CARDIOVASCULAR PHARMACOLOGY OF ATRIAL NATRIURETIC FACTOR

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Atrial natriuretic factor (ANF) is a polypeptide hormone which exhibits potent natriuretic, diuretic and vascular smooth muscle- relaxing actions. Animal studies indicate that mechanical or volume-induced atrial stretch, sodium loading, and vasopressor agonists stimulate the release of ANF. Bolus infusions cause a brief fall in blood pressure which precedes the diuresis and natriuresis stimulated by ANF. Overall, the studies in animals suggest that ANF functions as a volume-regulatory hormone in concert with the actions of antidiuretic hormone and aldosterone. To date, human studies with ANF have shown diuretic and natriuretic actions of single bolus infusions of ANF, with no studies of the mechanisms and stimuli which regulate release of ANF. In our preliminary studies, a high salt diet promoted a weight gain-related increase in plasma ANF concentrations. Upright posture provoked a fall in plasma ANF, suggesting that right sided filling pressures regulate ANF release. In cardiac catheterization studies we found a marked increase in plasma ANF concentrations in the right atrium, and the ANF levels correlated positively with atrial pressure. Elevation of the legs increased atrial pressure and stimulated an increase in secretion rate of ANF across the heart. Altogether, our studies support the hypothesis that ANF may function in humans as a volume- regulatory hormone whose plasma concentration is modulated by atrial pressure. The studies outlined in this proposal are designed to 1) determine the physiological, hormonal and volume stimuli which regulate human plasma ANF concentrations, 2) characterize the cardiovascular actions of ANF in normal subjects, and 3) elucidate the physiological regulation and cardiovascular actions of ANF in patients with essential hypertension. We plan to systematically manipulate atrial pressure, test a series of vasoactive agonists and manipulate plasma volume and osmolarity to determine the contribution of each of these stimuli to the regulation of plasma ANF concentration. Second, using bolus and sustained infusions of synthetic ANF we will determine its cardiovascular hemodynamic effect. Finally, we plan to test the hypothesis that the regulation of release and/or the cardiovascular actions of ANF are abnormal in human essential hypertension. The significance of these studies is that they will test the theory that ANF functions as a volume-regulatory hormone in human subjects, and that its cardiovascular actions are important to systemic and local vascular responsiveness. Secondly, these studies will determine whether the disordered volume regulation and altered vascular tone found in hypertension is due to abnormalities in the control of ANF release and/or in the actions of ANF.