U50,488H Inhibits Effects of Norepinephrine in Rat Cardiomyocytes-Cross-Talk between kappa-opioid and beta-adrenergic Receptors

Author： Chun Yu X. Yu Li H. Xin Wang H. Ming Wong T.

Publisher： Academic Press

ISSN： 0022-2828

Source： Journal of Molecular and Cellular Cardiology, Vol.30, Iss.2, 1998-02, pp. : 405-413

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Abstract

In order to determine the effect of kappa-opioid receptor agonist on the beta 1 -adrenoceptor stimulation in the heart, the effects of norepinephrine (NE), a beta 1 -adrenoceptor agonist, on contraction and electrically induced intracellular calcium ([Ca2+] i ) transient in the single rat ventricular myocyte pretreated with a kappa-opioid receptor agonist, trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)-benzeneacetamid e(U50,488H), at 0.01-1 muM were studied with a video edge tracker method and a spectrofluorometric method using fura-2 as calcium indicator, respectively. NE at 0.01-10 muM augmented both twitch amplitude and electrically induced [Ca2+] i transient dose-dependently, which were abolished by propranolol at 1 mum, a beta-adrenoceptor antagonist. The effects of NE on both contraction and [Ca2+] i transient were attenuated in a dose-dependent manner by U50,488H at 0.01-1 muM, which itself had no effect at all. The maximum response (E max ) was decreased, while the concentration that produces 50% of the maximum response (EC 50 ) was enhanced, by U50,488H. The inhibitory effects of U50,488H on beta-adrenoceptor stimulation were completely blocked by pretreatment with norbinaltorphimine, a specific kappa-opioid receptor antagonist at 1 muM, or preincubation with pertussis toxin (PTX) at 200 ng/ml for 6 h. On the other hand, the inhibition on NE-induced augmentation in electrically induced [Ca2+] i transient by U50,488H was not affected by pretreatment with U73122, a specific inhibitor of phospholipase C (PLC), at 10 mum for 30 min. U50,488H attenuated the augmentation of the electrically stimulated [Ca2+] i transient induced by forskolin at 0.1 and 0.5 muM. It did not, however, affect the augmentation of the electrically induced [Ca2+] i transient by N6,2'-O-dibutyryl adenosine cyclic monophosphate (DB-cAMP). The results suggest that kappa-opioid receptor stimulation by U50,488H at 10-6 M or lower may inhibit the effects of beta-adrenoceptor stimulation by acting at a PTX-sensitive G-protein and AC, but not via the phosphoinositol pathway.Copyright 1998 Academic Press Limited