Mechanism of methylxanthine sensitization of norepinephrine responses in a coronaryartery.
Beta-adrenergic receptor-mediated relazation to norepinephrine was enhanced by caffeine amd aminophylline in a coronary artery preparation of the beef in vitro. Augmented responses were not obtainable in the presence of known inhibitors of the extraneuronal uptake and metabolism of norepinephrine, estradiol-17beta, and the haloalkylamine GD-131, which themselves potentiate responses.  In addition, the effect on the norepinephrine dose-response curve of the combination of a methyixanthine and U-0521,the latter a potent inhibitor of catechol O-methyltransferase, the major enzyme of catecholamine inactivation in vascular tissue, did not differ from that of U-0521 alone. Studies of the extraneuronal accumulation of '3H-labeled norepinephrine revealed that caffeine and aminophylline, along with the known inhibitors, materially reduced theaccumulation of label in coronary tissue.  It is concluded that the methylxanthinesenhance beta-adrenergic receptor-mediated responses via a blockade of catecholamine uptake, giving rise to an increased concentration of agonist at receptors, and not by an action linked to cyclic AMP accumulation, consequent to receptor activation.
D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects*; D003510:Cyclohexanes / Q000494:pharmacology; D004048:Diethylamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D011427:Propiophenones / Q000494:pharmacology; D013268:Stimulation, Chemical; D014970:Xanthines / Q000494:pharmacology*
D065098:Catechol O-Methyltransferase Inhibitors; D003510:Cyclohexanes; D004048:Diethylamines; D011427:Propiophenones; D014970:Xanthines; D000628:Aminophylline; C009965:GD-131; D002110:Caffeine; D004958:Estradiol; C006104:U 0521; D009638:Norepinephrine