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, generation of oxygen free radicals (OFR) via i.v. administration of Xanthine plus Xanthine Oxidase [X + XO] resulted in death of about 90% of the animals within a 120-min observation period. Pretreatment of the rats with endogenous scavengers Superoxide Dismutase and Catalase, or with felodipine, a dihydropyridine calcium channel blocker, and/or with dopexamine, an agonist of beta 2 adrenoceptors as well as dopamine (DA-1) receptors significantly enhanced the survival rate to over 70%. The present study was designed to investigate whether lipid peroxidation and ensuing respiratory depression contributed to the lethal toxicity of the free radicals. In the control group, the death of the rats administered [X + XO] was proceeded by significant increases in the plasma lipid peroxides (PLP) and by a severe hypertensive response characteristic of an intense ischemic state, which was confirmed by the presence of hypercapnia, hypoxemia, and acidosis. Placement of the animals on the positive 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 to 70%. In contrast, both felodipine as well as dopexamine prevented any increases in PLP, normalized blood gas profile, and significantly increased survival rate to 80 to 90%. These observations suggest that the lethal toxicity produced by oxygen free radical was due to respiratory distress. The relationship between increases in the PLP and respiratory depression and the mechanisms via which two pharmacologically distinct agents, felodipine and dopexamine, facilitated the salutary effects cannot be conclusively stated at this time. It is further suggested that although the doses of these two drugs employed in the present studies are not adequate to function as antioxidants, such a possibility cannot be entirely ruled out.
Jacinto
S M
SM
Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, TX 77204-5515, USA.
Lokhandwala
M F
MF
Jandhyala
B S
BS
D000758:Anesthesia; D000818:Animals; D002245:Carbon Dioxide / Q000097:blood; D004298:Dopamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015736:Felodipine / Q000627:therapeutic use*; D006439:Hemodynamics; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D010100:Oxygen / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000517:prevention & control*; D014665:Vasodilator Agents / Q000627:therapeutic use*; D019820:Xanthine; D014969:Xanthine Oxidase / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D014970:Xanthines; D002245:Carbon Dioxide; D019820:Xanthine; C046318:dopexamine; D014969:Xanthine Oxidase; D015736:Felodipine; D010100:Oxygen; D004298:Dopamine