Xestospongin C, a selective and membrane-permeable inhibitor of IP3 receptor, attenuates the positive inotropic effect of α-adrenergic stimulation in guinea-pig papillary muscle

1 We evaluated the role of the inositol 1,4,5-triphosphate (IP3) receptor-mediated Ca2+ release on the positive inotropic effects of a-adrenergic stimulation using a novel, potent, selective membrane-permeable blocker of IP3 receptor, xestospongin C. 2 Guinea-pig papillary muscle permeabilized with saponin exhibited spontaneous oscillatory contractions in solution buffered with pCa(2+) 6.5 by a low concentration of EGTA. The oscillatory activity was increased by adding 100 mu M IP3 and abolished by 1 mu M ryanodine or 30 mu M cyclopiazonic acid. Xestospongin C (3 mu M) inhibited the IP3-induced increase in the oscillatory contractions without affecting basal oscillations. 3 In intact papillary muscle, xestospongin C (3 mu M) inhibited the positive inotropic effects of phenylephrine, resulting in a rightward and downward shift of the concentration-response curve for phenylephrine. On the contrary, xestospongin C did not affect the concentration-response curve for phenylephrine obtained in the presence of ryanodine (1 mu M). 4 On the other hand, xestospongin C affected neither basal contractions nor the positive inotropic effects of a high extracellular Ca2+ concentration (3.2 mM) or that of isoprenaline (1 and 10 nM). 5 These results suggest that the IP3-mediated increase in Ca2+ release is involved in the positive inotropic effects of alpha-adrenergic stimulation in the guinea-pig cardiac muscle.