Indiscriminative Effects of Repaglinide and Other Specific Modulators of Transmembrane KATP-Channel Gating Properties upon Ischaemic/Hypoxic Bovine Coronary Artery Smooth Muscle Relaxation

[摘要] The opening of KATP channels both in myocardium and vascular smooth muscle constitutes an important mechanism in the regulation of myocardial metabolism and perfusion, in particular, during hypoxia and ischaemia. In coronary smooth muscle, KATP channel opening invariably leads to vasodilation and hence to improved myocardial perfusion. Blockade of these channels may disturb this pivotal response. We compare the effects of glibenclamide with two new sulfonylureas on coronary artery dilation secondary to hypoxia and simulated ischaemia. We use bovine coronary arteries in a modified Tyrode solution (equilibrated with 95 % O2 and 5 % CO2 at 37 °C at a constant pH of 7.4). The solution contained the following solutes (in mM): NaCl 112.8, KCl 26.8, CaCl2 1.36, MgSO4 1.16, NaHCO3 11.9, glucose 10.1. Hypoxia was mimicked by changing 95 % O2 to 95 % N2 in the perfusate. Ischaemia was simulated biochemically using iodoacetate (IAA; 0.5 mM) and dinitrophenol (DNP; 1 mM).We found competitive binding of the three drugs (glibenclamide, glimepiride and repaglinide) to KATP channels with pinacidil and cromakalim showing similar dose response curves. Hypoxic control arteries relaxed by 50 %, which was invariably reduced by the three drugs in a dose dependent manner (for glibenclamide and repaglinide to 16 %, by glimepiride to 20 %). Similar results were obtained for DNP. IAA, an inhibitor of G3P-dehydrogenase, relaxed the arteries, but relaxation could not be affected by either drug (effects of glycolytic metabolites on KATP channel modulation).Our results show that newly designed sulfonylureas have the same effects on coronary arteries as the well known old drug glibenclamide. The experiments provide insight into one particular aspect of the cardiovascular effects of these drugs, namely on hypoxic vasodilation. Since UKPDS provides clinical evidence for the cardiovascular safety of glibenclamide, the coronary effects of sulfonylureas may not be of major importance as far as the hard endpoints of the study are concerned. Possibly KATP channel opening exerts clinically relevant effects more in the sense of transient regulation of metabolism and perfusion than by myocardial protection in the case of myocardial infarction itself and other major cardiovascular events.

[学科分类] 心脏病和心血管学

[关键词] Glatte Muskelzelle;Glimepirid;Hypoxie;Ischämie;Kardiologie;KATP-Kanal;Koronararterie;Repaglinid;cardiology;coronary artery;glimepiride;hypoxia;ischaemia;KATP-channel;Repaglinide;smooth muscle cell