Ip3 Receptor Mediated Ca Release in Atrial Cells from Normal and Failing Hearts

Abstract

We studied excitation-contraction coupling (ECC) and inositol-1,4,5-triphosphate (IP3)-dependent Ca release in atrial cells from normal and heart failure (HF) rabbit hearts. Elementary Ca release events (Ca puffs) from IP3 receptors (IP3Rs) were detected in permeabilized myocytes after inhibition of ryanodine-receptor mediated Ca spark activity with tetracaine. Puff activity was induced by IP3 exposure and blocked by 2-APB, identifying their origin from IP3Rs. In normal myocytes puff activity was low and restricted to the cell periphery, whereas in HF myocytes their overall frequency was increased and puffs were more prominent in the cell center. Compared to normal cells, in HF atrial myocytes diastolic [Ca]i was increased, action potential (AP)-induced Ca transients (CaTs) were larger in amplitude (primarily due to enhanced Ca release from central non-junctional sarcoplasmic reticulum, SR), propagation of activation from cell periphery to the center was accelerated, and fractional SR Ca release was increased, whereas no difference in SR Ca load was observed. These differences were largely abolished by exposure to 2-APB, suggesting an increased basal IP3 activity in HF. Angiotensin II (AngII) increased diastolic [Ca]i in normal and HF myocytes whereas the effect was more pronounced in HF. The amplitude of AP-dependent CaTs was increased in the presence of AngII or after photolytical release of caged IP3 in normal cells, whereas the opposite effect was observed in HF. The frequency of spontaneous Ca waves was increased in HF, and returned to levels comparable to normal myocytes after 2-APB exposure. In conclusion, HF atrial myocytes revealed enhanced Ca release during ecc and more frequent spontaneous Ca waves, presumably resulting from increased basal IP3R-mediated Ca release. However, additional neurohumoral stimulation with AngII, as it might occur in-vivo in cardiac disease, negatively affected atrial Ca signaling during ECC.