Tissue selectivity of antidiabetic agent nateglinide: Study on cardiovascular and beta-cell K-ATP channels

Nateglinide (NAT) stimulates insulin secretion from pancreatic beta-cells b y closing K-ATP channels. Because K-ATP channels are widely distributed in cardiovascular (CV) tissues, we assessed the tissue specificity of NAT by e xamining its effect on K-ATP channels in enzymatically isolated rat beta-ce lls, rat cardiac myocytes, and smooth muscle cells from porcine coronary ar tery and rat aorta with the patch-clamp method. The selectivity of known an tidiabetic agents glyburide (GLY) and repaglinide (REP) was also studied fo r comparison. NAT was found to inhibit K-ATP channels in the cells from por cine coronary artery and rat aorta with IC(50)s of 2.3 and 0.3 mM, respecti vely, compared with 7.4 mu M in rat beta-cells, indicating a respective 311 - and 45-fold selectivity (p < .01) for beta-cells. With an IC50 of 5.0 nM in beta-cells, REP displayed an similar to 16-fold (p < .05) selectivity fo r beta-cells over both types of vascular cells. GLY was nonselective betwee n vascular and beta-cells. At equipotent concentrations (2X respective IC(5 0)s in beta-cells), NAT, GLY, and REP all caused 62% reduction of pancreati c K-ATP current but a respective 39, 55, and 66% inhibition of cardiac K-AT P current. These data collectively indicate that NAT, when compared with GL Y and REP, at concentrations effective in stimulating insulin secretion is least likely to cause detrimental CV effects via blockade of CV K-ATP chann els.