title: Sildenafil reduces cardiovascular remodeling associated with hypertensive cardiomyopathy in NOS inhibitor-treated rats.
abstract: Many of the physiological responses to nitric oxide (NO) are mediated by cyclic 5'-guanosine monophosphate (cGMP), the intracellular levels of which are regulated by phosphodiesterase type 5 (PDE5). In situations of reduced NO formation, the inhibition of PDE5 by selective inhibitors such as sildenafil could be beneficial in restoring physiological functions by enhancing the intracellular levels of cGMP. In this study, we evaluated the effects of sildenafil on the hemodynamic and histological alterations induced by the chronic treatment of rats with N(omega)-nitro-L-arginine-methyl ester (L-NAME). After 8 weeks of concomitant treatment with sildenafil and L-NAME, arterial blood pressure was significantly lower (P<0.05) than in L-NAME-treated rats. The fall in blood pressure was associated with a slight reduction in the total peripheral vascular resistance (P<0.05). Sildenafil partially prevented the decrease in cardiac output seen in L-NAME-treated rats. Morphologically, sildenafil reduced the total area of the myocardial lesions and attenuated the cardiomyocyte and vascular smooth muscle remodeling seen with L-NAME. These results show that sildenafil prevented the deleterious hemodynamic and morphological alterations associated with L-NAME-induced hypertension. This beneficial effect was probably mediated by an increase in cardiac and vascular cGMP levels as reflected in circulating plasma cGMP levels.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, Institute of Biology, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Silvia Elaine
authors.initials: SE
authors.lastname: Ferreira-Melo
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Yugar-Toledo
authors.forename: Otávio Rizzi
authors.initials: OR
authors.lastname: Coelho
authors.forename: Iara M
authors.initials: IM
authors.lastname: De Luca
authors.forename: José Eduardo
authors.initials: JE
authors.lastname: Tanus-Santos
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyslop
authors.forename: Maria Cláudia
authors.initials: MC
authors.lastname: Irigoyen
authors.forename: Heitor
authors.initials: H
authors.lastname: Moreno
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D009202:Cardiomyopathies / Q000503:physiopathology*; D006152:Cyclic GMP / Q000097:blood / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones
chemical_list: D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester