Cardiovascular effects of sulphonylurea derivatives

Abstract

The classical sulphonylurea derivative glibenclamide is widely prescribed for the treatment of non-insulindependent diabetes mellitus (NIDDM). The mechanism of action of this drug is based on an augmented release of insulin from the beta cells of the pancreas, triggered by the closing of so-called ATP-dependent potassium channels (ATP: adenosine'5-triphosphate) [1]. This ultimately results in an influx of calcium via opening of voltage-dependent calcium-ion channels, and the subsequent binding of calcium ions to calmodulin triggers the exocytosis of insulin-containing secretory granules. The central issue of this presentation is the fact that the occurrence of K ATP -channels is not restricted to the pancreatic beta cells. These particular ion channels occur in several organ systems, including the cardiovascular system [2,3].The open state probability of K ATP -channels is dependent on the cytosolic concentration of ATP. During hypoxia and/or ischaemia, the cytosolic concentration of ATP falls which directly results in opening of K ATP -channels. The subsequent efflux of potassium induces hyperpolarization of the cell membrane which shortens the action potential in the myocardial cell leading to a reduction in the contractile amplitude of myocardial cells. In vascular smooth muscle cells, opening of K ATP -channels and subsequent hyperpolarization exerts relaxation of these cells, resulting in an obvious vasodilator response.The vascular smooth muscle cell K ATP -channels can be opened pharmacologically by potassium-channel-opening drugs such as cromakalim and the classical vasodilator drug diazoxide [3]. Glibenclamide is able to reduce the vasodilator response to these K ATP channel-opening drugs, indicating the ability to block vascular K ATP -channels. Apart from the interaction with K ATP -channel-opening drugs, glibenclamide has also been reported to inhibit the vasodilator response to adenosine, and to (endothelium-dependent) vasodilators such as acetylcholine, vasoactive intestinal peptide and insulin [4]. Also in the myocardial cell, glibenclamide is able to reduce the response to K ATP -channel-opening agents [4].Animal experiments have shown that the ischaemia-induced opening of myocardial K ATP -channels is an endogenous cardioprotective mechanism against ischaemia and reperfusion damage. In several ischaemia models glibenclamide increased infarct size [5,6]. On the other hand blockade of the sulphonylurea receptor is associated with a reduction in ischaemia-related arrhythmias [4]. Not only myocardial K ATPchannels are involved in the response to ischaemia. Other investigators have demonstrated that the vascular smooth muscle cell response to ischaemia is also inhibited by sulphonylurea derivatives, represented by a reduction of the post-occlusive hyperaemic response after pretreatment with glibenclamide.Interestingly, the newly developed sulphonylurea derivative glimepiride seems to act more selectively, since its hypoglycaemic action is more pronounced than that of glibenclamide, whereas animal dat...

Oral hypoglycaemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes

“…Data from this study have also strongly indicated that insulin secretagogues and insulin treatment do not lead to increased CVD risk. A potential inhibition of potassium channels in the heart during SU treatment, in addition to the suspicion of a relatively pro-atherogenic effect of hyperinsulinaemia, previously gave rise to concern about increased CVD risk of treatment with insulin or insulin secretagogues (47). However, the possibility that the higher glycaemic level in the conventional (diet) treatment group increased CVD risk cannot be excluded.…”

Role of pyroptosis in inflammation and cancer

“…Additionally, kanglexin, a novel anthraquinone compound, prevents cardiac injury from myocardial infarction (MI) and alleviates cardiac dysfunction by attenuating NLRP3 inflammasome activation and subsequent NLRP3-mediated pyroptosis of myocardial cells, which indicates that kanglexin has the potential to mitigate ischemic heart disease [256]. In addition to kanglexin, there are many other agents associated with cardiovascular diseases, such as glyburide derivatives, colchicine, dapansutrile, melatonin, and liraglutide [257][258][259][260][261][262][263] (Fig. 10).…”

Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients

“…Indeed, sulphonylureas with a greater selectivity for b-cell receptors, such as glimepiride and gliclazide, have been associated with a lower CV risk (25,37), whereas glibenclamide has been associated with an excess allcause and CV mortality (15,25,26,27). The adverse effects reported for glibenclamide include increased peripheral vascular tone, reduced diazoxide-induced vasodilatation, the inhibition of preconditioning, increased infarct size, the inhibition of the fibrinolytic system and increased QT interval dispersion (2,36,38). Accordingly, we found an excess of mortality among the glibenclamide-treated patients in our study: 45.5% of the glibenclamide-treated survived vs 72.4% of the gliclazide-treated in monotherapy.…”