Inositol 1,4,5-trisphosphate supports the arrhythmogenic action of endothelin-1 on ventricular cardiac myocytes

Although ventricular cardiomyocytes express inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] receptors, it is unclear how these Ca2+ channels contribute to the effects of Gq-coupled agonists. Endothelin-1 augmented the amplitude of pacing-evoked Ca2+ signals (positive inotropy), and caused an increasing frequency of spontaneous diastolic Ca2+-release transients. Both effects of endothelin-1 were blocked by an antagonist of phospholipase C, suggesting that Ins(1,4,5)P-3 and/or diacylglycerol production was necessary. The endothelin-1-mediated spontaneous Ca2+ transients were abolished by application of 2-aminoethoxydiphenyl borate (2-APB), an antagonist of Ins(1,4,5)P-3 receptors. Incubation of electrically-paced ventricular myocytes with a membrane-permeant Ins(1,4,5)P-3 ester provoked the occurrence of spontaneous diastolic Ca2+ transients with the same characteristics and sensitivity to 2-APB as the events stimulated by endothelin-1. In addition to evoking spontaneous Ca2+ transients, stimulation of ventricular myocytes with the Ins(1,4,5)P-3 ester caused a positive inotropic effect. The effects of endothelin-1 were compared with two other stimuli, isoproterenol and digoxin, which are known to induce inotropy and spontaneous Ca2+ transients by overloading intracellular Ca2+ stores. The events evoked by isoproterenol and digoxin were dissimilar from those triggered by endothelin-1 in several ways. We propose that Ins(1,4,5)P-3 receptors support the development of both inotropy and spontaneous pro-arrhythmic Ca2+ signals in ventricular myocytes stimulated with a Gq-coupled agonist.