Tissue Selectivity of Antidiabetic Agent Nateglinide: Study on Cardiovascular and β-Cell KATP Channels

• Published in: The Journal of pharmacology and experimental therapeutics 1999-12, Vol.291 (3), p.1372
• Main Authors: Shiling Hu, Shuya Wang, Beth E. Dunning
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103

Nateglinide (NAT) stimulates insulin secretion from pancreatic β-cells by closing K ATP channels. Because K ATP channels are widely distributed in cardiovascular (CV) tissues, we assessed the tissue specificity of NAT by examining its effect on K ATP 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 K ATP channels in the cells from porcine coronary artery and rat aorta with IC 50 s 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 < .01) for β-cells. With an IC 50 of 5.0 nM in β-cells, REP displayed an ∼16-fold ( p < .05) selectivity for β-cells over both types of vascular cells. GLY was nonselective between vascular and β-cells. At equipotent concentrations (2× respective IC 50 s in β-cells), NAT, GLY, and REP all caused 62% reduction of pancreatic K ATP current but a respective 39, 55, and 66% inhibition of cardiac K ATP current. 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 K ATP channels.