Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis.
Previous studies suggested that increased activity of phosphodiesterase (PDE)5 in the kidneys of cirrhotic rats contributes to sodium retention. This study examined the role of PDE5 in the changes in vascular reactivity, hemodynamics, and sodium excretion in rats with liver cirrhosis. Four weeks after bile duct ligation (BDL) or sham operation (SO), in vitro reactivity of aortic rings to various agents and in vivo effects of a PDE5-selective inhibitor [1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3,4d]-pyrimidin-4-(5H)-one, DMPPO] were studied. The vasodilator responses to nitroglycerin and S-nitroso-N-acetyl-penicillamine (SNAP) in phenylephrine-precontracted rings without endothelium were attenuated in BDL compared with SO rats. Pretreatment with DMPPO (0.1 microM) enhanced these responses and eliminated the differences between the two groups. Vasodilation to DMPPO itself was also less in BDL rats. The responses to phenylephrine were attenuated in endothelium-rich aorta from BDL relative to SO rats, but they were similar in endothelium-denuded aorta and remained similar despite preincubation with SNAP (0.1 microM) alone or with SNAP and DMPPO. In vivo, BDL rats were vasodilated relative to SO rats; DMPPO (5 mg/kg i.v.) decreased arterial pressure and vascular resistance in both groups equally and caused significant increase in sodium excretion in BDL rats only. In conclusion, the results are in accordance with a possible increase in PDE5 activity in aorta and kidney of cirrhotic rats that results in reduced responses to NO donors and contributes to the increase in sodium retention. PDE5 inhibitors may ameliorate sodium retention in cirrhosis but may worsen vasodilation. Examining the effect of PDE5 inhibitors after chronic administration will be more revealing.
Tahseldar-Roumieh
Rima
R
Dept. of Pharmacology and Therapeutics, Faculty of Medicine, American Univ. of Beirut, Beirut, Lebanon.
Ghali-Ghoul
Rana
R
Lugnier
Claire
C
Sabra
Ramzi
R
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000493:Allopurinol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003981:Diazoxide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology*; D007677:Kidney Function Tests; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D005996:Nitroglycerin / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
C097114:1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo(3,4-d)pyrimidin-4(5H)-one; D010726:Phosphodiesterase Inhibitors; C110881:S-nitro-N-acetylpenicillamine; D010656:Phenylephrine; D000493:Allopurinol; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D005996:Nitroglycerin; D010396:Penicillamine; D003981:Diazoxide