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

Abstract

Although ventricular cardiomyocytes express inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] 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)P3 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)P3 receptors. Incubation of electrically-paced ventricular myocytes with a membrane-permeant Ins(1,4,5)P3 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)P3 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)P3 receptors support the development of both inotropy and spontaneous pro-arrhythmic Ca2+ signals in ventricular myocytes stimulated with a Gq-coupled agonist.

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

“…Consistent with this notion, IP 3 Rs have been localized close to the dyadic junctions where excitation-contraction coupling is initiated [142], and direct activation of IP 3 Rs was found to enhance Ca 2+ spark occurrence throughout ventricular cells [41]. Furthermore, application of hormones that activate the production of IP 3 inside ventricular myocytes, such as endothelin-1 [11], enhances systolic Ca 2+ signals in rat and rabbit cells [41,128,143]. IP 3 can therefore be considered as a bona fide inotropic agent in some mammalian ventricular myocytes (but perhaps not all; see [41]).…”

“…IP 3 R expression has been qualified using real-time PCR [41,128,143]. IP 3 can therefore be considered as a bona fide inotropic agent in some mammalian ventricular myocytes (but perhaps not all; see [41]).…”

“…Rather than reinforcing their positive contribution to inotropy, the overwhelming majority of studies that have examined the consequence of activating IP 3 Rs in ventricular myocytes have concluded that the predominant effect is to stimulate arrhythmias [62,143]. Indeed, IP 3 R activity has been suggested to underlie ventricular arrhythmias resulting from hormonal stimulation [143], reperfusion [144,145], engagement of cytotoxic T-lymphocytes [146] and FAS receptor activation [147]. These data suggest that Ca 2+ flux through the relatively few IP 3 Rs in ventricular myocytes is perhaps more dangerous than beneficial, similar to the situation discussed above for atrial cells.…”

Increased InsP 3 Rs in the junctional sarcoplasmic reticulum augment Ca 2+ transients and arrhythmias associated with cardiac hypertrophy

“…Detailed methods for myocyte isolation, adenoviral infection, photometric, and confocal measurements of [Ca 2ϩ ]i, immunoblotting, immunofluorescence, quantitative RT-PCR, and cell length measurements are provided elsewhere (14,33) and in SI Methods and Fig. S5.…”

“…Although Ca 2ϩ flux via these InsP 3 Rs is relatively small in comparison to the large Ca 2ϩ transients occurring during every heartbeat, recent data suggests that InsP 3 Rs have an important role in cardiac physiology. We, and others have shown, that Ca 2ϩ release through InsP 3 Rs contributes to the inotropic, arrhythmogenic, and hypertrophic effect of G␣ q -coupled agonists such as the vasoactive peptide ET-1 (11)(12)(13)(14)(15)(16). Whether altered InsP 3 R signaling also contributes to remodeling of Ca 2ϩ homeostasis during cardiac hypertrophy is not yet determined.…”