Inhibition of cGMP-specific phosphodiesterase type 5 reduces sodium excretion and arterial blood pressure in patients with NaCl retention and ascites

Abstract

In the present study, we tested the hypothesis that inhibition of renal phosphodiesterase type 5 (PDE5) in patients with liver cirrhosis and ascites increases sodium excretion. The effect of sildenafil citrate was studied in a randomized double-blind. placebo-controlled crossover study. Diuretics were withdrawn, and a fixed sodium diet (100 mmol/day) was given to the patients for 5 days before both study days. After a 60-min basal period, eight patients received either oral sildenafil (50 mg) or placebo. Glomerular filtration rate (GFR) and renal blood flow (RBF) were determined by 99mTc-diethylenetriamine-pentaacetate and (131)I-hippuran clearances. In human nephrectomy specimens, PDE5 mRNA was expressed at similar levels in the cortex (n = 6) and inner medulla (n = 4). Histochemical staining showed PDE5 immunoreactivity in collecting ducts and vascular smooth muscle. At baseline, cirrhotic patients exhibited elevated plasma concentrations of ANP, renin, ANG II, and aldosterone that did not differ on the 2 study days. Basal sodium excretion was similar at the 2 study days (median 17 and 18 mmol, respectively), and patients were in positive sodium balance. Sildenafil increased heart rate, plasma renin activity, plasma ANG II, and aldosterone concentrations significantly after 60 min. Plasma cGMP concentration was increased after 120 and 180 min, and urinary sodium excretion and mean arterial blood pressure were decreased significantly at 120 and 180 min. Plasma ANP concentration, GFR, and RBF did not change after sildenafil. In patients with ascites and cirrhosis, inhibition of PDE5 did not promote natriuresis but led to increased plasma levels of the renin-angiotensin-aldosterone system.

Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis

“…It should be noted, however, that this was an acute intervention, and that the chronic effect of administration of PDE5 inhibitors in cirrhosis may be different and may actually worsen sodium retention because it will potentiate vasodilation, which may further stimulate the compensatory sodium-retaining mechanisms. This is especially relevant considering recent findings in which a single dose of sildenafil administered to patients with liver cirrhosis and ascites reduced sodium excretion and arterial pressure and was associated with increases in plasma renin activity and angiotensin II and aldosterone levels (28). The reasons for these contradictory results are not clear, but it should be noted that all these patients had advanced stages of cirrhosis (with ascites), indicating severe sodium retention and activation of compensatory mechanisms.…”

Expression, Distribution and Regulation of Phosphodiesterase 5

“…(3) regulation of antidepressant-sensitive serotonin transporter [9], (4) control of ion and fluid secretion in intestinal cells [10], (5) control of neurogenesis in the subventricular zone [11], (6) regulation of memory formation [12], and (7) handling of sodium secretion in renal cells [13].…”

Phosphodiesterase-5 gene (PDE5A) polymorphisms are associated with progression of childhood IgA nephropathy

“…Furthermore, when used, especially during the early stage of the disease, a PDE-5 inhibitor could prevent hypertension and renal deterioration, delay the onset of proteinuria, and reduce histological damage including glomerulosclerosis and tubulointerstitial damage [6]. The PDE-5 inhibitor was also shown to stimulate the renin-angiotensin-aldosterone system [26,27]. These data reflect that PDE-5 would play an important role in the modulation of mesangial proliferation and renal disease progression.…”