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1 Physiology, Faculty of Medicine, Porto, Portugal
* To whom correspondence should be addressed. E-mail: amoreira{at}med.up.pt.
In monocrotaline (MCT)-induced pulmonary hypertension (PH) only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whetherin longstanding PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed we evaluated myocardial function, histology and gene expression of autocrine/paracrine systems in rats with severe PH 6 weeks after subcutaneous injection of 60mg/Kg MCT. The overloaded RV underwent myocardial hypertrophy (P<0.001) and fibrosis (P=0.014) as well as increased expression of angiotensin-converting enzyme (ACE) by eight-fold (P<0.001), endothelin-1 (ET-1) by six-fold (P<0.001 and type-B natriuretic peptide (BNP) by fifteen-fold (P<0.001). Despite the similar eight-fold upregulation of ET-1 (P<0.001) and four-fold overexpression of ACE (P<0.001) without BNP elevation, the non- overloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility dP/dTmax (P<0.001) and relaxation 
(P=0.03) were however abnormal, and LV muscle strips from MCT-treated rats in opposition to sham presented negative (P=0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ETA antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P=0.005) from the negative inotropic effect exerted on sham. Chronic daily therapy with 250mg/Kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive. In conclusion the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis. Neuroendocrine mediators, particularly ET-1 might participate in this functional deterioration.
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