Blunted cGMP response to agonists and enhanced glomerular cyclic 3′,5′-nucleotide phosphodiesterase activities in experimental congestive heart failure

Abstract

The natriuretic peptide (NP) and nitric oxide (NO) systems are activated in congestive heart failure (CHF), resulting in increased synthesis of cGMP, which serves as a second messenger for both humoral systems. These two regulatory systems play functional roles in the preservation of glomerular filtration rate (GFR) and sodium excretion in both acute and chronic CHF. A progressive decline in glomerular responsiveness to atrial natriuretic peptide (ANP) characterizes the terminal stage of chronic CHF despite elevation of plasma ANP. Phosphodiesterase isozymes (PDEs) are integral factors in determining cellular content and accumulation of cGMP, and up-regulation of PDE activity could participate in the glomerular resistance to ANP in severe CHF. To date, characterization of possible alteration of glomerular PDE isozyme activities in CHF is unknown, as is the in vitro glomerular response to the nitric oxide-soluble guanylyl cyclase pathway. We, therefore, first determined cGMP generation in response to particulate and soluble guanylyl cyclase activation by ANP and sodium nitroprusside (SNP) in isolated glomeruli from normal (N = 6) and CHF dogs (N = 5) in which CHF was induced by rapid ventricular pacing for 18 to 28 days. Secondly, we explored the presence of major PDE isozymes in glomeruli isolated from the control and CHF dogs. When ANP or SNP (10(-10) to 10(-4) M) were incubated with the suspension of isolated glomeruli, cGMP accumulation was lower by -72 to -96% with ANP and -42 to -77% with SNP in all glomerular medias obtained from CHF compared to controls. PDE hydrolyzing activity of both cAMP and cGMP were higher in the glomerular homogenates obtained from the kidneys of the CHF group (N = 5) compared to those of the control group (N = 5). We conclude that in severe chronic experimental CHF, glomerular cGMP accumulation decreases in response to both ANP and SNP, and CHF is characterized by enhanced cGMP- and cGMP-PDE activities that may participate in glomerular maladaptation to this cardiovascular syndrome.

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

“…Both of these humoral systems play important roles in the preservation of myocardial, vascular, and renal function in acute and chronic heart failure (CHF) (1)(2)(3)(4). 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).…”

“…The exact mechanisms that mediate the attenuated response to NP in overt CHF remain poorly defined and most likely are multifactorial. These mechanisms may include increased degradation of the peptides, decreased number or reduced affinity of biologic receptors or postreceptor events that lead to reduced production of cGMP, or increased cGMP degradation (2,10). Elucidation of therapeutic strategies to restore the renal responsiveness to exogenous NP would be an advance in the therapy of advanced CHF.…”

“…Both of these humoral systems play important roles in the preservation of myocardial, vascular, and renal function in acute and chronic heart failure (CHF) (1)(2)(3)(4). 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).…”

Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide

“…The controls consist of the same composition with the exception that Krebs buffer alone was used instead of glomeruli suspended in Krebs buffer. The final assay volume was 500 L. The reaction was terminated by addition of ice-cold trichloroacetic acid (final concentration 6.6%) (16). Following centrifugation, a supernatant aliquot (800 L) was extracted with ether for cGMP assay (15,16), and the remaining supernatant was assayed for protein levels (BCA protein assay, Pierce Biotechnology).…”

“…Normal canine kidneys were harvested and glomeruli were isolated (16,17). After 10 min of preincubation (37°C), aliquots of glomeruli suspended in Krebs buffer were incubated with human BNP (hBNP, Phoenix Pharmaceuticals, Inc.) or ASBNP.1 (final concentration 10 Ϫ5 M for both hBNP and ASBNP.1) for 10 min in the presence of isobutylmethylxanthine (0.3 mM).…”