STUDIES ON THE PHARMACOLOGICAL INTERVENTIONS TO PREVENT OXYGEN-FREE RADICAL (OFR)-MEDIATED TOXICITY - EFFECTS OF DOPEXAMINE, A DA(1) RECEPTOR AND BETA(2) ADRENOCEPTOR AGONIST

We have previously demonstrated that the lethal effects of free radica ls generated by intravenous administration of Xanthine (X: 0.225 mg kg (-1)) and Xanthine Oxidase (XO: 5 u kg(-1)) were prevented by calcium channel blockers such as felodipine (a dihydropyridine calcium antagon ist) and verapamil. These studies have implicated that there may be po tential interactions between free radicals and cell calcium. However, alternate mechanisms such as hemodynamic changes in the overall effect s of calcium antagonists cannot be ruled out. Therefore, the present s tudies are conducted to further investigate the efficacy of various ca rdiovascular agents such as Dopexamine (DPX) on [X+XO]-induced mortali ty. Intravenous administration of [X+XO] to anesthetized rats produced a rapid decrease in blood pressure and a mortality rate of over 90%. Pretreatment with dopexamine, a dopamine receptor (DA(1)) and beta(2) adrenoceptor agonist significantly enhanced survival upto 70%. Neither dobutamine nor prenalterol, (preferential beta(1) agonists) both of w hich produced similar increases in heart rate as DPX, enhanced surviva l rate thus suggesting that cardiac stimulation alone, did not contrib ute to the protective effects of DPX. Likewise, fenoldopam, a DA(1) ag onist and a vasodilator also failed to have any significant protective effect on [X+XO]-induced mortality suggesting that the DA(1) receptor activation alone cannot account for the salutary effects of dopexamin e. Pretreatment of the rats with Salbutamol, a preferential beta(2) ag onist significantly enhanced survival upto 50% and a beta(2) antagonis t ICI 118,551 significantly attenuated the ability of dopexamine to pr omote survival. These observations suggest that activation of beta(2) adrenoceptors by dopexamine may play a primary role in the protective effects of DPX; however potential involvement of additional mechanisms in this effect cannot be ruled out at this time.