Inositol-1,4,5-trisphosphate-dependent Ca2+ signalling in cat atrial excitation-contraction coupling and arrhythmias

Inositol-1,4,5-trisphosphate (IN-dependent Ca2+ release represents the major Ca2+ mobilizing pathway responsible for diverse functions in non-excitable cells. In the heart, however, its role is largely unknown or controversial. In intact cat atrial myocytes, endothelin (ET-1) increased basal [Ca2+](i) levels, enhanced action potential-evoked [Ca2+], transients, caused [Ca2+](i) transients with alternating amplitudes (Ca2+ alternans), and facilitated spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) in the form of Ca2+ sparks and arrhythmogenic Ca2+ waves. These effects were prevented by the IP3 receptor (IP3R) blocker aminoethoxydiphenyl borate (2-APB), suggesting the involvement of IP3-dependent SR Ca2+ release. In saponin-permeabilized myocytes IP3 and the more potent IP3 R agonist adenophostin increased basal [Ca2+](i) and the frequency of spontaneous Ca2+ sparks. in the presence of tetracaine to eliminate Ca2+ release from ryanodine receptor (RyR) SR Ca2+ release channels, IP3 and adenophostin triggered unique elementary, non-propagating IP3R-dependent Ca2+ release events with amplitudes and kinetics that were distinctly different from classical RyR-dependent Ca2+ sparks. The effects of IP3 and adenophostin were prevented by heparin and 2-APB. The data suggest that IP3-dependent Ca2+ release increases [Ca2+], in the vicinity of RyRs and thus facilitates Ca2+-induced Ca2+ release during excitation-contraction coupling. It is concluded that in the adult mammalian atrium IP3-dependent Ca2+ release enhances atrial Ca2+ signalling and exerts a positive inotropic effect. In addition, by facilitating Ca2+ release, IP3 may also be an important component in the development of Ca2+-mediated atrial arrhythmias.