosterone secretion and therefore suggest that the adrenal dopamine receptor is not identical to the vascular DA1 receptor.

1 The effects of local administration of the selective DA1-receptor agonist fenoldopam into the isolated autoperfused rat hindquarters were studied in order to investigate the site of action of fenoldopam in this vascular bed. 2 Bolus injections of fenoldopam produced reductions in perfusion pressure in the preconstricted, constant flow perfused rat hindquarters vascular bed. 3 The vasodilator effect of fenoldopam was abolished by sectioning of the lumbar sympathetic nerves and by pretreatment with the ganglion-blocker hexamethonium or the alpha-adrenoreceptor antagonists phentolamine and prazosin. At the same concentration, local infusion of fenoldopam had no effect on vasoconstrictor responses to locally administered noradrenaline and phenylephrine. 4 The vasodilator effect of fenoldopam was antagonized by the non-selective dopamine receptor antagonist RS-sulpiride and by the selective DA1-receptor antagonist SCH 23390, but not by the selective DA2-receptor antagonist domperidone. 5 These results provide no evidence for the presence of postsynaptic DA1-receptors in the rat hindquarters vascular bed; they show that fenoldopam induces neurogenic vasodilatation in this vascular bed, probably via stimulation of ganglionic DA1-receptors.

The effect of local administration of the dopamine 2 (DA2)-receptor agonist quinpirole and of the DA1-receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat. Local infusion of quinpirole (30 micrograms kg-1 min-1 for 5 min) had no effect on baseline perfusion pressure; it reduced the pressor responses to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial sympathetic nerves to 45.6 +/- 2.1% of its original value but did not modify similar pressor responses produced by locally administered noradrenaline. The inhibitory effect of quinpirole was antagonized by the selective DA2-receptor antagonist domperidone (10 micrograms kg-1) but not by the selective DA1-receptor antagonist SCH 23390 (50 micrograms kg-1). Local infusion of fenoldopam (30 micrograms kg-1 min-1 for 5 min) reduced baseline perfusion pressure to 89.9 +/- 1.9%, increased the pressor response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial nerves to 134.7 +/- 14.0%, but reduced the pressor response to locally administered noradrenaline to 37.2 +/- 8.2%. Similar pressor responses induced by the selective alpha 1-adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 +/- 6.4%), but responses to locally administered angiotensin II were not modified. Pretreatment with SCH 23390 (50 micrograms kg-1) antagonized the effect of fenoldopam on baseline perfusion pressure, but had no influence on the effect of fenoldopam on responses to electrical stimulation or to noradrenaline. Pretreatment with the selective alpha 2-adrenoceptor antagonist rauwolscine (100 micrograms kg-1) had no effect on the reduction in baseline perfusion pressure induced by fenoldopam nor on its inhibitory effect on the response to noradrenaline, but it antagonized the stimulatory effect of fenoldopam on the response to electrical stimulation. 7 The results show that quinpirole inhibits neurogenic vasoconstriction in the rat superior mesenteric vascular bed through stimulation of presynaptic DA2-receptors while fenoldopam stimulates postsynaptic vasodilatory DA,-receptors. In addition, our results suggest that the inhibitory effect of fenoldopam on the vasoconstrictor response to noradrenaline may be due to an antagonistic action at postsynaptic alpha-adrenoceptors, while its potentiating effect on neurogenic vasoconstriction is due to blockade of presynaptic alpha 2-adrenoceptors.