Complex prejunctional actions of the D2 dopamine agonists N-0923 and N- 0924 in the rat tail artery

DJ Friedman, DN Krause and SP Duckles

Department of Pharmacology, College of Medicine, University of California, Irvine.

In rat tail arteries preloaded with [3H]norepinephrine, the D2 dopamine receptor agonist N-0923 [(S)-(-)-2-(N-propyl-N-2-thienylethylamino)-5- hydroxytetralin++ +], (S)-(-)-enantiomer of N-0437 [2-(N-propyl-N-2- thienylethylamino)-5-hydroxytetralin], inhibited tritium efflux and contractile responses evoked by nerve stimulation, indicating a prejunctional site of action. At higher concentrations (greater than or equal to 10(-7) M), N-0923 had additional effects which were blocked by the alpha-2 receptor antagonist yohimbine. In the presence of yohimbine, inhibition by N-0923 (10(-9) to 10(-6) M) of stimulation- evoked contractile responses correlated well with inhibition of tritium efflux, effects which were antagonized by sulpiride. The (R)-(+) enantiomer, N-0924 [(R)-(+)-2-(N-propyl-N-2-thienylethylamino)-5- hydroxytetralin++ +], also inhibited stimulation-evoked contractile responses (EC50 = 5.0 x 10(-7) M) and tritium efflux (EC50 = 6.0 x 10(- 7) M) in the presence of yohimbine, but with reduced potency compared to N-0923 (EC50 = 4.0 x 10(-9) and 4.2 x 10(-9) M, respectively). At high concentrations (10(-6) M), both enantiomers also increased basal tritium efflux, an effect which coincided with contraction in the case of N-0923. The effect of N-0923 at the D2 receptor, measured as inhibition of stimulation-evoked contractile responses, was greatest when the intensity of stimulation was low (low frequency or short train lengths). When extracellular calcium was lowered to 1.0 mM, the inhibitory effect of N-0923 was increased whereas elevated calcium (5.0 mM) attenuated the action of N-0923.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 260, Issue 2, pp. 568-575, 02/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics