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

Abstract

Type V phosphodiesterase (PDE V) metabolizes cyclic guanosine monophosphate (cGMP) and is abundant in the kidney and vasculature and was found recently in the heart. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, lusitropic, and natriuretic properties that are mediated via cGMP. It was hypothesized that chronic inhibition of PDE V (PDE VI) will enhance the renal actions of exogenous BNP by potentiating the renal cGMP. The cardiorenal and humoral function was determined at baseline in two groups of dogs with pacing-induced overt chronic heart failure (CHF; 240 bpm for 10 d): Group 1 (n ‫؍‬ 6) received Sildenafil 50 mg orally three times daily during the 10 d of pacing, and group 2 (n ‫؍‬ 5) received no PDE V inhibitor. The response to acute subcutaneous BNP (5 g/kg) administration also was compared in both groups on day 11. The GFR was assessed by inulin clearance (P < 0.05). There was no improvement of renal function in group 1 after 10 d of PDE VI as compared with group 2, despite having higher cardiac output (P < 0.05). Group 1 had significantly higher plasma (44 ؎ 2 versus 21 ؎ 3 pmol/ml; P < 0.05) and urinary cGMP (4219 ؎ 900 versus 1954 ؎ 300 pmol/min; P < 0.05) as compared with group 2. With acute subcutaneous BNP administration, group 1 had a natriuretic and diuretic response that was associated with an increase in GFR (30 ؎ 6 to 45 ؎ 6 ml/min; P < 0.05) and that was not observed in group 2 (25 ؎ 6 to 29 ؎ 4 ml/min). Plasma BNP increased to a similar extent in both groups with subcutaneous BNP. In contrast, group 1 had a much greater urinary cGMP excretion (4219 ؎ 900 to 8600 ؎ 1600 pmol/min; P < 0.05) as compared with group 2 (1954 ؎ 300 to 3580 ؎ 351 pmol/min; P < 0.05). In experimental overt CHF, chronic administration of PDE V inhibitor did not enhance renal function despite an improvement in cardiac output. However, chronic PDE VI significantly enhanced the renal hemodynamic and excretory responses to exogenous BNP. This study supports a role for PDE V as contributing to renal maladaptation in a model of experimental overt CHF and the strategy of maximizing the renal cGMP system by combined PDE VI and natriuretic peptides in CHF to improve renal function.

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

“…These results suggest that survival benefit would depend on the duration of functional cGMP levels in the lungs that can reduce MPAP rather than a maximum level, because the retention time in lungs will correlate with the exposure of tadalafil that is proportionally elevated with the doses, and the longer sustained relaxation of the pulmonary vasculature will reduce RV stress and delay the time to RV failure. In addition, there have been reports that inhibition of PDE5 potentiated the response to natriuretic peptides (NPs) in failing hearts (37,38). NPs such as atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) act protectively on the cardiovascular system through diuresis, vasodilation, and inhibition of the renin-angiotensin system.…”

Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent

“…[184][185][186][187][188][189] In one canine study, 188 tolerance was not observed following chronic administration of BNP. Development of orally available peptides has long been a challenge, given various barriers to protein absorption and penetration.…”

The Tumultuous Journey of Nesiritide

“…Supporting studies need to be conducted in humans to define the synergy between phosphodiesterase V inhibition and BNP. 29,30 In summary, the idea that we can take a peptide that is synthesized in the heart and that possesses intrinsic cardiorenal protective and enhancing actions and transform it into an effective drug for the treatment of CHF is exciting. The FUSION II investigators are to be congratulated for providing us with important new knowledge about nesiritide in a large clinical trial that helps point us in new directions.…”