Long Chao-Liang, Qin Xiu-Chuan, Pan Zhi-Yuan, Chen Kai, Zhang Yan-Fang, Cui Wen-Yu, Liu Guo-Shu, Wang Hai
Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
J Hypertens. 2008 Dec;26(12):2326-38. doi: 10.1097/HJH.0b013e328312c8c1.
It has been demonstrated that hyperuricemia induces reno-cardiovascular damage resulting in hypertension and renal injury because of vascular endothelial dysfunction. The pathogenesis of hyperuricemia, endothelial dysfunction, hypertension, and renal injury is progressive, and develops into a vicious cycle. It is reasonable to suggest that an antihypertensive drug with endothelial protection may block this vicious cycle. Iptakalim, a novel antihypertensive drug undergoing phase-three clinical trials, is a new ATP-sensitive potassium channel opener and can ameliorate endothelial dysfunction. We hypothesized that iptakalim could prevent hypertension and retard the pathogenesis of endothelial dysfunction and renal injury in hyperuricemic rats.
In rats with hyperuricemia induced by 2% oxonic acid and 0.1 mmol/l uric acid, iptakalim prevented increases in systolic blood pressure, reduced the impairment of endothelial vasodilator function, and attenuated renal dysfunction and pathological changes in glomerular and renal interstitial tissue at 0.5, 1.5, and 4.5 mg/kg orally daily for 4 weeks. Serum levels of nitric oxide and prostacyclin, and gene expression of endothelial nitric oxide synthase in the aortic and intrarenal tissue, were increased, whereas the serum levels of endothelin-1 and gene expression of endothelin-1 in aortic and intrarenal tissue were decreased. However, serum levels of angiotensin II and renin remained unchanged in the hyperuricemic rats treated with iptakalim. In cultured rat aortic endothelial cells, amelioration of endothelial dysfunction by iptakalim was suggested by inhibition of the overexpression of intercellular adhesive molecule-1, vascular cell adhesive molecule-1, and monocyte chemoattractant protein-1 mRNA induced by uric acid, and reversal of the inhibitory effects of uric acid on nitric oxide release in a concentration-dependent manner, which could be abolished by pretreatment with glibenclamide, an ATP-sensitive potassium channel blocker. Iptakalim ameliorated hyperuricemia in this rat model by decreasing renal damage through its antihypertensive and endothelial protective properties, and it had no direct effects on anabolism, catabolism and excretion of uric acid.
These findings suggest that the activation of ATP-sensitive potassium channels by iptakalim can protect endothelial function against hypertension and renal injury induced by hyperuricemia. Iptakalim is suitable for use in hypertensive individuals with hyperuricemia.
已有研究表明，高尿酸血症可导致肾心血管损害，因血管内皮功能障碍而引发高血压和肾损伤。高尿酸血症、内皮功能障碍、高血压及肾损伤的发病机制呈进行性发展，并形成恶性循环。有理由认为，一种具有内皮保护作用的降压药物可能会阻断这一恶性循环。伊普卡林是一种正在进行三期临床试验的新型降压药物，是一种新型的ATP敏感性钾通道开放剂，可改善内皮功能障碍。我们推测，伊普卡林可预防高尿酸血症大鼠的高血压，并延缓内皮功能障碍和肾损伤的发病进程。
在由2%氧嗪酸和0.1 mmol/L尿酸诱导的高尿酸血症大鼠中，伊普卡林以每日0.5、1.5和4.5 mg/kg的剂量口服给药4周，可预防收缩压升高，减轻内皮舒张功能损害，减轻肾功能障碍以及肾小球和肾间质组织的病理变化。血清一氧化氮和前列环素水平以及主动脉和肾内组织中内皮型一氧化氮合酶的基因表达增加，而主动脉和肾内组织中内皮素-1的血清水平和内皮素-1的基因表达降低。然而，在接受伊普卡林治疗的高尿酸血症大鼠中，血管紧张素II和肾素的血清水平保持不变。在培养的大鼠主动脉内皮细胞中，伊普卡林对内皮功能障碍的改善表现为抑制尿酸诱导的细胞间黏附分子-1、血管细胞黏附分子-1和单核细胞趋化蛋白-1 mRNA的过度表达，并以浓度依赖的方式逆转尿酸对一氧化氮释放的抑制作用，而这种作用可被ATP敏感性钾通道阻滞剂格列本脲预处理所消除。伊普卡林通过其降压和内皮保护特性减轻肾损伤，从而改善该大鼠模型的高尿酸血症，且对尿酸的合成、分解代谢及排泄无直接影响。
这些研究结果表明，伊普卡林激活ATP敏感性钾通道可保护内皮功能，对抗高尿酸血症诱导的高血压和肾损伤。伊普卡林适用于患有高尿酸血症的高血压患者。
