G protein-coupled receptor (GPCR) agonists through their receptors can transactivate protein tyrosine kinase receptors such as epidermal growth factor receptor and serine/threonine kinase receptors most notably transforming growth factor (TGF)‐β receptor (TβRI). Several GPCR agonists such as Ang II, thrombin, ET-1 can mediate the transactivation of a multitude of protein tyrosine kinase receptors[3]. Endothelin (ET) is an endothelium-derived 21-residue vasoconstrictor peptide. The ETs have three distinct isoforms, namely ET-1, ET-2, and ET-3. ET-1 is the most abundant isoform and the best characterized in vivo, and it is the only one that is constitutively released by the vascular endothelium[4]. Bosentan hydrate (BST) is a competitive dual endothelin receptor antagonist that is nonselective for both endothelin A and endothelin B receptors with a Ki of 4.1 - 4.7 nM[5]. It decreases both pulmonary vascular resistance and systemic vascular resistance and hence increases cardiac output without increasing the heart rate[6]. In a vivo study, the rats were intragastrically administered with 100 mg/kg bosentan half an hour after Paraquat exposure, and then once a day. After bosentan administration, the ET-1 and TGF-β1 content of the serum and lungs gradually decreased and were markedly lower than in the Paraquat group on the 21st day which indicated that early treatment with bosentan after Paraquat poisoning may be helpful in ameliorating lung injury and decreasing lung fibrosis[4]. In a study, bosentan was given orally (1000 mg b.i.d.) for 14 days to patients who were also being treated for chronic heart failure (CHF) with digitalis, angiotensin-converting enzyme inhibitors (ACEIs) and diuretics and the results demonstrated that addition of bosentan to ongoing therapy for patients with CHF reduced systemic and pulmonary vascular resistance and increased cardiac index, without affecting heart rate. Bosentan treatment of patients with CHF already receiving ACEIs and diuretics significantly decreased plasma aldosterone levels[5].
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