Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Long
Chao-Liang
CL
Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Qin
Xiu-Chuan
XC
Pan
Zhi-Yuan
ZY
Chen
Kai
K
Zhang
Yan-Fang
YF
Cui
Wen-Yu
WY
Liu
Guo-Shu
GS
Wang
Hai
H
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000809:Angiotensins; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D033461:Hyperuricemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D054086:KATP Channels / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010094:Oxonic Acid / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014503:Urate Oxidase / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D000809:Angiotensins; D019332:Endothelin-1; D054086:KATP Channels; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D011437:Propylamines; D000804:Angiotensin II; D014527:Uric Acid; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D010094:Oxonic Acid; D014969:Xanthine Oxidase; D014503:Urate Oxidase