Xestospongin C, a selective and membrane-permeable inhibitor of IP(3) receptor, attenuates the positive inotropic effect of alpha-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 alpha-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 microM IP(3) and abolished by 1 microM ryanodine or 30 microM cyclopiazonic acid. Xestospongin C (3 microM) inhibited the IP(3)-induced increase in the oscillatory contractions without affecting basal oscillations. In intact papillary muscle, xestospongin C (3 microM) 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 microM). On the other hand, xestospongin C affected neither basal contractions nor the positive inotropic effects of a high extracellular Ca(2+) concentration (3.2 mM) or that of isoprenaline (1 and 10 nM). These results suggest that the IP(3)-mediated increase in Ca(2+) release is involved in the positive inotropic effects of alpha-adrenergic stimulation in the guinea-pig cardiac muscle.
Miyamoto
S
S
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Izumi
M
M
Hori
M
M
Kobayashi
M
M
Ozaki
H
H
Karaki
H
H
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D012433:Ryanodine / Q000494:pharmacology; D012503:Saponins / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D015220:Calcium Channels; D002316:Cardiotonic Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D012503:Saponins; C108644:xestospongin A; D012433:Ryanodine; D010656:Phenylephrine