盐酸埃他卡林对内皮素系统的影响

Effects of iptakalim hydrochloride on the functions of endothelin system

目的 研究新型抗高血压药物盐酸埃他卡林(iptakalim hydrochloride，Ipt)对内皮素(ET)系统的作用。方法 以放射免疫法测定大鼠血浆内皮素水平和培养的血管内皮细胞释放的内皮素量；以RT-PCR技术，测定内皮素及其转化酶(ECE)基因表达的变化；在离体血管标本上，观察内皮素对血管平滑肌张力的影响；在麻醉大鼠上，插入肺内动脉导管测定肺动脉压。结果 ①在SHRsp上，Ipt0．25～4．0mg·kg^-1，po，1次／d，3个月，可对抗血浆中内皮素水平的病理性增高；②在培养的新生小牛主动脉内皮细胞(BAEC)上，Ipt在1～1000μmol·L^-1浓度范围内，能剂量依赖性地抑制培养的新生小牛主动脉内皮细胞分泌内皮素；③并能抑制培养的新生小牛主动脉内皮细胞内皮素和内皮素转化酶基因的表达；④在离体大鼠主动脉标本上，Ipt0．5～100μmol·L^-1可浓度依赖性地对抗ET-1的缩血管作用，此作用在无钙营养液中明显减弱；⑤在麻醉的SD大鼠上，经肺内动脉注入ET-1可以诱发肺动脉收缩，肺动脉压增高。Ipt0．5和1．0mg·kg^-1可对抗肺动脉内注射ET-1诱发的肺动脉高压，但对正常肺动脉压无明显影响。结论 盐酸埃他卡林可对抗内皮素系统的功能，其特征包括抑制血管内皮细胞内皮素转化酶和内皮素基因的表达，抑制内皮素的释放，对抗高血压状态下血浆内皮素水平的病理性增高，并可对抗内皮素诱发的肺动脉高压。

Aim To investigate the effects of iptakalim hydrochl or ide (Ipt), a new antihypertensive drug, on the functions of endothelin system. Methods Radioimmunoassay was used to test the plasma endotheli n (ET) concentration of rats and endothelin released from cultured vasocular end othelial cells. The expressions of ET and endothelin converting enzyme (ECE) wer e determined by RT-PCR. The effects of endothelin on vascular tone were studied in isolated rat aorta. The pulmonary artery pressure was measured in anaestheti zed rats. Results ①In stroke-prone spontaneously hypertensive rats (SHRsp), the plasma levels of endothelin were increased, which could be re versed by the treatment with Ipt at the doses of 0.25,1.0 and 4.0 mg·kg - 1 po, once a day, for 3 months.② In cultured neonatal bovine aortic endotheli al cells (BAEC), Ipt at thc concentrations of 1～1000 μmol·L -1, inhibite d the secretion of ET in a concentra- tion-dependent manner. ③ Under the same experimental conditions, Ip t also inhibited the expressions of ET and ECE in BAEC. ④ In isolated preparati ons derived from rat aorta, the vascular contraction evoked by ET-1 was antagon ized by Ipt at the concentrations of 0.5～100 μmol·L -1in a concentratio n-dependent manner. The vasorelaxative effects of Ipt were attenuated significa ntly in buffer without Ca 2+. ⑤ In anaesthetized SD rats, intrapulmonary a rtery administration of ET-1 induced vascular contraction in vivo, resulti ng in intrapulmonary artery hypertension, which was prevented by iptakalim hydro chloride at the doses of 0.5～1.0 mg·kg -1. But it had no effects on nor mal pulmonary artery pressure. Conclusion Ipt could antagonize the functions of endothelin system. Its characteristics include inhibiting the e xpression of ET-1 and ECE, inhibiting the releasing of ET-1, reversing the in creased plasma levels of ET-1 under pathological condition, and preventing intr apulmonary artery hypertension induced by ET-1.