UCL Discovery

Abstract

Inositol 1,4,5-trisphosphate (InsP(3)) is ail established calcium-mobilizing messenger, which is well-known to activate Ca2+ signaling in many cell types. Contractile cardiomyocytes express hormone receptors that are coupled to the production of InsP(3). Such cardioactive hormones, including endothelin, may have profound inotropic and arrhythmogenic actions, but it is unclear whether InsP(3) underlies any of these effects. We have examined the expression and localization of InsP(3) receptors (InsP(3)Rs), and the potential role of InsP(3) in modulating cardiac excitation-contraction Coupling (EC coupling). Stimulation of electrically-paced atrial and ventricular myocytes with a membrane-permeant InsP(3) ester was found to evoke an increase in the amplitudes of action potential-evoked Ca2+ transients and to cause pro-arrhythmic diastolic Ca2+ transients. All the effects of the InsP(3) ester could be blocked using a membrane-permeant antagonist of InsP(3)Rs (2-aminoethoxydiphenyl borate; 2-APB). Furthermore, 2-APB blocked arrhythmias evoked by endothelin and delayed the onset of positive inotropic responses. Our data indicate that atrial and ventricular cardiomyocytes express functional InsP(3)Rs, and these channels have the potential to influence EC coupling.