ANF-mediated renal cGMP generation in congestive heart failure

Abstract

Previous studies have demonstrated that the biological actions of atrial natriuretic factor (ANF) are mediated via increases in its intracellular second messenger guanosine 3',5'-cyclic monophosphate (cGMP). Because cGMP egresses rapidly from target cells after ANF binding to particulate guanylate cyclase-linked receptors, extracellular cGMP may be a useful biological marker for the action of ANF in vivo under pathophysiological conditions. The present studies tested the hypothesis that the avid sodium retention and renal ANF resistance characteristic of chronic congestive heart failure (CHF) are associated with attenuated renal cGMP responses to ANF. We assessed the natriuretic and cGMP responses to endogenous and exogenous ANF during the evolution of CHF produced by 6 days of rapid ventricular pacing in conscious dogs (n = 6). Simultaneous measurement of plasma and urinary cGMP concentrations allowed determination of the net renal generation of cGMP, an indicator of the renal contribution to total urinary cGMP excretion. In early CHF, increased sodium excretion and renal cGMP production were observed in association with increases in plasma ANF. Exogenous ANF administration (10 micrograms/kg iv) before CHF also produced parallel increases in sodium excretion and renal cGMP production. In more advanced CHF produced by 6 days of pacing, we observed avid sodium retention in association with reversal of earlier increases in renal cGMP production despite progressive increases in circulating ANF. Natriuretic and renal cGMP responses to exogenous ANF were similarly attenuated in chronic CHF. These studies suggest that 1) renal cGMP production is a useful biological marker for the renal natriuretic action of ANF; 2) endogenous ANF contributes to the maintenance of sodium excretion in early CHF via increases in renal cGMP production; and 3) the avid sodium retention and renal ANF resistance in advanced CHF are, in part, linked to attenuated renal cGMP responses to endogenous and exogenous ANF.

Angiotensin inhibition potentiates the renal responses to neutral endopeptidase inhibition in dogs with congestive heart failure.

“…One possible explanation is that the renin angiotensin aldosterone system activation in CHF is impairing cGMP generation in congestive heart failure. In fact, a recent study (13) demonstrates that despite steadily increasing plasma ANF concentrations, plasma cGMP levels plateau during the evolution of experimental heart failure in association with progressive increases in plasma renin activity. Moreover, an elegant in vitro study by Smith and Lincoln (30) demonstrates that angiotensin II mediated increases in intracellular phophodiesterases may impair ANF mediated increases in cyclic GMP.…”

“…However, several studies (2-7) have demonstrated a blunted renal response to exogenous ANF in CHF. Multiple mechanisms have been implicated in this blunted renal response to ANF in CHF including: changes in ANF receptor density (8)(9)(10), enhanced degradation and clearance of ANF (11,12), altered postreceptor signal transduction (13), activation ofcounterregulatory neurohumoral systems (14,15), and decreased renal perfusion pressure (5). These mechanisms are not mutually exclusive.…”

Maximizing the Renal Cyclic 3′-5′-Guanosine Monophosphate System with Type V Phosphodiesterase Inhibition and Exogenous Natriuretic Peptide

“…Recent evidence suggests that both the NP/cGMP and NO/cGMP signaling pathways are impaired in overt CHF and that such impairment may contribute to the progression of cardiorenal dysfunction in CHF (2,5). With regard to the kidney, we previously reported, as have others, that the glomerular, natriuretic, and urinary cGMP excretory responses to both atrial natriuretic peptide and brain NP (BNP) are attenuated in overt experimental and human CHF (6,7). In addition, Nesiritide, the recombinant human BNP (Scios, Inc., Fremont, CA) that is approved for the management of acute decompensated CHF, in some clinical studies failed to demonstrate a renal-enhancing property (8,9).…”

Distinct roles for renal particulate and soluble guanylyl cyclases in preserving renal function in experimental acute heart failure

“…After centrifugation at 2,500 rpm at 4°C for 10 min, plasma was separated and stored at Ϫ20°C until assay. Plasma levels of ANP, cGMP, and plasma renin activity were determined by radioimmunoassay (7,29). Plasma and urine concentrations for electrolytes and lithium were determined by flame photometer (model 1L943; Instrumentation Lab, Lexington, MA).…”

“…Infusion of these three NPs in animals and humans results in natriuresis and diuresis and, at certain doses, an increase in glomerular filtration rate (GFR; 9, 10, 23). It should be noted that in severe experimental or human heart failure, a renal hyporesponsiveness may occur to the NP system (NPS) with excessive hypotension linked to worsening renal function (29,37,42). The importance of the NPS and the NPR-A in renal regulation is underscored by studies of genetic and pharmacologic receptor disruption characterized by impaired renal sodium handling and often hypertension (5,12,24,34).…”