PHARMACOLOGICAL ANALYSIS OF THE ACTIONS OF SKF 82526 ON CARDIOVASCULAR DOPAMINE-RECEPTORS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 234  (2) , 337-344
Abstract
Experiments with SFK 82526, a selective dopamine (DA1) receptor agonist, were performed to determine whether this compound would activate either ganglionic and/or central DA [dopamine] receptors. Bilateral hindlimb perfusion was carried out at controlled flow rates and changes in hindlimb perfusion pressure were recorded to evaluate the action of SKF 82526 on vascular resistance in anesthetized dogs. Intracisternal administration of SKF 82526 (10 and 40 .mu.g/kg) did not produce any changes in blood pressure, heart rate or hindlimb vascular resistance. When the same doses were administered i.v., SKF 82526 produced hypotension and a decrease in perfusion pressure in the innervated limb. Perfusion pressure in the denervated limb was not altered. I.v. SKF 82526 did not produce any changes in heart rate. When given into the lower abdominal aorta, SKF 82526 caused a dose-dependent decrease in perfusion pressure only in the innervated hindlimb, no significant changes in perfusion pressure occurred in the denervated limb. The hypotensive and the hindlimb vasodilatory actions of SKF 82526 could be antagonized by RS-sulpiride. SCH 23390 [S-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hemimaleate], a selective DA1 receptor antagonist, was most potent in blocking the hypotensive action of i.v. SKF 82526; it did not influence the neurogenic hindlimb vasodilation produced by intra-aortic SKF 82526. R sulpiride, another selective DA1 receptor antagonist, significantly antagonized the hypotensive as well as hindlimb vasodilatory actions of SKF 82526. S-sulpiride, a selective DA2 receptor antagonist, was least effective in blocking hypotension and did not influence the hindlimb vasodilatory action. DKF 82526 failed to alter the positive chronotropic effect of postganglionic cardiac sympathetic nerve stimulation, which suggests that this compound does not activate presynaptic DA2 receptors. Hindlimb vasoconstriction elicited during preganglionic lumbar sympathetic nerve stimulation was significantly inhibited by SKF 82526, and this action was antagonized by R-sulpiride. Electrophysiological studies with the isolated 5th lumbar vertebral ganglia revealed that SKF 82526 produced inhibition of ganglionic transmission. This inhibitory action could be antagonized by R-sulpiride but not by either S-sulpiride, SCH 23390 or phentolamine. Apparently SKF 82526 does not exert any centrally mediated cardiovascular action. The hypotensive action of SKF 82526 results from the activation of peripheral vascular DA1 receptors. Although SKF 82526 causes inhibition of ganglionic transmission via activation of a DA receptor, the subtype of this receptor may not be similar to the vascular DA1 receptor.