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 in hibitor of the transient outward K+ current (I-to), alters the inotrop ic actions elicited via stimulation of WB4101- or chloroethylclonidine -sensitive receptors in rat myocardium. WB4101 (N-[2-(2,6-dimethoxyphe noxy)ethyl]-2, 3-dihydro-1,4-benzodioxin-2-methanamine) is a competiti ve antagonist that is selective for alpha(1A)- and alpha(1C)-adrenocep tors, while chloroethylclonidine is an irreversible blocker that is re ported to antagonize alpha(1B)-, alpha(1C)-, and alpha(1D)-adrenocepto r binding. Inotropic effects of the alpha(1)-adrenoceptor agonist phen ylephrine were examined in isolated left atrial and papillary muscle b efore and after addition of 4-aminopyridine, and before and after addi tion of 4-aminopyridine in preparations pretreated with chloroethylclo nidine 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. Phenylephr ine(10 mu M) 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 posit ive inotropic response). 4-Aminopyridine (1.0, 1.7, 3.0 mM) reduced th e 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 remaini ng inotropic actions of phenylephrine. The sustained positive inotropi c response to the alpha(1)-agonist in chloroethylclonidine-pretreated preparations was not inhibited by 100 nM staurosporine. These data sug gest that the sustained positive inotropic actions of alpha(1A)-adreno ceptor stimulation in rat atrial and ventricular myocardium are mediat ed via non-protein kinase C-associated reductions in I-to.