Thapsigargin, a new inotropic agent, antagonizes action of endothelin-1 in rat atrial cells.
In isolated newborn rat atrial cells, thapsigargin induced a slow rise in cytosolic free Ca2+ concentration ([Ca2+]i) (half-maximum effective concentration = 1 microM) that was independent of the presence of external Ca2+. A 5-min treatment of atrial cells with 5 mM caffeine reduced but did not abolish the action of thapsigargin on [Ca2+]i. A first treatment of atrial cells with 10 microM thapsigargin reduced the action of ionomycin on [Ca2+]i. It also antagonized in a noncompetitive manner the Ca(2+)-mobilizing action of 100 nM endothelin-1 (ET-1). The half-maximum concentration for the inhibition by thapsigargin of ET-1 action was 0.2 microM. Thapsigargin had no action on the basal or ET-1 (100 nM)-stimulated production of inositol phosphates. These results suggest that thapsigargin discharges an inositol 1,4,5-trisphosphate-sensitive and caffeine-insensitive intracellular Ca2+ pool distinct from the sarcoplasmic reticulum. In isolated rat left atria, paced at 1 Hz, thapsigargin (10 microM) produced a transient 48% increase in contractility. It did not alter the contractile responses to 1 microM isoproterenol or to 5 mM caffeine. It had no action on postrest potentiation. Thapsigargin (10 microM) almost completely suppressed the positive inotropic action of 100 nM ET-1. It had no action on the transient negative inotropic response to ET-1. These results suggest that most of the positive inotropic effect of ET-1 is linked to its capacity to mobilize an inositol 1,4,5-trisphosphate-sensitive intracellular Ca2+ pool distinct from the sarcoplasmic reticulum.
Vigne
P
P
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (UPR 411), Valbonne, France.
Breittmayer
J P
JP
Frelin
C
C
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D016232:Endothelins / Q000037:antagonists & inhibitors*; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051381:Rats; D013729:Terpenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019284:Thapsigargin
D002316:Cardiotonic Agents; D016232:Endothelins; D007295:Inositol Phosphates; D013729:Terpenes; D002110:Caffeine; D019284:Thapsigargin; D002118:Calcium