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.
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ABSTRACT: Activated matrix metalloproteinases (MMPs) cause cardiomyocyte injury during acute pulmonary thromboembolism (APT). However, the functional consequences of this alteration are not known. We examined whether doxycycline (a MMP inhibitor) improves right ventricle function and the cardiac responses to dobutamine during APT. APT was induced with autologous blood clots (350 mg/kg) in anaesthetized male lambs pre-treated with doxycycline (Doxy, 10 mg/kg/day, intravenously) or saline. Non-embolized control lambs received doxycycline pre-treatment or saline. The responses to intravenous dobutamine (Dob, 1, 5, 10 μg/kg/min.) or saline infusions at 30 and 120 min. after APT induction were evaluated by echocardiography. APT increased mean pulmonary artery pressure and pulmonary vascular resistance index by ~185%. Doxycycline partially prevented APT-induced pulmonary hypertension (P < 0.05). RV diameter increased in the APT group (from 10.7 ± 0.8 to 18.3 ± 1.6 mm, P < 0.05), but not in the Doxy+APT group (from 13.3 ± 0.9 to 14.4 ± 1.0 mm, P > 0.05). RV dysfunction on stress echocardiography was observed in embolized lambs (APT+Dob group) but not in embolized animals pre-treated with doxycycline (Doxy+APT+Dob). APT increased MMP-9 activity, oxidative stress and gelatinolytic activity in the RV. Although doxycycline had no effects on RV MMP-9 activity, it prevented the increases in RV oxidative stress and gelatinolytic activity (P < 0.05). APT increased serum cardiac troponin I concentrations (P < 0.05), doxycycline partially prevented this alteration (P < 0.05). We found evidence to support that doxycycline prevents RV dysfunction and improves the cardiac responses to dobutamine during APT.Journal of Cellular and Molecular Medicine 11/2013; · 4.75 Impact Factor
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ABSTRACT: Background The clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance.Methods2K1C hypertension was induced in C57BL/6 mice. Two weeks later, they were treated with sildenafil (40 mg/kg/day, via oral) or vehicle for 2 weeks and compared with sham mice. At the end of the treatment, the levels of plasma and intrarenal Ang peptides were measured. Endothelial function and ROS production were assessed in mesenteric arterial bed (MAB).ResultsThe 2K1C mice exhibited normal plasma levels of Ang I, II and 1¿7, whereas the intrarenal Ang I and II were increased (+35% and +140%) compared with the Sham mice. Sildenafil normalized the intrarenal Ang I and II and increased the plasma (+45%) and intrarenal (+15%) Ang 1¿7. The 2K1C mice exhibited endothelial dysfunction, primarily due to increased ROS and decreased NO productions by endothelial cells, which were ameliorated by treatment with sildenafil.Conclusion These data suggest that the effects of sildenafil on endothelial dysfunction in 2K1C mice may be due to interaction with RAS and restoring NO/ROS balance in the endothelial cells from MAB. Thus, sildenafil is a promising candidate drug for the treatment of hypertension accompanied by endothelial dysfunction and kidney disease.Journal of translational medicine. 09/2014; 12(1):250.
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ABSTRACT: Nitric oxide (NO)-derived metabolites including the anion nitrite can recycle back to NO and thus complement NO formation independent of NO synthases. While nitrite is as a major vascular storage pool and source of NO, little is known about drugs that increase tissue nitrite concentrations. This study examined the effects of atorvastatin or sildenafil, or the combination, on vascular nitrite concentrations and on endothelial dysfunction in the 2 kidney-1 clip (2K1C) hypertension model. Sham-operated or 2K1C hypertensive rats were treated with vehicle, atorvastatin (50 mg/Kg), sildenafil (45 mg/Kg), or both for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Nitrite concentrations were assessed in the aortas and in plasma samples by ozone-based reductive chemiluminescence assay. Aortic rings were isolated to assess endothelium-dependent and independent relaxation. Aortic NADPH activity and ROS production were evaluated by luminescence and dihydroethidium, respectively, and plasma TBARS levels were measured. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. Atorvastatin and sildenafil, alone or combined, significantly lowered SBP by approximately 40 mmHg. Atorvastatin significantly increased vascular nitrite levels by 70% in hypertensive rats, whereas sildenafil had no effects. Both drugs significantly improved the vascular function, and decreased vascular NADPH activity, ROS, and nitrotyrosine levels. Lower plasma TBARS concentrations were found with both treatments. The combination of drugs showed no improved responses compared to each drug alone. These findings show evidence that atorvastatin, but not sildenafil, increases vascular NO stores, although both drugs exert antioxidant effects, improve endothelial function, and lower blood pressure in 2K1C hypertension.Redox biology. 01/2013; 1(1):578-85.