AJP - Heart and Circulatory Physiology, Vol 263, Issue 6 1689-H1694, Copyright © 1992 by American Physiological Society

ARTICLES

Thapsigargin, a new inotropic agent, antagonizes action of endothelin-1 in rat atrial cells

P. Vigne, J. P. Breittmayer and C. Frelin
Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique (UPR 411), Valbonne, France.

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.

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