Gliclazide produces high-affinity block of K ATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells

Abstract

The sulphonylurea gliclazide is widely used in the treatment of Type II (non-insulin-dependent) diabetes mellitus because of its ability to stimulate insulin secretion from pancreatic beta-cells. Like other sulphonylureas, its principal target is the ATP-sensitive potassium (K ATP ) channel. This channel plays a major role in controlling the beta-cell membrane potential and thereby insulin release. At low plasma glucose concentrations, K ATP channels are open and the resulting K + efflux holds the beta-cell membrane at a hyperpolarized potential. Closure of K ATP channels by glucose or sulphonylureas causes depolarization of the beta-cell membrane, leading to opening of voltage-gated Ca 2+ channels, Ca 2+ influx and a rise in intracellular Ca 2+ which stimulates the exocytosis of insulin-containing secretory granules [1].K ATP channels are also found in a variety of other cell types including cardiac, smooth and skeletal muscle, and some brain neurones [2]. Although their roles in extrapancreatic tissues are less well characterised, it is likely that they open in response to metabolic stress, such as during cardiac and cerebral is- Abstract Aims/hypothesis. Sulphonylureas stimulate insulin secretion by closing ATP-sensitive potassium (K ATP ) channels in the pancreatic beta-cell membrane. K ATP channels are also found in other tissues, including heart and smooth muscle, where they link cellular metabolism to electrical activity. The sulphonylurea gliclazide blocks recombinant beta-cell K ATP channels (Kir6.2/ SUR1) but not heart (Kir6.2/SUR2A) or smooth muscle (Kir6.2/SUR2B) K ATP channels with high potency. In this study, we examined the specificity of gliclazide for the native (as opposed to recombinant) K ATP channels in beta cells, heart and smooth muscle. Methods. The action of the drug was studied by whole-cell current recordings of native K ATP channels in isolated pancreatic beta-cells and myocytes from heart and smooth muscle. Results. Gliclazide blocked whole-cell beta-cell K ATP currents with an IC 50 of 184 30 nmol/l (n = 6±10) but was much less effective in cardiac and smooth muscle (IC 50 s of 19.5 5.4 mmol/l (n = 6±12) and 37.9 1.0 mmol/l (n = 5±10), respectively). In all three tissues, the action of the drug on whole-cell K ATP currents was rapidly reversible. In inside-out patches on beta-cells, gliclazide (1 mmol/l) produced a maximum of 66 13 % inhibition (n = 5), compared with more than 98 % block in the whole-cell configuration. Conclusion/interpretation. Gliclazide is a high-potency sulphonylurea which shows specificity for the pancreatic beta-cell K ATP channel over heart and smooth muscle. In this respect, it differs from glibenclamide. The difference in the maximal block observed in the excised patch and whole-cell recordings from betacells, may be due to the absence of intracellular Mgnucleotides in the excised patch experiments. [Diabetologia (2001

Functional involvement of sulphonylurea receptor (SUR) type 1 and 2B in the activity of pig urethral ATP‐sensitive K+ channels

“…However, gliclazide (X10 mM) suppressed pinacidil (10 and 100 mM)-induced current by an interaction with a single affinity site. Similarly, in rat mesenteric artery, the pinacidil-induced current was also blocked by gliclazide at a single site (Lawrence et al, 2001). These results suggest that pinacidil and MCC-134 may selectively activate SUR2B, but not SUR1 in pig urethra, coinciding with observations in recombinant K ATP channels (pinacidil, Fujita & Kurachi, 2001;MCC-134, Shindo et al, 2000).…”

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

“…Certain pharmacological agents that increase insulin secretion, such as sulfonylureas and meglitinides, block K ATP channel activity by binding directly to the SUR1 subunit, and lead to depolarisation of the membrane potential; this depolarisation results in opening of voltagedependent calcium channels, which leads to elevation of intracellular calcium levels and ultimately stimulates insulin secretion [32,33]. Although thiazolidinediones have been shown to stimulate insulin secretion in insulin-secreting cells [13,14], the pathway leading to closure of K ATP channels is not clear.…”

Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes

“…SUs differ in affinity and specificity for the SUR subtypes present in various tissues [6,7]. While glibenclamide (gb) has moderate tissue specificity, gliclazide (gc) has high affinity for SUR1, the pancreatic receptor, but low affinity for cardiac SUR2A and vascular SUR2B [7,8]. Accordingly gb, but not gc, is reported to abolish ischaemic preconditioning of the heart [9].…”