Profibrillatory Actions of Pinacidil in a Conscious Canine Model of Sudden Coronary Death

Chi, Liguo; Uprichard, Andrew; Lucchesi, Benedict R.

doi:10.1097/00005344-199003000-00016

Cited by 142 publications

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“…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).…”

Section: : Discussionsupporting

confidence: 88%

“…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).…”

supporting

confidence: 91%

“…For example, during myocardial ischaemia, in dogs, rabbits, guinea-pigs and rats, K ATP openers are generally pro-arrhythmic (Chi et al, 1990;Bellemin-Baurreau et al, 1994;Workman et al, 2000) whilst K ATP blockers are anti-arrhythmic (Billman et al, 1993;Gwilt et al, 1992;Wolleben et al, 1989;Kantor et al, 1990;Rees and Curtis, 1995b). Moreover, in each of these species, reperfusion after only a short period of ischaemia is accompanied by both ventricular arrhythmias and acute action potential shortening.…”

Section: : Discussionmentioning

confidence: 99%

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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: 88%

supporting

confidence: 91%

Section: : Discussionmentioning

confidence: 99%

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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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“…[2][3][4] It was originally hypothesized that the shortening of repolarization acts as a protective mechanism by limiting calcium entry, although more recent studies ascribe the protective role to mitochondrial ATP channels. 15 Activation of the K ATP channels during acute ischemia is arrhythmogenic 16,17 ; the extracellular potassium accumulation and shortening of the refractory period favor the occurrence of reentrant excitation. 18 Pharmacological agents that increase K ATP channel conductance 9,19 have effects similar to those of ischemia on action potentials and are also arrhythmogenic.…”

Section: Role Of K Atp Channels In Ischemic Arrhythmiasmentioning

confidence: 99%

“…18 Pharmacological agents that increase K ATP channel conductance 9,19 have effects similar to those of ischemia on action potentials and are also arrhythmogenic. 14,16,20,21 The focus on the arrhythmogenic role of K ATP channel activation has been during acute ischemia. 4,14,17 During this period, epicardial muscle that eventually forms the EBZ undergoes more severe electrophysiological alterations than endocardial muscle, 22,23 partly related to greater activation of the K ATP channels.…”

Section: Role Of K Atp Channels In Ischemic Arrhythmiasmentioning

confidence: 99%

Effects of Pinacidil on Electrophysiological Properties of Epicardial Border Zone of Healing Canine Infarcts

et al. 2002

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Background-K ATP channels, activated by ischemia, participate in the arrhythmogenic response to acute coronary occlusion. The function of these channels in border zones of healing infarcts, where arrhythmias also arise, has not been investigated. Do these channels remain maximally activated during infarct healing, or do they downregulate after a period of time? Both might preclude further activation. Methods and Results-Myocardial infarction was produced in dogs by ligation of the left anterior descending coronary artery. Impulse propagation in the epicardial border zone (EBZ) of 4-day-old healing infarcts was mapped during administration of pinacidil, a K ATP channel activator, directly into the EBZ coronary blood supply. Pinacidil restored conduction and excitability when the EBZ was initially inexcitable and had large regions of block (6 of 8 experiments). This allowed reentrant circuits to form in the EBZ, causing tachycardia (4 of 8 experiments). In hearts with an initially excitable EBZ, pinacidil shortened the effective refractory period and abolished conduction block at short cycle lengths (7 experiments). This effect prevented initiation of reentry (1 of 2 experiments). Conclusions-The response to pinacidil indicates that K ATP channels in the EBZ remain functional and can be activated to influence electrophysiological properties and arrhythmogenesis.

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Myocardial Infarction Agents

Altschuld

2003

Burger's Medicinal Chemistry and Drug Discovery

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A myocardial infarction begins with the occlusion of a coronary artery, usually resulting from the rupture of an atherosclerotic plaque. Pharmacologic treatment begins with conventional pain relief and under appropriate circumstances thrombolytic agents are administered. Anticoagulants are used in conjunction with thrombolytic agents to assist thrombolysis and prevent reocclusion of the affected vessel. Lethal arrhythmias such as ventricular fibrillation are a major cause of death following myocardial infarction. β‐Adrenoceptor antagonists are used to reduce the incidence of this sudden cardiac death. Angiotensin converting enzyme inhibitors are used to reduce post‐infarction ventricular remodeling, which is a leading cause of congestive heart failure. Current therapy has significantly reduced in hospital mortality but acute myocardial infarction remains the leading cause of death in the United States. Congestive heart failure secondary to myocardial infarction is becoming an epidemic. Additional therapeutic agents and/or strategies are needed to reduce death and disability following myocardial infarction.

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Profibrillatory Actions of Pinacidil in a Conscious Canine Model of Sudden Coronary Death

Cited by 142 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

Effects of Pinacidil on Electrophysiological Properties of Epicardial Border Zone of Healing Canine Infarcts

Myocardial Infarction Agents

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