Selective <i>I</i><sub>K</sub> blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts

Rees, Siân; Curtis, Michael J.

doi:10.1111/j.1476-5381.1993.tb13453.x

Cited by 40 publications

(18 citation statements)

References 37 publications

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“…Tall P‐waves are consistent with atrial enlargement in the old Cry α B R120G TG mice. The QT interval increased during heart failure, as it does in rat, rabbit and primate isolated hearts . Ordinarily, QT prolongation indicates delayed repolarization .…”

Section: Discussionmentioning

confidence: 87%

αB‐Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca²⁺‐handling proteins and endoplasmic reticulum stress in mice

Jiao

Sanbe

Zhang

et al. 2014

Clin Exp Pharma Physio

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Mutations of αB-crystallin (CryαB), a small heat shock protein abundantly expressed in cardiac and skeletal muscles, are known to cause desmin-related myopathies. The CryαB R120G allele has been linked to a familial desminopathy and, in transgenic mice, causes a sudden death at about 28 weeks of age. To investigate the mechanisms of the sudden cardiac arrest of CryαB R120G transgenic mice, we prepared protein samples from left ventricular tissues of two different age groups (10 and 28 weeks) and examined Ca(2+) -handling proteins. Expression of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) 2, phospholamban, ryanodine receptor 2 and calsequestrin 2 was significantly decreased in 28- versus 10-week-old CryαB R120G transgenic mice. In addition, low heart rate variability, including heart rate, total power and low frequency, was observed and continuous electrocardiogram monitoring revealed cardiac arrhythmias, such as ventricular tachycardia, atrioventricular block and atrial flutter, in 28-week-old CryαB R120G transgenic mice. In contrast, expression of endoplasmic reticulum (ER) degradation enhancing α-mannosidase-like protein, inositol requirement 1 and X-box binding protein 1 were increased significantly in 28- versus 10-week-old CryαBR120G transgenic mice, suggesting that the CryαBR120G transgenic mice exhibit increased ER stress compared with wild-type mice. Together, the data suggest that the CryαB R120G dominant variant induces ER stress and impairs Ca(2+) regulation, leading to ageing-related cardiac dysfunction, arrhythmias and decreased autonomic tone with shortened lifespan.

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Section: Discussionmentioning

confidence: 87%

αB‐Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca²⁺‐handling proteins and endoplasmic reticulum stress in mice

Jiao

Sanbe

Zhang

et al. 2014

Clin Exp Pharma Physio

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“…The transient outward current I,, is very important in the rat (38) and the I,,-blocker tedisamil has been shown to suppress VT and VF in the rat (39), but azimilide does not inhibit this current (5). Although azimilide, at high in vitro concentrations, has been shown to block I,, (3) and I,, has been identified in adult rat ventricle (40), this action is unlikely to be effective in the rat, which was not protected from ventricular arrhythmias by the I,,-blocker UK 66,914 (41). Since an L-type calcium current ICaL contributes to repolarization of the rat ventricular action portential (42) and azimilide inhibits this current (3, it is reasonable to posit that ICaL block contributes to azimilide's efficacy in the rat CALR model.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of the Class III Antiarrhythmic Agent Azimilide in Rodent Models of Ventricular Arrhythmia

Brooks¹,

Carpenter

Miller

et al. 1996

Experimental Biology and Medicine

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Azimilide exhibited antiarrhythmic activity in several rodent models of ventricular arrhythmias. In the mouse chloroform model, azimilide provided limited efficacy by the i.p. route (50% at 100 mg/kg versus 20% by vehicle), and no efficacy by the oral route (300 mg/kg). In a rat model in which arrhythmias are induced by ligation and reperfusion of the left descending coronary artery (CALR model), azimilide provided dose-dependent (1-18 mg/kg) efficacy by the intravenous route. The estimated dose that suppressed ventricular fibrillation (VF) was 5.0 mg/kg i.v. At 18 mg/kg i.v. azimilide also partially suppressed ventricular tachyarrhythmia (VT) and extrasystoles (VES). Rats dosed orally (100 mg/kg) were fully protected from VF. In isolated guinea pig hearts exposed to 1 microM ouabain, azimilide at 10 microM prevented the VT and VF seen in 69% and 23%, respectively, of control hearts. In anesthetized guinea pigs, azimilide at 10 and 30 mg/kg i.v. increased the dose of ouabain required to induce VES. While sematilide, dofetilide, and E-4031 significantly increased sensitivity to the arrhythmogenic actions of ouabain (by lowering the dose that caused VF), azimilide did not. Azimilide's antiarrhythmic profile in these rodent models differs from that of other class III agents, since azimilide had less efficacy in the mouse chloroform model, could suppress VT and VES as well as VF in the CALR rat model, and protected from or did not aggravate cardiac glycoside-induced arrhythmias in guinea pigs. These results demonstrating the antiarrhythmic efficacy of azimilide in the intact animal suggest that the compound has a different profile than other class III agents.

