TY - JOUR T1 - Tissue Selectivity of Antidiabetic Agent Nateglinide: Study on Cardiovascular and β-Cell K<sub>ATP</sub> Channels JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1372 LP - 1379 VL - 291 IS - 3 AU - Shiling Hu AU - Shuya Wang AU - Beth E. Dunning Y1 - 1999/12/01 UR - http://jpet.aspetjournals.org/content/291/3/1372.abstract N2 - Nateglinide (NAT) stimulates insulin secretion from pancreatic β-cells by closing KATP channels. Because KATP channels are widely distributed in cardiovascular (CV) tissues, we assessed the tissue specificity of NAT by examining its effect on KATP channels in enzymatically isolated rat β-cells, rat cardiac myocytes, and smooth muscle cells from porcine coronary artery and rat aorta with the patch-clamp method. The selectivity of known antidiabetic agents glyburide (GLY) and repaglinide (REP) was also studied for comparison. NAT was found to inhibit KATP channels in the cells from porcine coronary artery and rat aorta with IC50s of 2.3 and 0.3 mM, respectively, compared with 7.4 μM in rat β-cells, indicating a respective 311- and 45-fold selectivity (p &lt; .01) for β-cells. With an IC50 of 5.0 nM in β-cells, REP displayed an ∼16-fold (p &lt; .05) selectivity for β-cells over both types of vascular cells. GLY was nonselective between vascular and β-cells. At equipotent concentrations (2× respective IC50s in β-cells), NAT, GLY, and REP all caused 62% reduction of pancreatic KATP current but a respective 39, 55, and 66% inhibition of cardiac KATPcurrent. These data collectively indicate that NAT, when compared with GLY and REP, at concentrations effective in stimulating insulin secretion is least likely to cause detrimental CV effects via blockade of CV KATP channels. The American Society for Pharmacology and Experimental Therapeutics ER -