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Vol. 291, Issue 3, 1372-1379, December 1999
-Cell KATP Channels
Metabolic and Cardiovascular Diseases, Novartis Institute for
Biomedical Research, Summit, New Jersey
Nateglinide (NAT) stimulates insulin secretion from pancreatic
-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
-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 -cells, indicating a
respective 311- and 45-fold selectivity (p < .01) for -cells. With an IC50 of 5.0 nM in -cells, REP
displayed an ~16-fold (p < .05) selectivity for
-cells over both types of vascular cells. GLY was nonselective
between vascular and -cells. At equipotent concentrations (2×
respective IC50s in -cells), NAT, GLY, and REP all
caused 62% reduction of pancreatic KATP current but a
respective 39, 55, and 66% inhibition of cardiac KATP
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 KATP channels.
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