Xestospongin C, a selective and membrane‐permeable inhibitor of IP 3 receptor, attenuates the positive inotropic effect of α‐adrenergic stimulation in guinea‐pig papillary muscle

We evaluated the role of the inositol 1,4,5‐triphosphate (IP 3 ) receptor‐mediated Ca 2+ release on the positive inotropic effects of α‐adrenergic stimulation using a novel, potent, selective membrane‐permeable blocker of IP 3 receptor, xestospongin C. 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 μ M IP 3 and abolished by 1 μ M ryanodine or 30 μ M cyclopiazonic acid. Xestospongin C (3 μ M ) inhibited the IP 3 ‐induced increase in the oscillatory contractions without affecting basal oscillations. In intact papillary muscle, xestospongin C (3 μ 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 μ M ). On the other hand, xestospongin C affected neither basal contractions nor the positive inotropic effects of a high extracellular Ca 2+ concentration (3.2 m M ) or that of isoprenaline (1 and 10 n M ). These results suggest that the IP 3 ‐mediated increase in Ca 2+ release is involved in the positive inotropic effects of α‐adrenergic stimulation in the guinea‐pig cardiac muscle.British Journal of Pharmacology (2000) 130 , 650–654; doi: 10.1038/sj.bjp.0703358