The objective of this renewal application is to define cardiorenal mechanisms which regulate sodium excretion with a focus upon atrial natriuretic factor (ANF). While an understanding of the atrial peptide systems continues to emerge, the physiologic role of ANF remains controversial. Our working hypothesis is that ANF is a functionally important hormone which serves a key role in acute CHF to offset central volume overload. Should acute CHF evolve to chronic CHF, this role is limited by maximal release of ANF and by release of an altered molecular form with minimal biological activity which contributes to a dominance of opposing vasoconstrictor-antinatriuretic systems. To test this working hypothesis, integrative studies are proposed in the dog. Studies are proposed in four core areas related to ANF in acute and chronic CHF: I) ANF release by atrial and ventricular myocardium, II) the functional role of elevated endogenous ANF, III) mechanism(s) of renal hyporesponsiveness to ANF, and IV) renal metabolism and urinary clearance.
Specific Aims : (Core I: Release): To determine a) if acute ANF depletion occurs in acute CHF, b) the temporal onset of ventricular ANF in CHF, c) if ventricular ANF release is regulated, d) if maximal release for ANF exists and e) if an altered molecular form is released. (Core II: Functional Role of Endogenous ANF): To determine a) if ANF participates in a preservation of glomerular filtration rate and sodium excretion and inhibition of the renin-angiotensin-aldosterone system (RAAS) despite renal hypoperfusion, b) the role of renal interstitial hydrostatic pressure in mediating the action of ANF upon whole kidney proximal tubule reabsorption and renin release and c) if depletion and/or maximal release of ANF contributes to activation of the RAAS with avid sodium retention. (Core III: Mechanism(s) of the Renal Hyporesponsiveness to ANF): To determine a) if the intrarenal generation of cGMP is altered, b) if lowered renal perfusion pressure prevents an ANF effect upon renal interstitial hydrostatic pressure, c) the modulating action of renal sympathetic nerves and/or the intrarenal renin-angiotensin system and d) if beta-ANF antagonizes the intrarenal action of ANF. Core IV: Renal Metabolism and Urinary Clearance): To determine a) if ANF metabolism and clearance increases in CHF, b) if neutral endopeptidase inhibition in CHF enhances the tubular action of endogenous ANF in CHF, and c) if the unique tubular potentiation of endogenous ANF by NEP-I may be enhanced by antagonism of the ANF clearance receptor.
Showing the most recent 10 out of 241 publications
