Cardiovascular pharmacology of ASL-7022. II. Mechanisms of inotropic selectivity.
The effect of ganglionic blockade (GB, hexamethonium, 10 mg/kg i.v.) upon the inotropic/chronotropic actions of ASL-7022 (2-[2-(3,4-dihydroxyphenyl)-1-methylethyl]-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene) was examined in anesthetized, vagotomized, open chest dogs instrumented for measurement of blood pressure, heart rate (HR) and right ventricular contractile force (strain-gauge). In a separate series of experiments, the effect of ASL-7022 upon sympathetic neurotransmission to the sinoatrial node was also examined. ASL-7022 preferentially increased contractile force at doses which were smaller than required to increase HR. HR decreased slightly over most of the inotropic dose range. The compound also caused a marked decline in blood pressure. GB converted the negative chronotropic effect to positive chronotropic action but had no effect on the inotropic dose-response relation. Thus, the inotropic selectivity of the compound was reduced by GB, but was still similar to that of dobutamine under conditions of GB. ASL-7022 also produced a dose-dependent inhibition of the positive chronotropic effect of sympathetic nerve stimulation and this action was blocked by phentolamine. These results demonstrate that the inotropic selectivity of ASL-7022 is related in part to the negative chronotropic action of the compound. However, the compound does possess intrinsic inotropic selectivity in the absence of its negative chronotropic action, i.e., in the presence of GB. The HR lowering effect is most likely due to sympathoinhibition due to action at inhibitory alpha adrenergic receptors located at ganglionic and/or presynaptic sites.
D000818:Animals; D002395:Catecholamines / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D018738:Hexamethonium; D006584:Hexamethonium Compounds / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010646:Phentolamine / Q000494:pharmacology; D012849:Sinoatrial Node / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D002395:Catecholamines; D005730:Ganglionic Blockers; D006584:Hexamethonium Compounds; D018738:Hexamethonium; C036054:ASL 7022; D010646:Phentolamine