Glibenclamide, but not class III drugs, prevents ischaemic shortening of the refractory period in guine-pig hearts

Tweedie, David; Henderson, Christopher; Kane, Kathleen A.

doi:10.1016/0014-2999(93)90906-x

Cited by 27 publications

(11 citation statements)

References 22 publications

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“…In the guinea-pig perfused heart, reduction of coronary flow (to 10% of the control) results in ischaemia and reduced effective refractory period, as would be expected with K + -ATP channel activation [26]. In this study, the ischaemic response was reversed by the K + -ATP channel blocker glibenclamide but not by ibutilide or dofetilide [26], consistent with neither agent having K + -ATP-channel blocking effects. In contrast, in a rabbit isolated heart model (employing hypoxia and reoxygenation in conjunction with the K + -ATP channel opener pinacidil), ibutilide decreased the incidence of ventricular fibrillation in a concentration-dependent fashion [27].…”

Section: Cellular and Molecular Electropharmacologysupporting

confidence: 82%

Ibutilide – recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation

Doggrell

Hancox

2005

Expert Opinion on Investigational Drugs

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Ibutilide is a 'pure' class III antiarrhythmic drug, used intravenously against atrial flutter and fibrillation. At a cellular level it exerts two main actions: induction of a persistent Na+ current sensitive to dihydropyridine Ca2+ channel blockers and potent inhibition of the cardiac rapid delayed rectifier K+ current, by binding within the channel pore cavity upon channel gating. Ibutilide has been shown to terminate atrial flutter and fibrillation in animal studies, with some risk of ventricular pro-arrhythmia. Experimental models of hypertrophy/heart failure show altered sensitivity to ibutilide, with increased dispersion of repolarisation and incidence of pro-arrhythmia. Patient trials show that ibutilide is effective at terminating atrial arrhythmias when given alone, and that it can increase effectiveness and reduce energy requirements of electrical cardioversion. The risk to patients of polymorphic ventricular tachycardia necessitates careful patient selection and monitoring during and after treatment. An ibutilide analogue, trecetilide, requires further investigation but may offer a less readily metabolised and pro-arrhythmic alternative to ibutilide.

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Section: Cellular and Molecular Electropharmacologysupporting

confidence: 82%

Ibutilide – recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation

Doggrell

Hancox

2005

Expert Opinion on Investigational Drugs

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“…In a number of preparations it was reported that glibenclamide prevents the APD shortening only partially, even at high concentration [31,33,35,36] or even failed completely to prevent hypoxia-induced APD shortening [37]. On the other hand, some investigators reported complete prevention of the hypoxia-induced APD shortening [38] or of shortening of the effective refractory period [39] by sulfonylurea drugs. These dramatic differences in the sensitivity of K ATP channels to sulfonylurea drugs indicate that there is still much to do in order to Gögelein/Hartung/Englert elucidate the action of sulfonylureas in hypoxic conditions.…”

Section: Pharmacology Of Hmr 1883mentioning

confidence: 98%

Molecular Basis, Pharmacology and Physiological Role of Cardiac K<sub>ATP</sub> Channels

Gögelein

Hartung²,

Englert³

1999

Cell Physiol Biochem

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ATP-dependent potassium (K_ATP) channels exist in high density in the sarcolemmal membrane of heart muscle cells. Under normoxic conditions these channels are closed, but they become active when the intracellular ATP level falls. This leads to a shortening of the action potential duration, rendering the heart susceptible for life-threatening arrhythmias. Molecular biology has revealed that K_ATP channels consist of heteromultimers of the inwardly rectifying channel Kir6.2 and the sulfonylurea receptor SUR. To date, three types of SURs were identified, representing the pancreatic (SUR1), the cardiac (SUR2A) and the smooth muscle (SUR2B) K_ATP channel. In order to develop a novel therapeutic principle against ischemia-induced life-threatening arrhythmias leading to sudden cardiac death, the cardioselective K_ATP channel blocker HMR 1883 was developed. This substance inhibits the sarcolemmal cardiac K_ATP channel activated by the channel opener rilmakalim halfmaximally at concentrations of 0.6–2.2 μmol/l, and substantially affects pancreatic K_ATP channels at 9–50 times higher concentrations. K_ATP channels of the coronary vascular system are only slightly blocked by HMR 1883 when activated by hypoxia. The substance was potently effective in preventing ventricular fibrillation in a conscious dog model, and thus can be considered to be a potential novel drug candidate against sudden cardiac death.

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“…Such results have led to the suggestion that opening of KATP channels may not be solely responsible for the action potential shortening caused by hypoxia or ischaemia. Interestingly, in our other studies on guinea-pig isolated perfused hearts paced at 4 Hz, glibenclamide at a concentration of 3 ILM completely prevented the abbreviation of the effective refractory period induced by a reduction in coronary flow (Tweedie et al, 1992). This raised the possibility that the opening of KATP channels during hypoxia may have contributed to a lesser extent in the papillary muscle preparation than in perfused hearts because of the lower stimulation frequency used.…”

Section: Discussionmentioning

confidence: 79%

Attenuation by phentolamine of hypoxia and levcromakalim‐induced abbreviation of the cardiac action potential

Tweedie

Boachie-Anash

Henderson

et al. 1993

British J Pharmacology

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1 The effects of phentolamine (5-30 JAM) and glibenclamide (10 JM) on action potential characteristics were examined in guinea-pig papillary muscle exposed to either hypoxia or levcromakalim (20 gM).2 The hypoxia-induced abbreviation of action potential duration (APD) and effective refractory period (ERP) were attenuated but not abolished by glibenclamide (10 JAM). Hypoxia reduced APD by 24 ± 2 vs 65 ± 4% in glibenclamide-and vehicle-treated tissue, respectively.3 Phentolamine (10-30JM) was less effective than glibenclamide in attenuating the hypoxic shortening of APD since APD was reduced by 38 ± 10, 51 ± 6% vs 65 ± 4% in 10 and 30 JAM phentolamine and vehicle-treated muscle, respectively.4 Phentolamine, at concentrations of 10 and 30 JAM, also reduced the upstroke velocity of the action potential and at 5 JAM it increased the APD from 193 ± 9 to 221 ± 12 ms. 5 Glibenclamide completely abolished and phentolamine (30 JAM) significantly attenuated levcromakalim-induced changes in duration and ERP. Levcromakalim reduced APD by 71 ± 2 and 55 ± 2% in control and phentolamine pretreated muscle, respectively. 6 It is concluded that phentolamine may block KATP channels at concentrations that also block sodium channels.

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Glibenclamide, but not class III drugs, prevents ischaemic shortening of the refractory period in guine-pig hearts

Cited by 27 publications

References 22 publications

Ibutilide – recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation

Ibutilide – recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation

Molecular Basis, Pharmacology and Physiological Role of Cardiac K<sub>ATP</sub> Channels

Attenuation by phentolamine of hypoxia and levcromakalim‐induced abbreviation of the cardiac action potential

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