The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

Abstract

Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K ؉ channel (K ATP channel) in the pancreatic ␤-cell membrane. K ATP channels subserve important functions also in the heart. First, K ATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia. Second, K ATP channels in the sarcolemma of cardiomyocytes (sarcK ATP channels) are required for adaptation of the heart to stress. In addition, the opening of sarcK ATP channels and of K ATP channels in the inner membrane of mitochondria (mitoK ATP channels) plays a central role in ischemic preconditioning. Opening of sarcK ATP channels also underlies the STsegment elevation of the electrocardiogram, the primary diagnostic tool for initiation of lysis therapy in acute myocardial infarction. Therefore, inhibition of cardiovascular K ATP channels by insulin secretagogues is considered to increase cardiovascular risk. Electrophysiological experiments have shown that the secretagogues differ in their selectivity for the pancreatic over the cardiovascular K ATP channels, being either highly selective (ϳ1,000؋; short sulfonylureas such as nateglinide and mitiglinide), moderately selective (10 -20؋; long sulfonylureas such as glibenclamide [glyburide]), or essentially nonselective (<2؋; repaglinide). New binding studies presented here give broadly similar results. In clinical studies, these differences are not yet taken into account. The hypothesis that the in vitro selectivity of the insulin secretagogues is of importance for the cardiovascular outcome of diabetic patients with coronary artery disease needs to be tested. Diabetes 53 (Suppl. 3):S156 -S164, 2004 I nsulin secretagogues are widely prescribed in the treatment of type 2 diabetes. They close the ATPsensitive K ϩ channel (K ATP channel) in the membrane of the pancreatic ␤-cell, thereby depolarizing the cell and triggering insulin secretion. K ATP channels are gated by intracellular nucleotides with ATP inducing channel closure and MgADP channel opening. The ␤-cell is special in that physiological changes in plasma glucose change the intracellular ATP and ADP concentrations such that the channel opens and closes; hence, the channel functions as the glucose sensor in this cell (1-3). K ATP channel subtypes are found in many cell types. The generation of mice in which the genes for the K ATP channel subunits were deleted have shed new light on the diverse functions of the K ATP channels in various tissues in physiological and pathophysiological conditions (1). In brain, K ATP channels are involved in actions as diverse as the control of glucose homeostasis and the regulation of neuronal excitability in hypoxia (1); however, the insulin secretagogues do not cross the blood-brain barrier easily enough to affect these channels at therapeutic plasma levels (4). In several vascular beds, the K ATP channel in the vascular myocytes is involved in the regulation of vessel tone; opening is triggered in particular by stimuli inc...

The Actions of a Novel Potent Islet β-Cell–Specific ATP-Sensitive K+ Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1

“…The ␤-cell currents were sensitive to tolbutamide inhibition applied in the presence of 3 mol/l NNC55-0462, confirming the identity of the activated currents to be K ATP currents (IK ATP ). K ATP channel openers have negative allosteric effects on glibenclamide binding to SUR (36,37). In fact, such SUR1-specific K ATP channel openers could displace 3 H-glibenclamide binding (24), which, taken along with the high affinity of NNC55-0462 for SUR1, led us to use a higher concentration of tolbutamide to inhibit the channels.…”

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

“…Sulfonylureas and glinides can be divided into three groups according to their binding site(s) in the large sulfonylurea-binding pocket of SUR [15][16][17][18]. The short sulfonylureas bind to subcompartment A of the binding pocket, and a single amino acid in SUR1 (Ser 1237 which, in SUR2, is replaced by Tyr 1206) affords to these compounds a selectivity of up to 1,000-fold for the pancreatic K ATP channel [18,19].…”

“…[21]; review [18]). There has been a long-standing controversy about whether or not therapy with glibenclamide increases cardiovascular mortality (review [15]). The UK Prospective Diabetes Study did not support this suspicion [13], even in the high-risk group of patients with acute myocardial infarction [22].…”

“…For these reasons, the selectivity of sulfonylureas and glinides for the pancreatic compared with the cardiovascular K ATP channels has become an issue of clinical relevance [12][13][14][15]. Sulfonylureas and glinides can be divided into three groups according to their binding site(s) in the large sulfonylurea-binding pocket of SUR [15][16][17][18].…”

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

“…[26] Drug binding sites SURs are the targets for various compounds that bind and either stimulate or inhibit K ATP channel activity. We [26] and others [72,104,118,120] have reviewed this area recently. Therapeutic agents, like tolbutamide, glibenclamide, glipizide, glimeperide, nateglinide, repaglinide, etc., which antagonize the activity of the SUR1/K IR 6.2 β-cell channels, are perhaps best known because of their wide use as hypoglycemic agents that restore first phase of insulin secretion in patients with type 2 diabetes.…”