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Calcium regulatory mechanisms involved in the inotropic effect of digitalis
43 CALCIUM REGULATORY MECHANISMS INVOLVED IN THE INOTROPIC EFFECT T. Godfraind, F. Noel & M. Finer,, Laboratoire de Pharmacodynamie gie, Universit6 Catholique de Louvain, UCL 7350, Av. E. Mounier,
OF DIGITALIS. G&n. & de Pharmacolo73, B-1200 Bruxelles.
Several cellular mechanisms control cytoplasmic calcium concentration and allow its modification with the cardiac cycle. This calcium regulation is for a large part dependent on transmembrane Na-Ca exchange and on opening of Ca channels. The amount of calcium entering the cell is amplified through Ca-induced Ca-release. The inhibition of the Na-K pump evokes a gain in cellular Na that interferes with the Na-Ca exchange and thereby is responsible for increase in cardiac contractility. It has been proposed that another mechanism could be responsible for ouabain inotropy. This hypothesis is supported by the observation that for a same change in ionic gradient evoked by different glycosides, the inotropic response is not the same (Godfraind and Ghysel-Burton, PNAS (USA), 77, 3067-3069, 1980). Furthermore, the inotropic action of ouabain can be antagonized by dihydroouabain without producing any change in the Na-K pump inhibition (Godfraind et al., Nature, 299, 824-826, 1982). Studies on rat isolated ventricles where high and low affinity si= for ouabain can be easely identified allow a clear dissociation of the two mechanisms. The high affinity inotropic process is antagonized by dihydroouabain. It is unlikely related to Na-Ca exchange alteration, we propose that Ca-induced Ca-release could be augmented in this inotropic process.
OF DIGITALIS. G&n. & de Pharmacolo73, B-1200 Bruxelles.
Several cellular mechanisms control cytoplasmic calcium concentration and allow its modification with the cardiac cycle. This calcium regulation is for a large part dependent on transmembrane Na-Ca exchange and on opening of Ca channels. The amount of calcium entering the cell is amplified through Ca-induced Ca-release. The inhibition of the Na-K pump evokes a gain in cellular Na that interferes with the Na-Ca exchange and thereby is responsible for increase in cardiac contractility. It has been proposed that another mechanism could be responsible for ouabain inotropy. This hypothesis is supported by the observation that for a same change in ionic gradient evoked by different glycosides, the inotropic response is not the same (Godfraind and Ghysel-Burton, PNAS (USA), 77, 3067-3069, 1980). Furthermore, the inotropic action of ouabain can be antagonized by dihydroouabain without producing any change in the Na-K pump inhibition (Godfraind et al., Nature, 299, 824-826, 1982). Studies on rat isolated ventricles where high and low affinity si= for ouabain can be easely identified allow a clear dissociation of the two mechanisms. The high affinity inotropic process is antagonized by dihydroouabain. It is unlikely related to Na-Ca exchange alteration, we propose that Ca-induced Ca-release could be augmented in this inotropic process.