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A new ATP-sensitive potassium channel opener protects endothelial function in cultured aortic endothelial cells

, : A new ATP-sensitive potassium channel opener protects endothelial function in cultured aortic endothelial cells. Cardiovascular Research 73(3): 497-503

Objective: Endothelial dysfunction is an early risk factor for cardiovascular disease and hypertension. Mechanisms that participate in endothelial dysfunction include reduced nitric oxide (NO) generation and increased endothelin-1 (ET-1) generation. Endothelial ATP-sensitive potassium (K-ATP) channels are responsible for maintaining the resting potential of endothelial cells and modulating the release of vasoactive compounds. We hypothesized that activation of endothelial K-ATP channels might result in the protection against endothelial dysfunction.Methods: Using cultured bovine or rat aortic endothelial cells, we examined the effects of a new K-ATP channels opener, iptakalim, on the secretion of vasoactive substances. We also investigated its effects on the expression of adhesion molecules in metabolically disturbed cultured endothelial cells.Results: In cultured aortic endothelial cells, iptakalim caused a concentration-dependent inhibition of ET-1 release and synthesis that correlated with reduced levels of mRNA for ET-1 and endothelin-converting enzyme. These effects of iptakalim were significantly inhibited by pretreatment with glibenclamide (a K-ATP channel blocker) for 1 h. Similarly, iptakalim enhanced the release of NO in a concentration-dependent manner and increased basal levels of free intracellular calcium. Iptakalim at the concentrations of 100 and 1000 mu M increased the activities of NO synthase (NOS) significantly. After the activity of NOS was blocked by L-N-omega-nitro-arginine methyl ester (L-NAME), the inhibition of iptakalim on ET-1 release was abolished. In endothelial cell models of metabolic disturbance induced by low-density lipoprotein, homocysteine, or hyperglycemia, treatment with iptakalim could inhibit the overexpression of monocyte chemoattractant protein-1 (MCP-1), Intercellular adhesive molecule-1 (ICAM-1), and vascular cell adhesive molecule-1 (VCAM-1) mRNA.Conclusion: Iptakalim is a promising drug that could protect against endothelial dysfunction through activating K-ATP channels in endothelial cells.


PMID: 17116295

DOI: 10.1016/j.cardiores.2006.10.007

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