β4-Adrenoceptors are more effective than β1-adrenoceptors in mediating arrhythmic Ca2+ transients in mouse ventricular myocytes

Putative β4-adrenoceptors mediate cardiostimulation and arrhythmias in mammalian heart. Both β1- and putative β4-adrenoceptors mediate arrhythmias but through different mechanisms. To elucidate further the mechanisms of cardiostimulation and arrhythmias we measured Ca2+ transients and L-type Ca2+ currents in mouse ventricular myocytes. We used (-)-CGP 12177, an antagonist of β1- and β2-adrenoceptors with agonist properties at the putative β4-adrenoceptor, and (-)-isoprenaline as an agonist for β1- and β2-adrenoceptors. (-)-CGP 12177 increased Ca2+ transients in electrically stimulated cells loaded with Indo-1. The maximum increase of Ca2+ transients caused by (-)-CGP 12177 amounted to approximately one-third of that caused by maximally effective (-)-isoprenaline concentrations. Both (-)-CGP 12177 and (-)-isoprenaline caused concentration-dependent arrhythmic Ca2+ transients. The arrhythmias appeared at paced Ca2+ transients and between paced Ca2+ transients. The arrhythmic potency of (-)-CGP 12177 (–logEC50=9.4) was approximately 40 times greater than that of (-)-isoprenaline (–logEC50=7.8).