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

Abstract

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.

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

“…The present results clearly demonstrate that the 7-consecutive-day oral administration of NO-aspirin before myocardial ischemia offers noticeable cardioprotection by significantly limiting infarct size and/or lowering the mortality rate caused by 25 min of LCA occlusion followed by 48 h of reperfusion, which confirms previous infarct-limiting effects during early reperfusion (5,36,46). Moreover, the NO-aspirin improved part of cardiac dysfunctional recovery was noted at 48 h of reperfusion.…”

“…NO-aspirin has been found to be involved in the inflammatory process of several cells (such as platelets, monocytes/macrophages, leukocytes, endothelial cells, and smooth muscle cells) and to interact with different inflammatory targets (3). Moreover, this compound exerts antiarrhythmic and infarct-limiting activity through inhibition of neutrophil invasion and platelet aggregation in normal/diabetic rats and pigs following myocardial ischemia-reperfusion (MI/R) (5,36,46). However, these cardioprotective effects against postischemic reperfusion injury are limited to 2-3 h, as shown by employing triphenyltetrazolium chloride (TTC) staining to assess infarcted myocardium.…”

“…However, these cardioprotective effects against postischemic reperfusion injury are limited to 2-3 h, as shown by employing triphenyltetrazolium chloride (TTC) staining to assess infarcted myocardium. Our present interest is whether NO-aspirin only delayed the progression of reperfusion injury during early reperfusion in the studies reported (5,36,46), because, to our knowledge, rats subjected to acute myocardial infarction (AMI) develop severe inflammation a few hours postsurgery and reach maximum injury/mortality by the next morning. Furthermore, in the setting of brief ischemia followed by reperfusion, we are interested in whether the reduction in TTC-negative tissue observed in early reperfusion signifies genuine reduction of eventual infarct size following extended reperfusion.…”

Comparison of thiopental and ketamine+xylazine anesthesia inischemia/reperfusion-induced arrhythmias in rats

“…For decades, researchers have sought to clarify the cellular mechanisms underlying the occurrence of ventricular arrhythmias and to test the antiarrhythmic potential of drugs and substances using the in vivo ischemia-reperfusion arrhythmia model (3)(4)(5). The main issue is an appropriate choice of the anesthetic agent used in this model (6).…”

The Nitric Oxide-Releasing Naproxen Derivative Displays Cardioprotection in Perfused Rabbit Heart Submitted to Ischemia-Reperfusion

“…In fact, this compound minimized cardiac mechanical abnormalities induced by ischemia in perfused rabbit hearts and remarkably reduced the mortality rate in rabbits with permanent ligature of anterior coronary artery (Rossoni et al, 2000). This nitroderivative of aspirin was also very active in diminishing infarct size caused by regional myocardial ischemia and reperfusion in anesthetized rats (Rossoni et al, 2001) and pigs (Wainwright et al, 2002). All this information prompted us to investigate the possible protecting activity of HCT-3012 in a model of perfused rabbit heart subjected to global ischemia and reperfusion.…”