The Effect of NCX4016 [2-Acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl Ester] on the Consequences of Ischemia and Reperfusion in the Streptozotocin Diabetic Rat

Abstract

The aim of this study was to assess the effect of chronic administration of NCX4016 [2 acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester], a nitric oxide-releasing aspirin derivative on the consequences of coronary artery occlusion in streptozotocin-diabetic rats. Rats were made diabetic by injection of streptozotocin (60 mg kg(-1)) and received insulin (2.5 U kg(-1) s.c.) daily for 4 weeks. Animals received vehicle (1 ml kg(-1) polyethylene glycol), aspirin (65.2 mg kg(-1)), NCX4016 (60 mg kg(-1)), or (iv) NCX4016 (120 mg kg(-1)) orally, once daily for the last 5 days before coronary artery occlusion (CAO). One hour after the last dose, pentobarbital-anesthetized rats were subjected to CAO for 30 min followed by 120-min reperfusion. Neither drug significantly modified initial hemodynamics or plasma glucose levels compared with vehicle treatment in either nondiabetic or diabetic rats. Neither drug modified the total ventricular premature beat (VPB) count in normal animals, although NCX4016, but not aspirin, reduced the total VPB count and the incidence of ventricular tachycardia in diabetic rats. In nondiabetic animals, both aspirin and NCX4016 reduced infarct size. However, in diabetic rats, infarct size was reduced only by the larger dose of NCX4016 (120 mg kg(-1)) but not by aspirin or the lower dose of NCX4016. These results demonstrate that the cardioprotective effects of NCX4016 are reduced in the presence of diabetes compared with the effects seen in nondiabetic animals. In summary, the present study confirms the protective effect of NCX4016 against ischemia-reperfusion injury in the normal rat heart and demonstrates for the first time its protective effect in the heart of streptozotocin-diabetic rats.

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.…”

“…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.…”

“…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.…”

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

“…First, naproxcinod and NCX‐4016 were shown to reduce blood pressure in hypertensive rats, while no alteration of blood pressure in normotensive animals was reported for aspirin and flurbiprofen prodrugs . Second, naproxcinod and NCX‐4016 were able to reduce myocardial damage induced by ischemia/reperfusion in animal experiments . Third, NCX‐4016 has exhibited antiatherosclerotic actions in rodent studies .…”

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH2Sand their Prodrugs

“…This concept, using a nitroaspirin compound from Nicox (NCX-4016) has subsequently been confirmed both in preclinical studies [488][489][490][491] and in clinical trials [492][493][494]. It is noteworthy that this compound appears to have pharmacological effects in models where the parent molecule (aspirin) is without marked effects, such as in animal models of myocardial ischemia-reperfusion [495] and vascular restenosis in hypercholesterolemia [496][497][498]. The potential clinical utility of the latter approach may be underlined by a recently completed clinical trial demonstrating the clinical effectiveness of NCX-4016 in patients with intermittent claudications [499].…”