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Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia.
J Hypertens. 2008 Dec; 26(12):2326-38.JH

Abstract

BACKGROUND AND OBJECTIVES

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.

METHODS AND 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.

CONCLUSION

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.

Authors+Show Affiliations

Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19008712

Citation

Long, Chao-Liang, et al. "Activation of ATP-sensitive Potassium Channels Protects Vascular Endothelial Cells From Hypertension and Renal Injury Induced By Hyperuricemia." Journal of Hypertension, vol. 26, no. 12, 2008, pp. 2326-38.
Long CL, Qin XC, Pan ZY, et al. Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia. J Hypertens. 2008;26(12):2326-38.
Long, C. L., Qin, X. C., Pan, Z. Y., Chen, K., Zhang, Y. F., Cui, W. Y., Liu, G. S., & Wang, H. (2008). Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia. Journal of Hypertension, 26(12), 2326-38. https://doi.org/10.1097/HJH.0b013e328312c8c1
Long CL, et al. Activation of ATP-sensitive Potassium Channels Protects Vascular Endothelial Cells From Hypertension and Renal Injury Induced By Hyperuricemia. J Hypertens. 2008;26(12):2326-38. PubMed PMID: 19008712.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia. AU - Long,Chao-Liang, AU - Qin,Xiu-Chuan, AU - Pan,Zhi-Yuan, AU - Chen,Kai, AU - Zhang,Yan-Fang, AU - Cui,Wen-Yu, AU - Liu,Guo-Shu, AU - Wang,Hai, PY - 2008/11/15/pubmed PY - 2009/2/14/medline PY - 2008/11/15/entrez SP - 2326 EP - 38 JF - Journal of hypertension JO - J Hypertens VL - 26 IS - 12 N2 - BACKGROUND AND OBJECTIVES: 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. METHODS AND 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. CONCLUSION: 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. SN - 0263-6352 UR - https://www.unboundmedicine.com/medline/citation/19008712/Activation_of_ATP_sensitive_potassium_channels_protects_vascular_endothelial_cells_from_hypertension_and_renal_injury_induced_by_hyperuricemia_ L2 - https://doi.org/10.1097/HJH.0b013e328312c8c1 DB - PRIME DP - Unbound Medicine ER -