title: Cassaine: mechanism of inhibition of Na+ +K+ -ATPase and relationship of this inhibition to cardiotonic actions.
abstract: The erythrophleum alkaloid  cassaine shares many of the pharmacological actions of the cardiac glycosides but lacks the structural characteristics typical of cardiac glycosides. To further investigate the relationship between Na+ +K+ -ATPase inhibition and the cardiotonic actions of these drugs we investigated the interaction of cassaine with the Na+ +K+ -ATPase. Cassaine inhibited rat brain Na+ +K+ -ATPase with about one quarter of the apparent affinity of ouabain for this enzyme. This inhibition was non-competitive with respect to K+. Cassaine also inhibited this enzyme in the presence of Mg2+ and this inhibition was enhanced by Pi and antagonized by Na+. In the presence of Na+, Mg2+ and (gamma-32P)-ATP cassaine acted to stabilize the phosphorylated intermediate of Na+ +K+ -ATPase. Cassaine also acted to displace specifically bound (3H)-ouabain from this enzyme. These observations suggested that cassaine inhibited the Na+ +K+ -ATPase by interacting at the cardiotonic steroid binding sites of Na+ +K+ -ATPase. Consistent with this hypothesis, dog, guinea pig and rat heart Na+ +K+ -ATPase showed differing sensitivities to cassaine paralleling their differing sensitivities to ouabain. The principal difference between the interaction of cassaine and ouabain with Na+ +K+ -ATPase appeared to be the more rapid dissociation of cassaine from the cardiotonic steroid binding site(s) of Na+ +K+ -ATPase. In keeping with this the rates of offset of cassaine-induced inotropy in Langendorff perfused dog and guinea pig hearts were several times faster than those of ouabain-induced inotropy.
mesh_terms: D045784:Abietanes; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D010042:Ouabain / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology*; D011188:Potassium; D051381:Rats; D012964:Sodium
chemical_list: D045784:Abietanes; D000470:Alkaloids; D010616:Phenanthrenes; D010042:Ouabain; D012964:Sodium; D000251:Adenosine Triphosphatases; C010696:cassaine; D011188:Potassium