| Summary: | 碩士 === 高雄醫學大學 === 藥理學研究所 === 96 === In this study, we examined whether KMUP-1 could restore the vessel tone in pulmonary artery hypertension (PAH) rats, and its action mechanisms on the K+-channel and Rho-kinase (ROCK). The PAH model was induced by single intraperitoneal injection (i.p.) of monocrotaline (MCT, 60 mg/kg) into rats after 3 weeks. Animals were divided into 3 groups including the control, MCT-treated and KMUP-1-treated. In MCT-treated rats, increased right ventricular systolic pressure (RVSP) and right ventricle hypertrophy were induced significantly. These untoward effects were prevented by treating KMUP-1 (5 mg/kg, i.p.) once daily for 3 weeks. In isolated pulmonary arteries (PAs), KCl (80 mM) or phenylephrine (10 μM)-induced contraction was weaker in MCT-treated than in control rats, but the action was reversed in KMUP-1-treated rats. Additionally, the vasocontractile effects of various K+ channel blockers TEA (10 mM), 4-AP (5 mM), paxilline (10 μM) were weaker in MCT-treated than in control rats, and the effects were also reversed in KMUP-1-treated rats. Moreover, the ROCK inhibitor Y27632 (0.1 μM)-induced relaxation was stronger in MCT-treated than in control rats, and the action was reversed in KMUP-1-treated rats. In isolated pulmonary arteries permeabilized with ionomycin, CaCl2 (1.25 mM)-induced contraction was stronger in MCT-treated than in control rats, and the action was reversed in KMUP-1-treated rats. These results indicated that KMUP-1 could improve the dysfunction of vessel tone in MCT-treated rats. Furthermore, the protein levels of large-conductance Ca2+-activated K+ (BKCa) and voltage-gated K+ channels (including Kv2.1 and Kv1.5), and ROCK II were increased in isolated PAs from MCT-treated rats and these proteins were reversed in KMUP-1-treated rats. In light of these results suggested that the prevention of PAH and improvement of vessel tone by KMUP-1 could be due to the alterations of ROCK and K+-channel functions.
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