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


CONCLUSIONS
Iptakalim is a promising drug that could protect against endothelial dysfunction through activating K(ATP) channels in endothelial cells.
Wang
Hai
H
Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. wh9588@yahoo.com.cn
Long
Chaoliang
C
Duan
Zhibian
Z
Shi
Cuige
C
Jia
Guodong
G
Zhang
Yingli
Y
D018528:ATP-Binding Cassette Transporters / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001011:Aorta; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011437:Propylamines / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019332:Endothelin-1; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011437:Propylamines; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D005905:Glyburide; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester