κ-阿片受体激动剂防治低氧性肺动脉高压的研究进展与展望

Research advance and prospect of κ-opioid receptor agonist in prevention and treatment of hypoxic pulmonary hypertension

低氧性肺动脉高压(HPH)尚缺乏较为理想的治疗方法。预防内皮功能失调和抑制平滑肌细胞的增殖是防治HPH新的潜在策略。κ-阿片受体(κ-OR)激动剂U50、488H既可以内皮依赖性地舒张正常大鼠的肺动脉又可显著舒张HPH大鼠的肺动脉,其作用机制与电压依赖性钾通道(KV通道)及一氧化氮(NO)途径密切相关,预防性给予U50、488H可显著升高HPH大鼠血液及肺组织NO水平的同时,降低内皮素(ET)和血管紧张素Ⅱ(AngⅡ)浓度,显著改善低氧诱导的内皮功能失调,另一方面发现U50、488H能有效降低HPH大鼠的平均肺动脉压(mPAP),并能明显减轻HPH大鼠的肺血管重建和右心室肥厚程度。另外,U50、488H可抑制低氧下的肺动脉平滑肌细胞(PASMC)增殖,这可能是其抑制肺血管重建的原因,提示U50、488H对大鼠HPH具有明确的防治作用。U50、488H内皮依赖性的舒张肺动脉、降低肺动脉压、改善内皮功能失调及抑制PASMC增殖等作用均由κ-OR所介导,提示κ-OR有可能成为临床防治HPH新的药理学靶点。

Currently,there is still no effective therapy for hypoxic pulmonary hypertension(HPH).Preventing endothelial dysfunction and inhibiting smooth muscle cell proliferation are new potential strategies for prevention and treatment of HPH.U50,488H,a κ-opioid receptor(κ-OR) agonist,not only relaxes pulmonary artery from normal rats in an endothelium-dependent manner,but also dilates pulmonary artery from HPH rats dramatically,the underlying mechanism of which is closely associated with voltage-gated potassium channel(KV channel) and nitric oxide(NO) pathways.Pretreatment with U50,488H elevates NO level in the blood and pulmonary tissues of rats obviously and lowers endothelin(ET) and angiotensin Ⅱ(AngⅡ) levels,which remarkably ameliorates endothelial dysfunction induced by hypoxia.On the other hand,we have discovered that U50,488H effectively lowers the mean pulmonary artery pressure(mPAP) of HPH rats,inhibits vascular remodeling and decreases right ventricular hypertrophy in HPH rats.Moreover,U50,488H inhibits the proliferation of pulmonary artery smooth muscle cell(PASMC),which may contribute to its inhibitory effect on pulmonary vascular remodeling and suggest a specific effect of U50,488H on prevention and treatment of HPH.The endothelium-dependent relaxing effect on pulmonary artery,the decrease in mPAP,the amelioration of endothelial dysfunction and the inhibition of PASMC proliferation by U50,488H are all mediated by κ-OR,which indicates that κ-OR may be a new pharmacological target in clinical prevention and treatment of HPH.