Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing, China.
J Cardiovasc Pharmacol Ther. 2013 Jan;18(1):60-9. doi: 10.1177/1074248412458154. Epub 2012 Sep 4.
We sought to investigate the experimental therapeutic effects and mechanisms of iptakalim, a new adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) opener, on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right heart ventricle remodeling in rats.
Rats were injected with a single dose (50 mg/kg, ip) of MCT and given iptakalim (1, 3, and 9 mg/kg·per d, orally [po]) or saline for 28 days. The hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis.
Treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg from the day of MCT injection attenuated the high right ventricle systolic pressure (RVSP) and the increased weight ratio of right ventricle (RV) to left ventricle (LV) plus septum (S) (RV/(LV+S)), decreased heart rate (HR) and decreased mean arterial pressure (MAP), inhibited the RV myocardial tissue cell apoptosis, and the RV myocardial cell B-type natriuretic peptide (BNP) protein expression. Iptakalim also decreased the serum levels of nitric oxide (NO), endothelin 1 (ET-1), BNP, and the levels of NO, ET-1, and tumor necrosis factor-alpha (TNF-α) in the lung tissue.
These results indicate that iptakalim prevents MCT-induced PAH and RV remodeling and its mechanisms are related to inhibiting the pathological increases in NO, ET-1, BNP, and TNF-α, and Iptakalim may be a promising candidate for the treatment of PAH.
我们旨在研究新型三磷酸腺苷（ATP）敏感性钾通道（KATP）开放剂伊帕立林（iptakalim）对野百合碱（MCT）诱导的肺动脉高压（PAH）和大鼠右心室重构的实验治疗作用及其机制。
大鼠单次腹腔注射（ip）给予 MCT（50 mg/kg），并给予伊帕立林（1、3 和 9 mg/kg·d，po）或生理盐水，共 28 天。评估血流动力学和形态计量学参数。采集组织和血浆样本进行组织学和分子分析。
从 MCT 注射之日起，每天口服给予伊帕立林 1、3 和 9 mg/kg，可减轻右心室收缩压（RVSP）升高和右心室（RV）与左心室（LV）加室间隔（S）的重量比（RV/（LV+S）增加），降低心率（HR）和平均动脉压（MAP），抑制 RV 心肌细胞凋亡，RV 心肌细胞 B 型利钠肽（BNP）蛋白表达。伊帕立林还降低了血清中一氧化氮（NO）、内皮素 1（ET-1）、BNP 的水平以及肺组织中 NO、ET-1 和肿瘤坏死因子-α（TNF-α）的水平。
这些结果表明，伊帕立林可预防 MCT 诱导的 PAH 和 RV 重构，其机制与抑制 NO、ET-1、BNP 和 TNF-α的病理性增加有关，伊帕立林可能是治疗 PAH 的有前途的候选药物。
