Myocardial protection by the nitroderivative of aspirin, NCX 4016: in vitro and in vivo experiments in the rabbit.
BACKGROUND
A new family of nitroderivatives of conventional non-steroidal anti-inflammatory drugs capable of releasing nitric oxide has been synthesized. Among these compounds, a nitroderivative of aspirin (NCX 4016), which displays antiplatelet and vasodilating activities, appears to have clinical potential in cardiac pathology related to coronary insufficiency.


METHODS
In this study the beneficial effects of NCX 4016 and aspirin were evaluated in vitro in a model of myocardial ischemia-reperfusion of the rabbit and in vivo in a model of acute myocardial infarction of the same animal species.


RESULTS
The NCX 4016 (from 1 x 10(-5) M to 3 x 10(-4) M) caused dose-dependent cardiac protection in isolated rabbit hearts subjected to low flow ischemia-reperfusion. Inhibition of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) generation and proportional reduction of creatine kinase (CK) activity at reperfusion was observed. Aspirin (1 x 10(-4)M) markedly worsened the post-ischemic ventricular dysfunction and this event was paralleled by a 63% increase in CK activity and abolition of 6-keto-PGF1alpha formation. Perfusion of the hearts with NG-monomethyl-L-arginine (1 x 10(-5) M) worsened the ischemia-reperfusion damage in perfused hearts. This event was prevented by prior treatment with NCX 4016 (1 x 10(-4) M) but not with aspirin (1 x 10(-4) M). Ligation of the first antero-lateral branch of the left coronary artery in rabbits resulted in acute myocardial infarction with a mortality rate of 60% at 24 hours. NCX 4016 (0.5 mg/kg/min for 2 hours) significantly reduced the mortality rate by 10%, protected the rabbits against electrocardiogram derangement and almost abolished CK activity in plasma and myeloperoxidase activity in cardiac tissue. Aspirin was devoid of any protective activity.


CONCLUSIONS
In the rabbit NCX 4016 appears to exert a relevant cardioprotection likely mediated by nitric oxide donation. These results suggest that this nitroderivative of aspirin may lead to innovative therapy in myocardial ischemia and infarction.
Rossoni
G
G
Department of Pharmacology, Chemotherapy and Medical Toxicology, Institute of Pharmacological Sciences, University of Milan, Italy. giuseppe.rossoni@unimi.it
Berti
M
M
Colonna
V D
VD
Bernareggi
M
M
Del Soldato
P
P
Berti
F
F
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003402:Creatine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000032:analysis; D011817:Rabbits; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D009195:Peroxidase; D003402:Creatine Kinase; C102148:nitroaspirin; D001241:Aspirin