The positive inotropic effect of alpha 1A-adrenoceptor stimulation is inhibited by 4-aminopyridine.
This study was designed to determine if 4-aminopyridine, a reported inhibitor of the transient outward K+ current (Ito), alters the inotropic actions elicited via stimulation of WB4101- or chloroethylclonidine-sensitive receptors in rat myocardium. WB4101 (N-[2-(2, 6-dimethoxyphenoxy)ethyl]-2,3-dihydro-1,4-benzodioxin-2-m ethanamine) is a competitive antagonist that is selective for alpha 1A- and alpha 1C-adrenoceptors, while chloroethylclonidine is an irreversible blocker that is reported to antagonize alpha 1B-, alpha 1C-, and alpha 1D-adrenoceptor binding. Inotropic effects of the alpha 1-adrenoceptor agonist phenylephrine were examined in isolated left atrial and papillary muscle before and after addition of 4-aminopyridine, and before and after addition of 4-aminopyridine in preparations pretreated with chloroethylclonidine or WB4101. In addition, effects of phenylephrine were examined before and after treatment with staurosporine (an inhibitor of protein kinase C) in chloroethylclonidine-pretreated preparations. Phenylephrine (10 microM) elicited a sustained positive inotropic response in left atria and a triphasic inotropic action in papillary muscle (transient positive and negative inotropic components preceding a sustained positive inotropic response). 4-Aminopyridine (1.0, 1.7, 3.0 mM) reduced the sustained positive inotropic responses in the absence of antagonists and in chloroethylclonidine-pretreated preparations. However, in the presence of 10 nM WB4101, 4-aminopyridine had no effect on the remaining inotropic actions of phenylephrine. The sustained positive inotropic response to the alpha 1-agonist in chloroethylclonidine-pretreated preparations was not inhibited by 100 nM staurosporine. These data suggest that the sustained positive inotropic actions of alpha 1A-adrenoceptor stimulation in rat atrial and ventricular myocardium are mediated via non-protein kinase C-associated reductions in Ito.
Williamson
A P
AP
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Seifen
E
E
Lindemann
J P
JP
Kennedy
R H
RH
D015761:4-Aminopyridine / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003000:Clonidine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004146:Dioxanes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D002316:Cardiotonic Agents; D004146:Dioxanes; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; C051731:chlorethylclonidine; D015761:4-Aminopyridine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D019311:Staurosporine; D003000:Clonidine