Pharmacological responses to dopamine in isolated guinea-pig cardiovascular tissues: mechanisms of action.
The mechanisms responsible for the positive inotropic, positive chronotropic and vasoconstrictor responses to dopamine in isolated guinea-pig cardiovascular tissues have been investigated in the present study. Since dopamine is the immediate precursor of noradrenaline, the role of noradrenaline in the pharmacological responses after addition of dopamine has been assessed. In isolated, contracting right ventricular papillary muscles, dopamine-induced positive inotropy (-log EC50, 4.77 +/- 0.06) was unaltered by incubation with dopamine antagonists (SCH 23390, domperidone), alpha-adrenoceptor antagonists (prazosin, yohimbine), or an inhibitor of uptake1 (cocaine). Practolol (selective beta 1-adrenoceptor antagonist) and ICI 118,551 (selective beta 2-adrenoceptor antagonist) were noncompetitive antagonists to dopamine. Block of vesicular uptake by reserpine antagonized the positive inotropic responses to dopamine (-log EC50, 4.03 +/- 0.05) but not to noradrenaline; these responses were antagonized by both practolol and ICI 118,551. Chemical sympathectomy by 6-hydroxydopamine antagonized the responses to dopamine (-log EC50, 3.76 +/- 0.11) but potentiated the responses to noradrenaline (-log EC50, 7.35 +/- 0.07). Inhibition of monoamine oxidase with pargyline potentiated the responses to dopamine (-log EC50, 6.05 +/- 0.04) and noradrenaline; the potentiation of dopamine responses was unaffected by chemical sympathectomy. Inhibition of dopamine beta-hydroxylase with sodium diethyldithiocarbamate antagonized the inotropic responses to dopamine (-log EC50, 4.36 +/- 0.05) but not to noradrenaline. Similar results were obtained in guinea-pig left atria (positive inotropy) and right atria (positive chronotropy), except that chemical sympathectomy failed to affect the chronotropic responses. In thoracic aortic rings, dopamine contracted vascular smooth muscle by direct partial agonism of alpha 1-adrenoceptors, without involvement of dopamine beta-hydroxylase. Thus, there is antagonism of the cardiac, but not the vascular responses to dopamine by inhibition of dopamine beta-hydroxylase. This shows that the conversion of dopamine to noradrenaline is important in the inotropic and chronotropic responses, but not the vascular responses to dopamine.
Brown
L
L
Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Australia.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects; D011217:Practolol / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D018492:Dopamine Antagonists; D004299:Dopamine beta-Hydroxylase; D011217:Practolol; D004298:Dopamine; D009638:Norepinephrine