Failure of nitric oxide donors to alter arrhythmias induced by acute myocardial ischaemia or reperfusion in anaesthetized rats

1 The eect of the nitro-derivative of aspirin, NCX4016, was assessed on ischaemic ventricular arrhythmias and myocardial infarct size in anaesthetized pigs in comparison to native aspirin. 2 Pigs were given aspirin (10 mg kg 71; n=6), low dose NCX4016 (18.4 mg kg 71; n=6) or high dose NCX4016 (60 mg kg 71 ; n=7) orally for 5 days prior to coronary occlusion and reperfusion. None of the interventions had any eect on baseline haemodynamics prior to coronary occlusion in comparison to control pigs (n=9). Aspirin and high dose NCX4016 both prevented the generation of thromboxane A 2 from platelets activated ex vivo with A23187 (30 mM), whereas all three interventions markedly attenuated platelet aggregation in response to collagen in whole blood in comparison to controls. 3 None of the drug interventions had any eect on the incidence of ventricular ®brillation (VF) during myocardial ischaemia (100% in all groups). However, 60 mg kg 71 NCX4016 signi®cantly attenuated the total number of premature ventricular beats (PVB's) (62+16 vs 273+40 in control pigs; P50.05) during the ®rst 30 min of occlusion. The higher dose of NCX4016 also signi®cantly reduced myocardial infarct size (22.6+3.7% of area at risk vs 53.0+2.8% of area at risk in control pigs; P50.05). 4 These results suggest that the nitro-derivative of aspirin, NCX4016, is an eective antiplatelet agent, which unlike aspirin also reduces the extent of myocardial injury following ischaemia and reperfusion.

Section: +4* 187+13{mentioning

confidence: 99%

NCX4016 (NO‐aspirin) reduces infarct size and suppresses arrhythmias following myocardial ischaemia/reperfusion in pigs

Wainwright

Miller

Work

et al. 2002

“…Part of this work has been presented to the British Pharmacological Society (Shaw & Coker, 1992 Pharmacology (1996) 117, 817-822 thetized with sodium pentobarbitone (60 mg kg-', i.p.) and prepared for coronary artery occlusion by surgical techniques which have been described in detail recently (Barnes & Coker, 1995). Briefly, a femoral vein was cannulated to allow administration of further anaesthetic and drugs, a tracheotomy was performed to permit artificial ventilation when required, and a carotid artery was cannulated for blood pressure measurement.…”

Section: Introductionmentioning

confidence: 99%

Suppression of reperfusion‐induced arrhythmias with combined administration of 5‐HT₂ and thromboxane A₂ antagonists

Shaw

Coker

1996

Self Cite

3BX1 The effects of the 5-HT2 antagonist, ICI 170,809 and the thromboxane A2 antagonist, ICI 192,605, given alone and in combination (n = 12 per group), were examined in anaesthetized rats. Haemodynamics and arrhythmias induced by permanent coronary artery occlusion or by reperfusion after 5 min of ischaemia were monitored. 2 In a study on reperfusion-induced arrhythmias, the only significant effect of ICI 170,809 (1 mg kg', i.v.) was a reduction in the number of ventricular premature beats (VPBs). ICI 192,605 (1 mg kg-' min-1, iv.) did not alter reperfusion-induced arrhythmias. However, in combination, when compared with controls, these drugs caused significant reductions in the incidence of ventricular tachycardia (VT), 100% to 58%; ventricular fibrillation (VF), 92% to 33%; and the mortality due to sustained VF, 67% to 17%. There was also a significant reduction in the number of VPBs following reperfusion. 3 In a second study with lower doses of drugs, ICI 170,809 (0.3 mg kg-1) and ICI 192,605 (0.3 mg kg-' min-') had no significant effects on reperfusion-induced arrhythmias either alone or in combination. 4 A third study examined the effects of the higher doses of the drugs on ischaemia-induced arrhythmias. Neither drug alone, nor in combination, altered the incidence of ischaemia-induced VT, VF, the mortality, or the number of VPBs. 5 These results indicate that, in contrast to the administration of either drug alone, combined administration of a 5-HT2 antagonist and a thromboxane A2 antagonist caused marked suppression of reperfusion-induced but not ischaemia-induced arrhythmias.

“…Experiments were conducted in either male or female Wistar rats (Charles River, Margate, UK) within the weight range of 250-350 g. Animals were housed in rooms maintained at 201C on a 12 h light/dark cycle with food and water available ad libitum. Rats were anaesthetized with sodium pentobarbital 60 mg kg À1 , i.p., and prepared for coronary artery occlusion using the methods described previously (Clark et al, 1980;Barnes and Coker, 1995). All experiments were performed in accordance with the UK Animals (Scientific Procedures) Act 1986; under the authority of Project Licence number PPL 40/1702.…”

Section: Methodsmentioning

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

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.