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

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Abstract
We evaluated the role of the inositol 1,4,5‐triphosphate (IP3) receptor‐mediated Ca2+ release on the positive inotropic effects of α‐adrenergic stimulation using a novel, potent, selective membrane‐permeable blocker of IP3 receptor, xestospongin C. Guinea‐pig papillary muscle permeabilized with saponin exhibited spontaneous oscillatory contractions in solution buffered with pCa2+ 6.5 by a low concentration of EGTA. The oscillatory activity was increased by adding 100 μM IP3 and abolished by 1 μM ryanodine or 30 μM cyclopiazonic acid. Xestospongin C (3 μM) inhibited the IP3‐induced increase in the oscillatory contractions without affecting basal oscillations. In intact papillary muscle, xestospongin C (3 μM) 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 μM). 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). These results suggest that the IP3‐mediated increase in Ca2+ 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

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