Selective antagonism of the hypotensive effects of dopamine agonists in spontaneously hypertensive rats.

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Abstract
Agonists of dopamine receptors can lower blood pressure by vasodilation through action on dopamine1 receptors, inhibition of sympathetic nerve activity by action on dopamine2 receptors, or actions in the central nervous system. Fenoldopam, a selective dopamine1 agonist, piribedil, a selective dopamine2 agonist, and dipropyl dopamine, a mixed dopamine1 and dopamine2 agonist, were injected intravenously in pentobarbital-anesthetized, spontaneously hypertensive rats (SHR). The mechanism for the antihypertensive effect was evaluated by administration of the selective dopamine1 antagonist SCH 23390 and the selective dopamine2 antagonist domperidone. While SCH 23390 only antagonized the hypotensive effects of fenoldopam, domperidone abolished the fall in blood pressure produced by dipropyl dopamine and piribedil but not by fenoldopam. Increments in heart rate and plasma norepinephrine levels accompanied the hypotensive effects of fenoldopam. The increase in heart rate was abolished by a dose of SCH 23390 sufficient to completely block the hypotensive effects and was significantly attenuated by the ganglionic blocking agent hexamethonium, which suggests that the increase in heart rate was due to a baroreceptor reflex. Fenoldopam does not cross the blood-brain barrier, which suggests that its hypotensive effect was mediated by peripheral dopamine1 receptors. Since domperidone does not cross the blood-brain barrier and significantly antagonized the hypotensive and bradycardic effects of dipropyl dopamine and piribedil, these effects were mediated primarily by peripheral dopamine2 receptors. These results indicate that SCH 23390 and domperidone are useful agents to identify the receptor subtype mediating the action of dopamine agonists in SHR.