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.

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

“…via a large‐bore cannula placed in the right atrium. This model of APT is very similar to that previously reported . After, at least 20 min.…”

Atorvastatin and sildenafil decrease vascular TGF-β levels and MMP-2 activity and ameliorate arterial remodeling in a model of renovascular hypertension

“…Because we found in a previous study that both atorvastatin or sildenafil completely blunted 2K1C hypertension-induced oxidative stress under the same conditions of the present study [42] , it is possible that antioxidant effects exerted by both drugs may have inhibited hypertension-induced increases in vascular MMP-2 expression and activity, as shown with other antioxidant compounds [28] . Similar antioxidant effects of sildenafil leading to lower MMP activity has been shown under other conditions [18,20] , and the same has also been reported with atorvastatin [14,15,43] . Moreover, the inhibition of vascular remodeling associated with lower MMP-2 expression and activity that we found are not explained by direct inhibition of MMP-2 by either atorvastatin or sildenafil, as demonstrated by lack of significant effects of both drugs on rhMMP-2 activity that we found in the present study.…”

“…Moreover, sildenafil prevents cardiovascular remodeling [17] and inhibits MMP-9 and TGF-β expression [18,19] . Interestingly, some studies suggest that the combination of a statin with sildenafil further increases the protective effects of each drug alone [20–22] . However, although there is some evidence that both statins and phosphodiesterase-5 inhibitors may inhibit profibrotic mechanisms, it is not known whether atorvastatin or sildenafil attenuates the vascular remodeling associated with hypertension, or whether the combination of these drugs increases the possible effects associated with each drug alone.…”

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

“…Our findings show that rhMMP-2 exerts no major haemodynamic effects in lambs. However, rhMMP-2 impairs the responses elicited by activation of b-adrenoreceptors.Growing evidence supports the involvement of a group of enzymes named matrix metalloproteinases (MMPs) in the pathogenesis of many disease conditions, including diseases affecting the cardiovascular system [1][2][3][4]. Particular attention has been paid to MMP-2 because imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling [5][6][7] and in other alterations of the cardiovascular system [8][9][10].…”