Cardiovascular effects of sulphonylurea derivatives Implications for the treatment of NIDDM?

Smits, P.; Thien, Theo

doi:10.1007/s001250050261

Cited by 26 publications

(47 citation statements)

References 17 publications

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“…Glibenclamide is a potent blocker of the ATPdependent K + -channels, not only in the pancreas but also in the myocardium, and the cardiovascular effects of sulphonylureas are under discussion [15,42,43]. There are only a few human studies in this area.…”

Section: Q T D I S P E R S I O N a N D H Y P O G L Y C A E M Imentioning

confidence: 99%

Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus

Landstedt-Hallin

Englund

Adamson

et al. 1999

Journal of Internal Medicine

125

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Abstract. Landstedt-Hallin L, Englund A, Adamson U, Lins P-E (Karolinska Institute, Danderyd Hospital, Danderyd; and Uppsala University Hospital, Uppsala, Sweden). Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus. J Intern Med 1999; 246: 299±307.Objectives. To study effects of insulin-induced hypoglycaemia on the cardiac repolarization, using QT interval measurements, in patients with type 2 diabetes. Design. Hypoglycaemia was induced by an i.v. insulin-infusion and blood glucose was clamped at 2.7 mmol L 21 for 60 min (T = 90±150 min) in two experiments, with (+GLIB) and without (±GLIB) glibenclamide. In a third experiment, with similar hyperinsulinaemia, glucose was clamped at a euglycaemic level (5 mmol L 21 ). ECG was continuously recorded for arrhythmia-monitoring, and 12-lead ECGs were recorded at T = 0 and 150 min. QT intervals were measured, and we determined QT dispersion (difference between the maximum and the minimum QT interval) reflecting interlead variability of repolarization.Subjects. Thirteen patients with type 2 diabetes, on combined insulin and glibenclamide treatment, were studied during hypoglycaemia, and eight of them participated in the euglycaemic experiment. Results. No significant arrhythmias were seen during hypoglycaemia but the mean QT intervals and QT dispersion increased significantly (P , 0.001), with no differences between ±GLIB and +GLIB. During the euglycaemic clamp all QT measurements remained unchanged. Serum potassium decreased significantly (P , 0.001) during all three clamps, but the decrease was more pronounced during hypoglycaemia. The change in potassium was not correlated to the degree of QT prolongation or QT dispersion. Conclusions. Significant changes in the repolarization of the heart can be seen during hypoglycaemia in patients with type 2 diabetes, indicating an increased risk of arrhythmia at low blood glucose levels.

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Section: Q T D I S P E R S I O N a N D H Y P O G L Y C A E M Imentioning

confidence: 99%

Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus

Landstedt-Hallin

Englund

Adamson

et al. 1999

Journal of Internal Medicine

125

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“…However, magnetic resonance spectroscopy recordings on skeletal muscle during ischaemia in humans do not show evidence for a fall in these ATP-concentrations after these short periods of ischaemia [28]. Apparently, other mechanisms may have contributed to the activation of K ATP channels as reviewed previously [15], …”

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confidence: 93%

“…All these effects of sulphonylurea derivatives have been demonstrated in animal models but, there are several arguments to suggest that they may also occur in humans [15]. Until now, data in humans on this important issue are very scarce.…”

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confidence: 99%

Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans

et al. 1996

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In 1983, Noma [1] was the first to describe that an outward potassium current increased significantly when guinea pig or rabbit cardiac muscle cells were subjected to hypoxia. This current was caused by the activation of potassium channels, which was independent of the intracellular Ca 2+ concentration, but dependent on the intracellular concentration of adenosine-5 ′-triphosphate ([ATP] i ). These so-called ATPsensitive potassium (K ATP ) channels were suggested to play a cardioprotective role during ischaemia. Later, K ATP channels were also found in skeletal muscle [2], smooth muscle [3] and pancreatic beta cells [4] from animals. In pancreatic beta cells the K ATP channels mediate insulin secretion [5] and are a target for sulphonylurea derivatives in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) [6]. Sulphonylurea derivatives are highly specific in blocking pancreatic and cardiovascular K ATP channels, and Diabetologia (1996Diabetologia ( ) 39: 1562Diabetologia ( -1568 Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans Summary Experimental data show that ATP-sensitive potassium (K ATP ) channels not only occur in pancreatic beta cells, but also in the cardiovascular system, where they mediate important cardioprotective mechanisms. Sulphonylurea derivatives can block the cardiovascular K ATP channels and may therefore interfere with these cardioprotective mechanisms. Therefore, it is of clinical importance to investigate whether sulphonylurea derivatives interact with vascular K ATP channels in humans. Using venous-occlusion strain-gauge plethysmography, we investigated whether ischaemia-induced reactive hyperaemia is reduced by the sulphonylurea derivative glibenclamide in 12 healthy male non-smoking volunteers. Forearm vasodilator responses to three periods of arterial occlusion (2, 5 and 13 min) during concomitant infusion of placebo into the brachial artery were compared with responses during concomitant intra-arterial infusion of glibenclamide (0.33A control study (n = 6) showed that time itself did not change the vasodilator response to ischaemia.Glibenclamide significantly increased minimal vascular resistance (from 2.1 ± 0.1 to 2.3 ± 0.2 arbitrary units, Student's t-test: p = 0.01), and reduced mean forearm blood flow (from 37.5 ± 2.0 to 35.4 ± 2.0 ml ⋅ min -1 ⋅ dl -1 after 13 min occlusion, ANOVA with repeated measures: p = 0.006) and flow debt repayment during the first reperfusion minute (ANOVA with repeated measures: p = 0.04). In contrast, total flow debt repayment was not affected. Infusion of glibenclamide into the brachial artery resulted in local concentrations in the clinically relevant range, whereas the systemic concentration remained too low to elicit hypoglycaemic effects. Our results suggest that therapeutic concentrations of glibenclamide induce a slight but significant reduction in the early and peak vasodilation during reactive hyperaemia.

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“…The m echasodilator response to adenosine, and to (endothenism of action of this drug is based on an augm ented lium -dependent) vasodilators such as acetylcholine, release of insulin from the beta cells of th e pancreas, vasoactive intestinal peptide and insulin [4], Also in triggered by the closing of so-called A T P -dependent the m yocardial cell, glibenclam ide is able to reduce potassium channels (A TP: adenosine'5-triphosphate) the response to K AT1,-channel-opening agents [4], ['11. This ultim ately results in an influx of calcium via A nim al experim ents have show n that the ischaeopening of voltage-dependent calcium -ion channels, m ia-induced opening of m yocardial K An.-ehannels is and the subsequent binding of calcium ions to calan endogenous cardioprotective m echanism against m odulin triggers the exocytosis of insulin-containing ischaemia and reperlusion dam age.…”

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confidence: 99%

“…The central issue of this presentamia models glibenclam ide increased infarct size [5 ,6], tion is the fact that the occurrence of K ATP-channels On the other hand blockade of the sulphonylurea reis not restricted to the pancreatic b eta cells. These ceptor is associated with a reduction in ischaem ia-reparticular ion channels occur in several organ syslated arrhythm ias [4]. N ot only m yocardial K A-n>-tems, including the cardiovascular system [2,3].…”

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confidence: 99%