Tissue selectivity of antidiabetic agent nateglinide: study on cardiovascular and beta-cell K(ATP) channels.
Nateglinide (NAT) stimulates insulin secretion from pancreatic beta-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 beta-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 microM in rat beta-cells, indicating a respective 311- and 45-fold selectivity (p <.01) for beta-cells. With an IC(50) of 5.0 nM in beta-cells, REP displayed an approximately 16-fold (p <.05) selectivity for beta-cells over both types of vascular cells. GLY was nonselective between vascular and beta-cells. At equipotent concentrations (2x respective IC(50)s in beta-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.
Hu
S
S
Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, New Jersey 07901-1027, USA. hiling.hu@pharma.novartis.com
Wang
S
S
Dunning
B E
BE
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
D002219:Carbamates; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D010880:Piperidines; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000077715:Nateglinide; D010649:Phenylalanine; C072379:repaglinide; D005905:Glyburide