P626Hemodynamic and neuroendocrine effects of tezosentan in chronic pulmonary hypertension

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Abstract

Purpose

Chronic pulmonary hypertension therapy is poorly investigated in intensive care. We aim to evaluate hemodynamic and neuroendocrine effects of the dual endothelin-1 blocker tezosentan in monocrotaline-induced pulmonary hypertension.

Methods

Male wistar rats (180-200 g, n = 194) randomly received monocrotaline (MCT, 60 mg/Kg, subcutaneously) or vehicle (0.9 % saline) in equivolumetric doses. Two days later, a subgroup of MCT-injected rats was gavaged with bosentan (MCT BOS, 300 mg/Kg/d) while another (MCT) and control rats (Ctrl) received vehicle. From 25th-30th day, rats were subjected to anesthesia, thoracotomy and hemodynamic analysis, 48 h after interrupting bosentan treatment. After dose-response evaluation (0.5-20 mg/Kg, n = 7 per group), rats randomly underwent a 4 h perfusion of tezosentan (20 mg/Kg in 10 min + 10 mg/g/h) or vehicle (n = 8 per group) for hemodynamic evaluation, blood gas analysis and sample collection. Plasma was used for endothelin-1, cytokine, nitrate and 6-keto-PGF1α assessment, while lung and right ventricular samples were used for determination of gene expression and activity of cyclooxygenase and nitric oxide synthase.

Results

MCT showed pulmonary hypertension, right ventricular dilation and decreased cardiac output that were attenuated in MCT BOS. Pulmonary hypertension was attenuated by tezosentan without systemic hypotension. Tezosentan increased cardiac output without changing ventilation-perfusion matching. Both bosentan and tezosentan reduced endothelin-1 and cytokine plasma levels and tissue expression, as well as, inducible nitric oxide synthase and cyclooxygenase-2 right ventricular activity. Bosentan increased nitrate plasma levels and non inducible nitric oxide synthase activity, whereas tezosentan decreased circulating 6-keto-PGF1α but increased lung cyclooxygenase-1 activity.

Conclusions

Tezosentan may be useful for hemodynamic handling and bosentan replacement in pulmonary hypertensive critically ill patients, exerting important beneficial neuroendocrine and anti-inflammatory actions.

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