Effects of glibenclamide on ventricular arrhythmias and cardiac function in ischaemia and reperfusion in isolated rat heart

Bril, Antoine; Laville, Marie-Paule; Gout, Bernard

doi:10.1093/cvr/26.11.1069

Cited by 37 publications

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Section: : Discussionsupporting

confidence: 92%

“…The lack of effect of glibenclamide on reperfusion arrhythmias is in agreement with previous studies in rats (Bernauer, 1997;Ferdinandy et al, 1995). Nevertheless, 1 µM glibenclamide has been reported to reduce the duration of reperfusion ventricular fibrillation in this species (Bril et al, 1992).Most K ATP openers are pro-arrhythmic during ischaemia (Chi et al, 1990;Wolleben et al, 1989). In agreement, we have previously demonstrated that Ro 31-6930 at relatively high concentration exerted substantial and glibenclamide-sensitive pro-arrhythmic, and action potential shortening, effects during ischaemia (Workman et al, 2000).…”

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confidence: 91%

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A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

Workman

Mackenzie

Northover

2001

European Journal of Pharmacology

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Low concentrations of certain K ATP openers have been reported to exert a moderate inhibitory effect on arrhythmias during post-ischaemic early myocardial reperfusion, but the accompanying effects on the time course of changes in action potentials in intact hearts have not yet been studied.We report that, in rat isolated hearts reperfusion following 10 min of regional no-flow ischaemia was associated with both an acute, marked, but transient, shortening of ventricular repolarisation (by 63%) during reperfusion, and a high incidence (90%) of ventricular tachyarrhythmias. The K ATP opener Ro 31-6930 [2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide] delivered prior to ischaemia at a relatively low concentration (0.5 µM), significantly reduced the incidence and duration of reperfusion arrhythmias, and prevented the associated acute action potential shortening during reperfusion, each in a glibenclamide (1 µM)-sensitive manner (P<0.05, n=10-15 hearts). This was associated with a moderate, and non-arrhythmogenic, action potential shortening during ischaemia (a potentially "cardioprotective" effect). However, these data highlight the potential harm these drugs may cause, since a higher concentration of Ro 31-6930 caused marked shortening of action potentials and significant pro-arrhythmia during ischaemia. KeywordsATP-sensitive potassium channel; Reperfusion; Isolated heart; Action potential; Ventricular arrhythmias. 1: IntroductionCardiac adenosine triphosphate-sensitive K + (K ATP ) channels, first identified in the sarcolemma (Noma, 1983), and more recently in the mitochondria (Inoue et al., 1991) are thought to remain closed under physiological conditions. It is well recognised that under certain pathological conditions, such as myocardial ischaemia, however, opening of sarcolemmal K ATP channels may contribute to the shortening of action potential duration (Wilde and Janse, 1994; Wilde, 1997). We recently reported (Workman et al., 2000) that in the rat isolated heart, ischaemia in the presence (but not the absence) of pharmacological K ATP activation, caused action potential shortening of a sufficient degree to cause ventricular tachyarrhythmias.It is also recognised that K ATP activation-induced action potential shortening, under certain conditions may help to protect the myocardium from the injury caused by excessive Ca 2+ influx and ATP consumption [see (Grover and Garlid, 2000) for recent review]. Several studies have highlighted the protective effects on the myocardium of pharmacological K ATP activation. In many cases such protection was demonstrated during post-ischaemic reperfusion. For example, K ATP openers have been shown, during reperfusion, to improve recovery of contractile function (Docherty et al., 1997), to restrain the rise in the intracellular Ca 2+ concentration, [Ca 2+ ] i (Behling and Malone, 1995), to enhance the restoration of high energy phosphates (Tanonaka et al., 1999), as well as limiting the extent of myocardial infarction after reperfusion (Grover et al., 1...

