title: 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 Diuretics were withdrawn, and a fixed sodium diet (100 mmol/day) was given to the patients for 5 days before both study days.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.
authors.affiliation: Department of Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark. h.thiesson@dadlnet.dk
authors.forename: Helle C
authors.initials: HC
authors.lastname: Thiesson
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.forename: Bente
authors.initials: B
authors.lastname: Jespersen
authors.forename: Ove B
authors.initials: OB
authors.lastname: Schaffalitzky de Muckadell
authors.forename: Claus
authors.initials: C
authors.lastname: Bistrup
authors.forename: Steen
authors.initials: S
authors.lastname: Walter
authors.forename: Peter D
authors.initials: PD
authors.lastname: Ottosen
authors.forename: Annegrete
authors.initials: A
authors.lastname: Veje
authors.forename: Ole
authors.initials: O
authors.lastname: Skøtt
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D001201:Ascites / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006728:Hormones / Q000097:blood; D006801:Humans; D006977:Hypertension, Renal / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007679:Kidney Medulla / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011188:Potassium / Q000652:urine; D011687:Purines; D051381:Rats; D000068677:Sildenafil Citrate; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013450:Sulfones; D014867:Water / Q000378:metabolism
chemical_list: D006728:Hormones; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D017673:Sodium Chloride, Dietary; D013450:Sulfones; D014867:Water; D012964:Sodium; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat; D006152:Cyclic GMP; D011188:Potassium