Inhibition of cyclic GMP phosphodiesterases augments renal responses to atrial natriuretic factor in congestive heart failure.
Atrial natriuretic factor (ANF), a cardiac peptide hormone with potent natriuretic and vasodilator actions, mediates its biologic responses via increases in intracellular cyclic guanosine monophosphate (cGMP). Recognizing that phosphodiesterases degrade cGMP and that congestive heart failure (CHF) is characterized by reduced renal responses to ANF, the authors hypothesized that cGMP phosphodiesterases limit the renal actions of exogenous and endogenous ANF in the presence of experimental CHF. In anesthetized dogs with severe CHF and avid sodium retention produced by rapid ventricular pacing, the authors explored the renal actions of M&B 22,948 (Rhône-Poulenc, Essex, UK), an inhibitor of cGMP-specific phosphodiesterases. High-dose intrarenal cGMP phosphodiesterase inhibition (PDI), with minimal effects upon systemic hemodynamics and hormones, significantly enhanced sodium excretion. This occurred primarily by decreasing distal nephron sodium reabsorption while enhancing renal cGMP generation. In separate groups of dogs, low-dose intrarenal cGMP PDI potentiated the actions of exogenous ANF on glomerular filtration and distal nephron sodium reabsorption, leading to enhanced natriuresis in the presence or absence of severe CHF. These studies support a link between ANF and the renal actions of cGMP PDI, and indicate that cGMP phosphodiesterases may contribute to sodium retention in advanced CHF by limiting the renal actions of increased endogenous ANF.
Margulies
K B
KB
Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Burnett
J C
JC
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000502:physiology*; D004285:Dogs; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology*; D006439:Hemodynamics; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000503:physiopathology; D008297:Male; D009399:Nephrons / Q000503:physiopathology
D009320:Atrial Natriuretic Factor; D015106:3',5'-Cyclic-GMP Phosphodiesterases