title: Sildenafil improves the beneficial hemodynamic effects exerted by atorvastatin during acute pulmonary thromboembolism.
abstract: We investigated whether atorvastatin has beneficial hemodynamic effects during acute pulmonary thromboembolism (APT) and whether sildenafil improves these effects. We studied the involvement of oxidative stress, matrix metalloproteinases (MMPs), and neutrophil activation. APT was induced with autologous blood clots (500 mg/kg) in anesthetized male lambs pretreated with atorvastatin (10 mg/kg/day, subcutaneously; 1 week) or vehicle (dimethyl sulfoxide 10% subcutaneously). Sildenafil (0.7 mg/kg intravenously) or saline infusions were performed 60 min after APT induction. Non-embolized control animals received saline. APT significantly increased pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (MPAP) by approximately 310% and 258% respectively. While atorvastatin pretreatment attenuated these increases (~150% and 153%, respectively; P < 0.05), its combination with sildenafil was associated with lower increases in PVRI and MPAP (~32% and 36%, respectively). Gelatin zymography showed increased MMP-9 and MMP-2 levels in the bronchoalveolar lavage, and increased MMP-9 levels in plasma from embolized animals. Atorvastatin pretreatment attenuated bronchoalveolar lavage MMP-2 increases. The combination of drugs blunted the MMPs increases in bronchoalveolar lavage and plasma (P < 0.05). Neutrophils accumulated in bronchoalveolar lavage after APT, and atorvastatin pretreatment combined with sildenafil (but not atorvastatin alone) attenuated this effect (P < 0.05). APT increased lung lipid peroxidation and total protein concentrations in bronchoalveolar lavage, thus indicating oxidative stress and alveolar-capillary barrier damage, respectively. Both increases were attenuated by atorvastatin pretreatment alone or combined with sildenafil (P < 0.05). We conclude that pretreatment with atorvastatin protects against the pulmonary hypertension associated with APT and that sildenafil improves this response. These findings may reflect antioxidant effects and inhibited neutrophils/MMPs activation.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Evandro M
authors.initials: EM
authors.lastname: Neto-Neves
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Dias-Junior
authors.forename: Juliana A
authors.initials: JA
authors.lastname: Uzuelli
authors.forename: Romaiana P
authors.initials: RP
authors.lastname: Pereira
authors.forename: Fernando
authors.initials: F
authors.lastname: Spiller
authors.forename: Paula G
authors.initials: PG
authors.lastname: Czaikoski
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D000208:Acute Disease; D000818:Animals; D000069059:Atorvastatin; D018893:Bronchoalveolar Lavage; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011655:Pulmonary Embolism / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D011687:Purines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D006538:Heptanoic Acids; D010879:Piperazines; D011687:Purines; D011758:Pyrroles; D013450:Sulfones; D000069059:Atorvastatin; D000068677:Sildenafil Citrate; D020782:Matrix Metalloproteinases