Prejunctional inhibitory effect of a dopamine D-2 agonist, N-0437, on vascular adrenergic responses

N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin], a potent and selective agonist for D-2 dopamine receptors, was used to investigate inhibitory prejunctional dopamine receptors in the rat tail artery and rabbit ear artery. N-0437 inhibited contractile responses to transmural nerve stimulation in a frequency dependent manner. Thus, N-0437 profoundly inhibited responses to nerve stimulation in the rat tail artery at a frequency of 1 Hz (ED50 = 1.6 nM), but had minimal effects when nerves were stimulated at 6 Hz. The D-1/D-2 dopamine agonist, apomorphine, exhibited a similar frequency dependent inhibitory effect but with less potency (ED50 = 30 nM at 1 Hz). In concentrations up to 1 microM, N-0437 had no effect on responses to exogenously applied norepinephrine, but N-0437 inhibited [3H] norepinephrine efflux induced by transmural stimulation. Inhibitory effects of N-0437 were blocked by the D-2 antagonist sulpiride but not by the D-1 antagonist SCH 23390. Furthermore, the selective D-1 agonist SKF 38393 did not inhibit vascular responses to adrenergic nerve stimulation. These data indicate that the inhibitory effects of N-0437 are via activation of D-2 dopamine receptors that inhibit norepinephrine release. Thus, N-0437 shows potency and selectivity of action for prejunctional D-2 dopamine receptors in vascular tissues. The frequency dependence of the actions of N-0437 suggest that the level of sympathetic activity is an important variable in determining effectiveness of prejunctional modulation.