Endogenous Ouabain: Recent Advances and Controversies

Abstract

In this brief article, we summarize recent reports about endogenous ouabain (EO), a cardiotonic steroid (CTS). This includes analysis of mammalian EO, the discovery of EO isomers, regulation of intracellular signaling by EO, and the roles of EO in hypertension, pregnancy, and heart and kidney diseases. Novel ouabain-resistant mice that elucidate the key roles of α2 Na⁺ pumps and their CTS binding site are also discussed.

Figure 1

Endogenous ouabain determined by LC-MS-MS in plasma from patients with cardiomyopathy. Panel A. Capillary LC-MS-MS product ion chromatogram for a plasma extract from a patient with cardiomyopathy. The ion current peaks represent positively charged molecular product ions with an M+Li⁺/z ratio equivalent to the lithiated aglycone of ouabagenin (m/z 445.4). Under the slow LC gradient conditions employed, the specific ion current peak at 52.6 minutes is the lithiated aglycone of EO and matches the retention time for EO in this system. Panel B. MS-MS spectrum for the ion current peak at 52.6 minutes. Arrow points to m/z 591 which corresponds to the lithiated EO parent ion. Inset: Correlation (r=0.89) between plasma EO determined by RIA and LC-MS/MS from four cardiomyopathic patients. The slope of the relationship indicates that EO per se explained ~15% of the RIA signal in this patient group (see Online Supplement for further information). Dashed lines are the 95 % confidence interval. From Pitzalis et al. with permission.