Effects of apomorphine on heart rate during simultaneous administration of sulpiride: a challenge of the composed concentration-effect model.
Apomorphine elicits opposite concentration-dependent effects on the heart rate in rat bradycardia at low concentrations and tachycardia at higher ones. This has been modeled with a composed sigmoid Emax equation. To challenge this model, a selective antagonist, sulpiride, was administered simultaneously with apomorphine. Four short intravenous infusions of apomorphine, at different rates, were administered to rats, while a steady state concentration of sulpiride was maintained by intravenous infusion. Another group of rats was infused with apomorphine at the same rates of infusion as in the above groups, together with saline. In this latter group a biphasic concentration-response relationship was observed, while in the group receiving sulpiride and apomorphine no bradycardia was detected. A sigmoid Emax model with one term describing bradycardia and one tachycardia was used for the saline plus apomorphine data. For the sulpiride plus apomorphine data a single-term sigmoid Emax model was used. The maximal induced tachycardia was found to be the same in both groups. The tachycardia occurred at lower concentrations in the sulpiride group, probably as a result of an antagonist-induced shift of the bradycardia towards higher concentrations. The obtained results show that a composite concentration-effect curve of apomorphine has experimental validity and that it is possible to separate its pharmacodynamic characteristics on heart rate into its components, bradycardia and tachycardia, by sulpiride.
Bredberg
E
E
Department of Biopharmaceutics and Pharmacokinetics, University of Uppsala, Sweden.
Paalzow
L K
LK
D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013469:Sulpiride / Q000493:pharmacokinetics / Q000494:pharmacology*
D013469:Sulpiride; D001058:Apomorphine