Different dopamine receptor subtypes mediate the neurogenic vasodilation produced by fenoldopam and SK & F 85174 in the dog hindlimb

The present study was performed to examine the effects of the mixed DA-1/DA-2 receptor agonist, SK & F 85174, on hindlimb vascular resustance and identify the DA receptor subtypes involved in the neurogenic hindlimb vasodilation produced by this compound. Bilateral hindlimb perfusion at controlled flow rates was carried out in anesthetized dogs and one hindlimb was surgically denervated whereas the other limb was kept neurally intact. Intravenous administration of SK & F 85174 and fenoldopam, a DA-1 receptor agonist, produced decreases in mean blood pressure and in the perfusion pressure in the innervated limb. Perfusion pressure in the denervated limb was not altered by fenoldopam and was increased by SK & F 85174. The DA-2 receptor antagonist, S-sulpiride, inhibited the neurogenic vasodilation produced by SK & F 85174 but not that produced by fenoldopam. The DA-1 receptor antagonist, SCH 23390, did not alter the hindlimb vasodilatory effects of either SK & F 85174 or fenoldopam in these animals, but it antagonized the hypotensive responses to both of these agents. Intra-aortic administration of SK & F 85174 and fenoldopam also resulted in neurogenic hindlimb vasodilation with the maximum response to fenoldopam occurring significantly faster than SK & F 85174 (2.5 ± 0.16 vs. 9.8 ± 1.2 s). S-Sulpiride antagonized the hindlimb vasodilation produced by SK & F 58174 but not by fenoldopam. R-Sulpiride antagonized the hindlimb vasodilatory effect of fenoldopam. These results show that SK & F 85174 produces neurogenic hindlimb vasodilation by stimulating presynaptic DA-2 receptors and although it activates vascular DA-1 receptors to cause hypotension, unlike the DA-1 receptor agonist fenoldopam it does not stimulate ganglionic DA receptors. These findings provide additional support for our previous suggestion that the vascular DA-1 receptor activated by fenoldopam may be different from ganglionic DA receptor inasmuch as another vascular DA-1 receptor agonist SK & F 85174 did not activate this receptor to cause neurogenic vasodilation as was the case with fenoldopam.