Abstract
Pulmonary arterial hypertension (PAH) and vascular remodeling may cause right ventricular hypertrophy and failure, which increases morbidity and mortality of patients. PAH is a progressive and fatal disease, Rho-kinase expression may be substantially involved in the pathogenesis of PAH. In this study, we examined the pulmonary vasodilation effects of KMUP-1, a cGMP-dependent Rho-kinase inhibitor, in chronic monocrotaline (MCT)-treated rats. Here, we report the preventive effects of KMUP-1 on MCT-induced PAH. Eight-week-old adult Wistar rats were given a single intraperitoneal injection of monocrotaline (MCT, 60mg/kg) to cause PAH at 21 days. For prevention of disease worsening, sublingual administration of KMUP-1(2.5 mg/kg) caused a pulmonary selective vasodilation, decreased medial thickness of the peripheral pulmonary artery and right ventricular hypertrophy in chronically MCT-treated rats.Western blotting analysis demonstrated that endothelial nitric oxide synthase (eNOS) and soluble guanylyl cyclase (sGC) in lung tissue were markedly decreased in the MCT-treated rats, but it was protected from worsening by KMUP-1. In addition, MCT increased expression of Rho kinase (ROCK II) which plays an important role to induce smooth muscle contraction and vascular remodeling. Theses finding indicated that sublingual administration of KMUP-1 can protect from MCT-induced PAH, without affecting systemic artery pressure in rats.
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