Sulfonylurea derivatives in cardiovascular research and in cardiovascular patients.

Sulfonylurea derivatives are hypoglycemic drugs frequently used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). In the beta-cell sulfonylureas act by blocking ATP-sensitive potassium channels (K.ATP channels). In several organ systems, including the cardiovascular system, sulfonylurea receptors and functional K.ATP channels have been identified. In the heart their role is not clear: an endogenous cardioprotective effect has been suggested. There is no doubt that K.ATP channels are effectively blocked by sulfonylureas. In the last decade sulfonylureas have been widely used as a pharmacological tool in experimental (cardiac) research. Blockade of K.ATP channels is the proposed cellular mechanism of action for all sulfonylurea-related effects. However, other membrane currents are affected as well. In addition, myocardial metabolism is modified by sulfonylurea pretreatment. Hence, it should seriously be questioned whether these drugs are suitable in assessing involvement of cardiac K.ATP channels in, for example, ischemia-related events. The detrimental effects of sulfonylureas in experimental studies on myocardial ischemia have led to speculation whether the widespread use of these drugs in patients with NIDDM, most often suffering from accompanying ischemic heart disease, should be reconsidered. However, a review of the clinical literature reveals that the most consistent finding is a lower incidence of ventricular arrhythmias associated with the use of glibenclamide, while no excess mortality has been shown for this agent in NIDDM with ischemic heart disease. Despite some direct effects on systemic and coronary vasculature, there are, at present, no firm clinical data on the basis of which sulfonylurea derivatives should be withheld from the cardiac patient.