Cardiovascular effects of sulphonylurea derivatives

The classical sulphonylurea derivatives like glibenclamide and tolbutamide are widely prescribed in non-insulin dependent diabetes mellitus in order to stimulate insulin secretion. The insulinotropic effect of these agents is based on the closure of adenosine-5'-triphosphate (ATP)-sensitive potassium channels (KATP-channels) in the beta-cells of the pancreas. Interestingly, the cardiovascular system also shares these KATP-channels. The open state probability of these channels is regulated by the intracellular concentration of ATP. During ischaemia, the KATP-channels are thought to open by a fall in the cytosolic ATP concentration. The increase in the extracellular adenosine concentration, and the release of endothelium-derived hyperpolarizing factor (EDHF) during ischaemia may further contribute to the opening of cardiovascular KATP-channels. Sulphonylurea derivatives like glibenclamide and tolbutamide have been reported to block the opening of KATP-channels in several types of tissues including myocardial and vascular smooth muscle cells. Since the opening of KATP-channels is regarded as an endogenous cardioprotective mechanism, the blocking effect of sulphonylurea derivatives in the cardiovascular system may have deleterious effects. Human studies on this issue have just been initiated, and preliminary results point towards a significant interaction between glibenclamide and cardiovascular KATP-channels at clinically relevant concentrations. In this regard, the introduction of more pancreas specific sulphonylurea derivatives like glimepiride, which do not interact with cardiovascular KATP-channels, is a promising development.