Ouabain-like activity in toad skin and its implications for endogenous regulation of ion transport

Abstract

THE demonstration that opium alkaloids of the plant kingdom mediate their effects on animals through specific receptors¹ led to the discovery that endogenous molecules with opiate activity exist widely in animals², including man. These studies raised the possibility that other potent pharmacological agents derived from plant sources might have active analogues in higher species. Thus, cardiac glycosides are found widely in the plant kingdom³; structurally similar compounds in the animal kingdom are known to exist only in the poison glands of certain toads³. The dried skins of Bufonid toads have been used in Chinese folk medicine for the treatment of cardiac failure⁴. Further, these poorly characterised medicinal preparations (Ch'an Su) were shown in the 1920s to contain ouabain-like compounds (bufotoxins) by chemical analysis⁵. However, although bufotoxins were shown to be a major constituent of the poison glands of Bufo marinus³ the possibility that similar compounds might also serve a physiological role apart from that of a defensive toxin was apparently not considered. More recently, two major observations make the consideration of such a physiological role seem reasonable. First, amphibian skin, which is a major organ for regulation of sodium and water homeostasis in these species⁶, has been shown to be rich in (Na⁺ + K⁺)-ATPase, the molecular mediator of sodium transport across the skin⁸. In fact, with toad bladder, amphibian skin has been widely used as a model of transepithelial ion transport in higher animals. Second, the pharmacological receptor for cardiac glycosides is now believed to be the (Na⁺ + K⁺)-ATPase^9,10, glycoside binding to this enzyme resulting in inhibition of both ATPase activity^11,12 and associated ion transport^13,14. This glycoside–enzyme interaction is considered to be the basis for the cardiac stimulating activity¹⁰ for which glycosides such as ouabain and digoxin are used in the therapy of cardiac disorders. We report here that extracts of the skin of three different species of toad each contain high concentrations of a substance with all the functional properties of cardiac glycosides. The widespread existence of ouabain-like activity in an organ rich in physiologically important (Na⁺ + K⁺)-ATPase suggests a possible role for these endogenous compounds in the regulation of transepithelial ion transport.