Abstract 15847: Excitation-Contraction Coupling and IP3-Dependent Ca Signaling in Atrial Myocytes From Normal and Failing Hearts
We studied excitation-contraction-coupling (ECC) and inositol-1,4,5-triphosphate (IP3) dependent Ca release in atrial myocytes from normal and heart failure (HF) rabbit hearts. Elementary Ca release events (Ca puffs) from IP3 receptors (IP3Rs) were detected in membrane-permeabilized myocytes after inhibition of ryanodine receptor mediated Ca sparks with tetracaine. Puff activity was induced by IP3 exposure and blocked by 2-aminoethoxydiphenyl borate (2APB), 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. In HF atrial myocytes, diastolic [Ca]i was increased and action potential (AP) induced Ca transients (CaTs) were larger in amplitude whereas no difference in sarcoplasmic reticulum Ca load was observed. Increased CaT amplitudes in HF myocytes were attenuated by 2APB or adenoviral expression of an IP3 sponge or 5’-phosphatase. Angiotensin II (AT) and photolytical release of caged IP3 increased diastolic [Ca]i in normal and HF myocytes whereas the effect was more pronounced in HF. The amplitude of CaTs was increased in the presence of AT or after IP3 uncaging in normal cells, however the opposite effect was observed in HF. The frequency of spontaneous Ca waves was higher in HF, and returned to normal levels after 2APB exposure. Nearly half of all Ca waves in normal cells, but <10% in normal cells pretreated with the Na/Ca exchange (NCX) inhibitor SEA0400 and none in ventricular cells triggered an AP (termed here 'arrhythmogenic Ca waves'). The incidence of spontaneous Ca waves, the fraction of arrhythmogenic Ca waves and NCX activity were significantly increased in HF. Furthermore, in HF mitochondrial density and mitochondrial Ca uptake were decreased as shown by the mitochondria targeted Ca probe Mitycam. In conclusion, HF atrial myocytes revealed enhanced Ca release during ECC and more frequent spontaneous Ca waves, presumably resulting from decreased mitochondrial Ca uptake and increased IP3R-mediated Ca release. However, additional neurohumoral stimulation with AT, as it might occur in-vivo in cardiac disease, negatively affected atrial Ca signaling during ECC.
Author Disclosures: F. Hohendanner: None. J.T. Maxwell: None. S. Walther: None. L.A. Blatter: None.
- © 2014 by American Heart Association, Inc.