TY - JOUR
T1 - KMUP-1 ameliorates monocrotaline-induced pulmonary arterial hypertension through the modulation of Ca2+ sensitization and K+-channel
AU - Dai, Zen Kong
AU - Cheng, Yung Jen
AU - Chung, Hui Hsuan
AU - Wu, Jiunn Ren
AU - Chen, Ing Jun
AU - Wu, Bin Nan
N1 - Funding Information:
We thank Ms. Li-Mei An and MSc Chiu-Yin Lin for their excellent technical assistance and Dr. Susan Olmstead-Wang at Johns Hopkins University for her editorial assistance with the manuscript. This study was supported by grants NSC-97-2320-B-037-006-MY3 to Dr. Bin-Nan Wu from the National Science Council, Taiwan , and KMUH96-6R04 to Dr. Zen-Kong Dai from Kaohsiung Medical University Hospital, Kaohsiung, Taiwan .
PY - 2010/5
Y1 - 2010/5
N2 - Aims: This study investigates the actions of KMUP-1 on RhoA/Rho-kinase (ROCK)-dependent Ca2+ sensitization and the K+-channel in chronic pulmonary arterial hypertension (PAH) rats. Main methods: Sprague-Dawley rats were divided into control, monocrotaline (MCT), and MCT. +. KMUP-1 groups. PAH was induced by a single intraperitoneal injection (i.p.) of MCT (60. mg/kg). KMUP-1 (5. mg/kg, i.p.) was administered once daily for 21. days to prevent MCT-induced PAH. All rats were sacrificed on day 22. Key findings: MCT-induced increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy were prevented by KMUP-1. In myograph experiments, KCl (80mM), phenylephrine (10μM) and K+ channel inhibitors (TEA, 10mM; paxilline, 10μM; 4-AP, 5mM) induced weak PA contractions in MCT-treated rats compared to controls, but the PA reactivity was restored in MCT+KMUP-1-treated rats. By contrast, in β-escin- or α-toxin-permeabilized PAs, CaCl2-induced (1.25mM, pCa 5.1) contractions were stronger in MCT-treated rats, and this action was suppressed in MCT+KMUP-1-treated rats. PA relaxation in response to the ROCK inhibitor Y27632 (0.1μM) was much higher in MCT-treated rats than in control rats. In Western blot analysis, the expression of Ca2+-activated K+ (BKCa) and voltage-gated K+ channels (Kv2.1 and Kv1.5), and ROCK II proteins was elevated in MCT-treated rats and suppressed in MCT+KMUP-1-treated rats. We suggest that MCT-treated rats upregulate K+-channel proteins to adapt to chronic PAH. Significance: KMUP-1 protects against PAH and restores PA vessel tone in MCT-treated rats, attributed to alteration of Ca2+ sensitivity and K+-channel function.
AB - Aims: This study investigates the actions of KMUP-1 on RhoA/Rho-kinase (ROCK)-dependent Ca2+ sensitization and the K+-channel in chronic pulmonary arterial hypertension (PAH) rats. Main methods: Sprague-Dawley rats were divided into control, monocrotaline (MCT), and MCT. +. KMUP-1 groups. PAH was induced by a single intraperitoneal injection (i.p.) of MCT (60. mg/kg). KMUP-1 (5. mg/kg, i.p.) was administered once daily for 21. days to prevent MCT-induced PAH. All rats were sacrificed on day 22. Key findings: MCT-induced increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy were prevented by KMUP-1. In myograph experiments, KCl (80mM), phenylephrine (10μM) and K+ channel inhibitors (TEA, 10mM; paxilline, 10μM; 4-AP, 5mM) induced weak PA contractions in MCT-treated rats compared to controls, but the PA reactivity was restored in MCT+KMUP-1-treated rats. By contrast, in β-escin- or α-toxin-permeabilized PAs, CaCl2-induced (1.25mM, pCa 5.1) contractions were stronger in MCT-treated rats, and this action was suppressed in MCT+KMUP-1-treated rats. PA relaxation in response to the ROCK inhibitor Y27632 (0.1μM) was much higher in MCT-treated rats than in control rats. In Western blot analysis, the expression of Ca2+-activated K+ (BKCa) and voltage-gated K+ channels (Kv2.1 and Kv1.5), and ROCK II proteins was elevated in MCT-treated rats and suppressed in MCT+KMUP-1-treated rats. We suggest that MCT-treated rats upregulate K+-channel proteins to adapt to chronic PAH. Significance: KMUP-1 protects against PAH and restores PA vessel tone in MCT-treated rats, attributed to alteration of Ca2+ sensitivity and K+-channel function.
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U2 - 10.1016/j.lfs.2010.03.011
DO - 10.1016/j.lfs.2010.03.011
M3 - Article
C2 - 20303989
AN - SCOPUS:77951934716
SN - 0024-3205
VL - 86
SP - 747
EP - 755
JO - Life Sciences
JF - Life Sciences
IS - 19-20
ER -