Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats
Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats
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盐酸沙格雷酯是一种血清素 5HT2A 受体拮抗剂，可改善大鼠慢性缺氧性肺动脉高压的发展
DOI：
10.1007/s00540-015-2015-y
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发表时间：
2015
期刊：
影响因子：
2.8
通讯作者：
et al.
中科院分区：
文献类型：
--
作者：
Zhang E;Maruyama J;et al.
目的本研究的目的是确定盐酸沙泊格雷酯（SPG），一种5 -羟色胺5HT2A受体拮抗剂，是否能阻止慢性缺氧诱导的肺动脉高压（PH）的发展和高血压性肺血管重构。方法雄性Sprague-Dawley大鼠41只，从第2天至第14天，分别于380 mmHg、10%氧气或室内空气条件下，每天1次灌胃给予SPG或载药50 mg/kg。测量平均肺动脉压（PAP）和右心室肥厚（RVH）。光镜下观察高血压肺血管重构。测定了24只大鼠离体肺动脉环血清素诱导的收缩。另一组大鼠肺组织进行Western blotting、实时聚合酶链反应和免疫荧光染色（n= 9）。结果慢性缺氧导致平均PAP和RVH升高，增加肺外周动脉肌化动脉百分比和小肌动脉内侧壁厚度，增强血清素诱导的收缩，SPG可显著改善这两种情况（p< 0.05）。慢性缺氧显著升高全肺组织内皮型一氧化氮合酶（eNOS）和磷酸化型eNOS （peNOS）蛋白、环鸟苷单磷酸和基质金属蛋白酶-13 (MMP-13) mRNA表达水平。SPG增加慢性缺氧大鼠肺外周动脉免疫荧光染色中peNOS的表达，降低慢性缺氧大鼠肺组织中MMP-13 mRNA表达。结论SPG可改善慢性缺氧PH和高血压肺血管改变的发展。
PurposeThe purpose of the present study was to determine if sarpogrelate hydrochloride (SPG), a serotonin 5HT2A receptor antagonist, prevented the development of chronic hypoxia-induced pulmonary hypertension (PH) and hypertensive pulmonary vascular remodeling.MethodsForty-one male Sprague–Dawley rats were exposed to hypobaric hypoxia (380 mmHg, 10 % oxygen) or room air and administered 50 mg/kg SPG or vehicle by gavage once daily from day −2 to day 14. The mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodelings were assessed morphometrically by light microscopy. Serotonin-induced contraction was determined in isolated pulmonary artery rings from 24 rats. In another set of rats, Western blotting, real-time polymerase chain reaction and immunofluorescent staining (n= 9) for lung tissue were performed.ResultsChronic hypoxia induced a rise in mean PAP and RVH, increased the percentage of muscularized arteries in peripheral pulmonary arteries and medial wall thickness in small muscular arteries, and potentiated serotonin-induced contraction, each of which was significantly (p< 0.05) ameliorated by SPG. Chronic hypoxia significantly increased the expression of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) protein levels, cyclic guanosine monophosphate, and matrix metalloproteinase-13 (MMP-13) mRNA levels in whole lung tissues. SPG increased peNOS expression in the immunofluorescent staining of peripheral pulmonary arteries from chronic hypoxic rats and decreased the MMP-13 mRNA in lung tissue in chronic hypoxic rats.ConclusionsThe administration of SPG ameliorated the development of chronic hypoxic PH and hypertensive pulmonary vascular changes.