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The positive inotropic effect of alpha 1A-adrenoceptor stimulation is inhibited by 4-aminopyridine
A P Williamson1, E Seifen, J P Lindemann
1Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Abstract:
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.
Insights
4-Aminopyridine reduces positive inotropic responses in rat heart muscle by inhibiting the transient outward potassium current (Ito). This effect is linked to alpha 1A-adrenoceptor stimulation and does not involve protein kinase C.
Area of Science:
- Cardiovascular Pharmacology
- Ion Channel Physiology
- Adrenoceptor Signaling
Background:
- The transient outward potassium current (Ito) plays a role in cardiac electrophysiology.
- Alpha-1 adrenoceptors (α1-ARs) influence myocardial contractility.
- The specific subtypes and signaling pathways of α1-ARs in rat myocardium require further elucidation.
Purpose of the Study:
- To investigate the effect of 4-aminopyridine, an Ito inhibitor, on inotropic responses mediated by specific α1-AR subtypes in rat myocardium.
- To determine the involvement of protein kinase C (PKC) in these responses.
Main Methods:
- Isolated rat left atrial and papillary muscle preparations were used.
- Inotropic effects of phenylephrine (α1-AR agonist) were measured.
- Experiments were conducted with and without 4-aminopyridine, WB4101 (α1A/α1C antagonist), chloroethylclonidine (α1B/α1C/α1D antagonist), and staurosporine (PKC inhibitor).
Main Results:
- Phenylephrine induced positive inotropic responses in atria and triphasic responses in papillary muscle.
- 4-Aminopyridine reduced sustained positive inotropic responses, particularly in chloroethylclonidine-pretreated preparations.
- In the presence of WB4101, 4-aminopyridine did not affect the remaining inotropic actions.
- Staurosporine did not inhibit the sustained positive inotropic response in chloroethylclonidine-pretreated preparations.
Conclusions:
- Sustained positive inotropic actions mediated by α1A-adrenoceptor stimulation in rat myocardium are associated with reductions in Ito.
- These effects are independent of protein kinase C signaling pathways.