EFFICACY AND MECHANISMS OF DOPEXAMINE IN THE PREVENTION OF ISCHEMIA-REPERFUSION INDUCED ORGAN DAMAGE - ROLE OF OXYGEN-FREE RADICALS

The studies reported in this article provide evidence that several com plex mechanisms are involved in the ability of dopexamine HCl (DPX) in preventing ischemia-reperfusion induced organ damage. In a canine mod el of hemorrhagic shock in which shed-blood was reinfused, DPX prevent ed deterioration in renal blood flow via an action on beta-2 and DA-1 receptors, whereas its ability to preserve tubular function was essent ially due its agonistic effects on DA-1 receptors. In a different expe rimental model in anesthetized rats, acute generation of oxygen free r adicals (OFR) via intravenous administration of Xanthine (X) followed by Xanthine Oxidase (XO) resulted in depression of circulation and dea th of more than 80% of the animals within the observation period of 12 0 min. Pretreatment of the rats with DPX significantly enhanced surviv al rate in a dose dependent manner to about 70%. Neither dobutamine no r prenalterol, which are beta-1 adrenoceptor agonists and like DPX, po tent chronotropic and inotropic agents were effective in preventing OF R induced lethal toxicity. In a separate series, a selective DA-1 rece ptor agonist felodopam had no protective effect and a DA-1 receptor an tagonist SCH-23390 failed to antagonize the salutary effects of DPX. I n contrast, salbutamol, a selective beta-2 adrenoceptor agonist signif icantly promoted the survival rate facilitated by DPX and a selective beta-2 adrenoceptor antagonist, ICI-558,551 significantly attenuated t he survival rate. These later studies suggest that unlike in hemorrhag ic shock, the beta-2 adrenoceptor agonistic properties are critical in the ability of DPX to attenuate lethal toxicity and these effects cou ld be related to prevention of lipid peroxidation induced by oxygen fr ee radicals.