Effects of SK&F 85174, a DA-1/DA-2 receptor agonist, on pre- and postganglionic sympathetic neurotransmission to the heart

We have performed experiments to determine the effects of SK&F 85174, a mixed DA-1/DA-2 receptor agonist, on the tachycardia elicited during pre- and postganglionic stellate stimulation in anesthetized dogs in order to identify a possible action of this compound on the stellate ganglia. SK&F 85174 produced hypotension and caused significant impairment of positive chronotropic responses elicited during pre- and postganglionic stellate stimulation. Pharmacological analysis of SK&F 85174-induced inhibition of cardiac sympathetic function with selective DA-1 and DA-2 receptor antagonists revealed that prior treatment with either S-sulpiride or domperidone (DA-2 receptor antagonists) significantly attenuated the inhibitory effects of SK&F 85174 on responses to pre- and postganglionic stellate stimulation. R-sulpiride (DA-1 receptor antagonist) failed to antagonize SK&F 85174-induced inhibition of tachycardia elicited during preganglionic stellate stimulation. Pretreatment with SCH 23390 (DA-1 receptor antagonist) did not modify the inhibitory effect of SK&F 85174 on responses to postganglionic nerve stimulation. However, SCH 23390 was most effective in antagonizing the hypotensive effect of SK&F 85174. These results show that SK&F 85174 inhibits sympathetic neurotransmission to the heart by activating presynaptic and possibly ganglionic DA-2 receptors, whereas the hypotension produced by SK&F 85174 results predominantly from the activation of the vascular DA-1 receptors. SK&F 85174 does not seem to exert any effect on the ganglionic DA receptors which are reported to be activated by the selective DA-1 receptor agonist, fenoldopam.