EFFECT OF PHARMACOLOGICAL INTERVENTIONS IN THE PREVENTION OF LIPID-PEROXIDATION AND RESPIRATORY DEPRESSION INDUCED BY OXYGEN-FREE RADICALS IN ANESTHETIZED RATS

We have recently reported that in an anesthetized rat model, generatio n of oxygen free radicals (OFR) via i.v. administration of Xanthine pl us Xanthine Oxidase [X+XO] resulted in death of about 90% of the anima ls within a 120-min observation period. Pretreatment of the rats with endogenous scavengers Superoxide Dismutase and Catalase, or with felod ipine, a dihydropyridine calcium channel blocker, and/or with dopexami ne, an agonist of beta(2) adrenoceptors as well as dopamine (DA-1) rec eptors significantly enhanced the survival rate to over 70%. The prese nt study was designed to investigate whether lipid peroxidation sind e nsuing respiratory depression contributed to the lethal toxicity of th e free radicals. In the control group, the death of the rats administe red [X+XO] was preceeded by significant increases in the plasma lipid peroxides (PLP) and by a severe hypertensive response characteristic o f an intense ischemic state, which was confirmed by the presence of hy percapnia, hypoxemia, and acidosis. Placement of the animals on the po sitive pressure ventilation prior to the administration of [X+XO] did not prevent increases in PLP but, prevented any adverse alterations in the respiratory markers and significantly enhanced survival rate up t o 70%. In contrast, both felodipine as well as dopexamine prevented an y increases in PLP, normalized blood gas profile, and significantly in creased survival rate to 80 to 90%. These observations suggest that th e lethal toxicity produced by oxygen free radical was due to respirato ry distress. The relationship between increases in the PLP and respira tory depression and the mechanisms via which two pharmacologically dis tinct agents, felodipine and dopexamine, facilitated the salutary effe cts cannot be conclusively stated at this time. It is further suggeste d that although the doses of these two drugs employed in the present s tudies are not adequate to function as antioxidants, such a possibilty cannot be entirely ruled out.