Abstract

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 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 < .01) for β-cells. With an IC₅₀ 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 IC₅₀s 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_ATPcurrent. 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.