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“…Although clear effects on I CaL were seen, estradiol may also have actions on other ion channels that could influence ischaemia-induced arrhythmias. Effects on the delayed rectifier K þ current (I Kr ) are unlikely to be relevant as rats do not express functional I Kr and I Kr blockers do not alter ischaemiainduced arrhythmias in rats (Rees and Curtis, 1993) but actions on other ionic currents cannot be excluded.…”

Section: Limitations Of the Studiesmentioning

confidence: 99%

Greater antiarrhythmic activity of acute 17β‐estradiol in female than male anaesthetized rats: correlation with Ca²⁺ channel blockade

Philp

Hussain

Byrne

et al. 2006

British J Pharmacology

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Background and purpose: Female sex hormones may protect pre-menopausal women from sudden cardiac death. We therefore investigated the effects of the main female sex hormone, 17b-estradiol, on ischaemia-induced cardiac arrhythmias and on the L-type Ca 2 þ current (I CaL ). Experimental approach: In vivo experiments were performed in pentobarbital-anaesthetized rats subjected to acute coronary artery occlusion. I CaL was measured by the whole-cell patch-clamp technique, in rat isolated ventricular myocytes. Key results: Acute intravenous administration of 17b-estradiol as a bolus dose followed by a continuous infusion, commencing 10 min before coronary artery occlusion, had dose-dependent antiarrhythmic activity. In female rats 300 ng kg -1 þ 30 ng kg À1 min À1 17b-estradiol significantly reduced the number of ventricular premature beats (VPBs) and the incidence of ventricular fibrillation (VF). A ten fold higher dose of 17b-estradiol was required to cause similar effects in male rats. In vitro 17b-estradiol reduced peak I CaL in a concentration-dependent manner. The EC 50 was ten-fold higher in male myocytes (0.66 mM) than in females (0.06 mM). Conclusions and implications:These results indicate that 17b-estradiol has marked dose-dependent antiarrhythmic activity that is greater in female rats than in males. A similar differential potency in blocking I CaL in myocytes from female and male rats can account for this effect. This provides an explanation for the antiarrhythmic activity of 17b-estradiol and gender-selective protection against sudden cardiac death.

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Selective I_K blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts

Cited by 40 publications

References 37 publications

αB‐Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca²⁺‐handling proteins and endoplasmic reticulum stress in mice

αB‐Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca²⁺‐handling proteins and endoplasmic reticulum stress in mice

Efficacy of the Class III Antiarrhythmic Agent Azimilide in Rodent Models of Ventricular Arrhythmia

Greater antiarrhythmic activity of acute 17β‐estradiol in female than male anaesthetized rats: correlation with Ca²⁺ channel blockade

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Selective IK blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts

Cited by 40 publications

References 37 publications

αB‐Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca2+‐handling proteins and endoplasmic reticulum stress in mice

αB‐Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca2+‐handling proteins and endoplasmic reticulum stress in mice

Efficacy of the Class III Antiarrhythmic Agent Azimilide in Rodent Models of Ventricular Arrhythmia

Greater antiarrhythmic activity of acute 17β‐estradiol in female than male anaesthetized rats: correlation with Ca2+ channel blockade

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Resources

About

Selective I_K blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts

αB‐Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca²⁺‐handling proteins and endoplasmic reticulum stress in mice

αB‐Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca²⁺‐handling proteins and endoplasmic reticulum stress in mice

Greater antiarrhythmic activity of acute 17β‐estradiol in female than male anaesthetized rats: correlation with Ca²⁺ channel blockade