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Section: : Discussionsupporting

confidence: 92%

supporting

confidence: 91%

A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

Workman

Mackenzie

Northover

2001

European Journal of Pharmacology

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“…Many Vaughan Williams class I anti-arrhythmic drugs inhibit K ATP channels in cardiac muscles (32)(33)(34). However, some investigators did not find effects of K ATP channel blockers, such as glibenclamide and 5-hydroxydecanoate, on the incidence of arrhythmia after ischemic insult (35)(36)(37). These controversial observations might be due to different experimental conditions or protocols, but it cannot be excluded that the effects of glibenclamide on mitochondrial channels differ in different animal models or conditions.…”

Section: Discussionmentioning

confidence: 99%

Thrombin Receptor and Ventricular Arrhythmias after Acute Myocardial Infarction

Tang

Deng

Long

et al. 2008

Mol Med

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The mechanism mediating the development of ventricular arrhythmia (VA) after acute myocardial infarction (AMI) is still uncertain. Thrombin receptor (TR) activation has been proven to be arrhythmogenic in many other situations, and we hypothesize that it may participate in the genesis of post-AMI VA. Using a left coronary artery ligation rat model of AMI, we found that a local injection of hirudin into the left ventricle (LV) significantly reduced the ratio of VA durations to infarction sizing, whereas injection of thrombin receptor-activating peptide (TRAP) increased the ratios of VA duration to infarction sizing. The effects of TR activation on whole-cell currents were investigated in isolated myocytes. TRAP increased a glibenclamide-sensitive outward current. Pretreatment of rats with glibenclamide (4 mg/kg intraperitoneally) eliminated the effects of a local injection of TRAP on the ratios of VA durations to infarction sizing. TR mRNA and protein expression in the ischemic left ventricle had reached its peak by 20 min postligation in the rat AMI model (P < 0.05). TR-immunoreactive myocytes were observed in infarcted LV but were seldom seen in the right ventricle or in the normal heart. By 60 min, TR transcript levels had returned to control levels. We conclude that increased TR activation and expression in the infarcted LV after AMI may contribute to VA through a mechanism involving glibenclamide-sensitive potassium channels.

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“…It has to be mentioned that antiarrhythmic efficacy of insulin-releasing K ATP channel blockers could not be found by a few authors: in acute ischaemia in the rat, glibenclamide did not significantly reduce the incidence of reperfusion arrhythmias (Bril et al 1992;Bernauer 1997). Likewise, in a model with acute ischaemia superimposed on a previous infarction glibenclamide and 5-hydroxydecanoate were ineffective (Chi et al 1989;Friedrichs et al 1996).…”

Section: Discussionmentioning

confidence: 99%

HMR 1883, a cardioselective KATP channel blocker, inhibits ischaemia- and reperfusion-induced ventricular fibrillation in rats

Wirth¹,

Klaus²,

Englert³

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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Ventricular fibrillation (VF) is a major cause of sudden cardiac death in which myocardial ischemia plays a leading role. During ischaemia activation of ATP-sensitive potassium channels (K(ATP)) occurs, leading to potassium efflux from cardiomyocytes and shortening of the action potential favoring the genesis of ventricular fibrillation. In confirmation of this concept the sulfonylurea glibenclamide, which stimulates insulin release by inhibition of pancreatic K(ATP) channels, has been shown to inhibit VF in different models of ischaemia by inhibition of myocardial K(ATP) channels. HMR 1883 (1-[15-12-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective K(ATP) channel blocker. The aim of this study was to show that with this compound it is possible to separate the antifibrillatory from the insulin-releasing effect for the treatment of patients at risk of ischaemia-induced arrhythmias and sudden death. In the present study HMR 1883 reduced VF in Sprague-Dawley rats during prolonged ischaemia and also diminished mortality and the duration of VF in a separate reperfusion experiment at 3 mg/kg and 10 mg/kg with no effect on blood glucose or insulin. Glibenclamide, which was antifibrillatory at 0.3 mg/kg and 1 mg/kg, increased plasma insulin and lowered blood glucose already at a dose as low as 0.01 mg/kg. In conclusion, based on its antifibrillatory action and the absence of significant pancreatic effects at therapeutic doses, HMR 1883 is of potential clinical utility for the prevention of severe arrhythmias in patients with ischaemic heart disease.

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Effects of glibenclamide on ventricular arrhythmias and cardiac function in ischaemia and reperfusion in isolated rat heart

Abstract: Glibenclamide may increase the probability of spontaneous termination of ventricular fibrillation and facilitate the restoration of the myocardial function during regional ischaemia.

Cited by 37 publications

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A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

Thrombin Receptor and Ventricular Arrhythmias after Acute Myocardial Infarction

HMR 1883, a cardioselective KATP channel blocker, inhibits ischaemia- and reperfusion-induced ventricular fibrillation in rats

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