Relative significance of dopamine receptors, beta adrenoceptors and norepinephrine uptake inhibition in the cardiovascular actions of dopexamine hydrochloride.
Studies in our laboratory have confirmed that dopexamine hydrochloride is a potent beta 2-adrenoceptor and DA1-dopamine receptor agonist. We examined the effects of dopexamine hydrochloride on both cardiac contractile force, determined by use of a Walton-Brodie strain-gauge arch sutured to the right ventricle, and heart rate in anesthetized dogs. Dopexamine hydrochloride increased cardiac contractile force and heart rate and decreased blood pressure. After administration of the ganglionic blocking agents, hexamethonium and atropine, or the selective beta 1-adrenoceptor antagonist, atenolol, the positive inotropic and chronotropic effects of dopexamine hydrochloride were reduced or eliminated, demonstrating that the drug had little or no direct beta 1-adrenoceptor action and that a myocardial beta 2-adrenoceptor action was not involved in its cardiac effects. During these investigations, dopexamine hydrochloride was found to be an inhibitor of norepinephrine uptake, potentiating the cardiac effects of both exogenously administered norepinephrine and norepinephrine released from sympathetic nerves. These results led to the following conclusions: Dopexamine hydrochloride stimulates the heart by 2 mechanisms--(1) baroreceptor-mediated release of norepinephrine resulting from hypotension produced by beta 2 adrenoceptor and DA1 dopamine receptor-mediated vasodilatation, and (2) potentiation of the released norepinephrine due to prevention of norepinephrine uptake by sympathetic nerves. The latter mechanism may be involved in the cardiac stimulation observed in patients with congestive heart failure and shock, since excessive sympathetic activity and elevated catecholamine levels are present in these conditions.
Goldberg
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Department of Pharmacological Sciences, University of Chicago, Illinois 60637.
Bass
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006339:Heart Rate / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011954:Receptors, Dopamine / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D011954:Receptors, Dopamine; C046318:dopexamine; D004298:Dopamine; D009638:Norepinephrine