Studies on the pharmacological interventions to prevent oxygen free radical (OFR)-mediated toxicity; effects of dopexamine, a DA1 receptor and beta 2 adrenoceptor agonist.
We have previously demonstrated that the lethal effects of free radicals 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 antagonist) and verapamil. These studies have implicated that there may be potential interactions between free radicals and cell calcium. However, alternate mechanisms such as hemodynamic changes in the overall effects of calcium antagonists cannot be ruled out. Therefore, the present studies are conducted to further investigate the efficacy of various cardiovascular agents such as Dopexamine (DPX) on [X+XO]-induced mortality. 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 (DA1) and beta 2 adrenoceptor agonist significantly enhanced survival upto 70%. Neither dobutamine nor prenalterol, (preferential beta 1 agonists) both of which produced similar increases in heart rate as DPX, enhanced survival rate thus suggesting that cardiac stimulation alone, did not contribute to the protective effects of DPX. Likewise, fenoldopam, a DA1 agonist and a vasodilator also failed to have any significant protective effect on [X+XO]-induced mortality suggesting that the DA1 receptor activation alone cannot account for the salutary effects of dopexamine. Pretreatment of the rats with Salbutamol, a preferential beta 2 agonist significantly enhanced survival upto 50% and a beta 2 antagonist ICI 118,551 significantly attenuated the ability of dopexamine to promote survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Jacinto
S M
SM
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, TX 77204-5515.
Lokhandwala
M F
MF
Jandhyala
B S
BS
D000322:Adrenergic Agonists / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004280:Dobutamine / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D018818:Fenoldopam / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000633:toxicity*; D017447:Receptors, Dopamine D1 / Q000819:agonists
D000322:Adrenergic Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D015259:Dopamine Agents; D017382:Reactive Oxygen Species; D017447:Receptors, Dopamine D1; C046318:dopexamine; D004280:Dobutamine; D018818:Fenoldopam; D004298:Dopamine