Progesterone derivative binds to cardiac ouabain receptor and shows dissociation between sodium pump inhibition and increased contractile force

Abstract

DIGITALIS and related steroid glycosides exert two well established action: augmentation of the contractile force of cardiac muscle, the basis for the clinical use of these drugs; and inhibition of Na-K-ATPase, a ubiquitous membrane enzyme concerned with maintenance of transcellular ionic gradients. There is much evidence to support the disputed view that the inotropic effect of the cardiotonic steroids is a direct result of Na-K-ATPase inhibition^1,2. In a previous study³ a large number of steroids, drugs and other substances were screened for potential activity in a radioreceptor assay for cardiac glycosides. High affinity saturable binding of ³H-ouabain to a particulate fraction from dog heart was highly specific and antagonised only by cardioactive glycosides or their aglycones and certain steroids related to hydroxyprogesterone. The most potent progestins active in the binding assay shared certain structural features: a 17α-acetoxy moiety and unsaturation or substitution in the B ring. Of the 17α-acetate progestins available for testing in the radioreceptor assay, chlormadinone acetate (CMA), 3,5-diene-3-one-17α-ol-6-chloro-pregn-17-acetate, was the most active. In this report we describe results of studies with CMA designed to ascertain other potential digitalis-like actions. Digitalis-sensitive processes include ion and sugar flux in rat hemi-diaphragm⁴ and guinea pig atrium⁵ and Na-K-ATPase activity in several tissues².