The human adrenal synthesizes and secretes a variety of important regulatory hormones. The adrenal cortex secretes an endogenous digoxin- like immunoreactive factor (DLIF) into the circulation. The chemical composition of DLIF is remarkably similar to that of the cardioactive cardenolides. We have recently identified a precursor and several metabolic products of DLIF. However, the detailed structure of these compounds is not known. Several studies demonstrate elevated levels of endogenous DLIF in serum from patients with essential hypertension (EH), pregnancy induced hypertension (PIH), and during cardiac dysfunction. DLIF may control the ion-transport activity of ouabain-sensitive sodium- potassium ATPase. Several isoforms of the Na,K-ATPase (sodium pump) have been identified in tissue. Na/K-ATPase is the only known receptor for the cardenolides and is an important modulator of vascular smooth muscle tone in arterioles as well as other cardiovascular events. Inhibition of the sodium pump causes vasoconstriction which leads to systemic hypertension. A combination of DLIF from the adrenal cortex (as hormone) and sodium pump isoforms (as receptors) may form a regulatory hormonal-axis and play an important role in the etiology of EH and PIH. We propose a working hypothesis: DLIF from human adrenal cortex are endogenous inhibitors of ouabain-sensitive sodium-potassium ATPase and by this mechanism affect blood pressure in mammals.
The aim of this project is to define the chemical structure of DLIF and its biotransformation in tissue. Several chemical-identification techniques will be used to determine the structure of DLIF and its metabolic congeners. Biotransformation will be studied using in vitro metabolic techniques. Four independent measures of digitalis-like activity (immunoreactivity; Na,K-ATPase receptor binding; Na,K-ATPase catalytic activity; and ion-transport activity) will be used to characterize the interaction of DLIF and its metabolic precursors and products with the sodium pump. This research will provide the much needed chemical structure of DLIF, define its structural changes during metabolism, and test the hypothesis that DLIF from adrenals are endogenous inhibitors of sodium-potassium ATPase. These factors may prove useful in elucidating the mechanism responsible for EH or PIH and provide much needed diagnostic markers for these and other cardiovascular diseases.
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