We have proposed the concept that oxygen-derived free radicals can make a major contribution to the genesis of reperfusion- induced arrhythmias. In support of this we have shown, in the rat heart with regional ischemia (both in vitro an in vivo) that 9 interventions, known to inhibit or scavenge free radicals, can greatly reduce reperfusion-induced arrhythmias. Furthermore, we have shown that two interventions which promote free radical production can exacerbate reperfusion-induced arrhythmias.
In specific aim 1 we propose to undertake, in vitro and in vivo, dose- response studies in the rat to characterize selected interventions so as to optimize their anti-arrhythmic properties (using allopurinol, pterinaldehyde, superoxide dismutase, catalase, mannitol, glutathione and mercaptopropionyl glycine) or arrhythmogenic properties (using hypoxanthine + xanthine oxidase and FeC13 + ADP). We propose to use these optimal doses to determine whether different 'classes' of intervention (acting on different free radicals, different free radical pathways or different subcellular sites) are additive and also ascertain whether anti-free radical interventions can overcome the arrhythmogenic effects of free radical generating systems.
In specific aim 2 we will address species specificity by investigating selected interventions in the rabbit heart in vitro and in vivo and the guinea pig heart in vitro. We will also assess whether xanthine oxidase activity, a major source of superoxide radicals, is present in human heart.
In specific aim 3 we will use electron spin resonance and spin trap techniques to demonstrate that 'bursts' of free radicals are actually produced during the early moments of reperfusion following brief (5-15 minutes) periods of ischemia; we will define the time course and relative extent of their production and will make a provisional identification of the radicals involved.
In specific aim 4 we will assess the relative importance of four major sources of free radicals (leukocytes, xanthine oxidase, catecholamines and the arachidonic acid pathway) in the genesis of reperfusion-induced arrhythmias in the rat and rabbit heart in vitro and in vivo.
In specific aim 5 we will define the mechanism(s) by which free radicals trigger arrhythmias and the mechanism(s) by which anti-free radical interventions afford protection. This project could lead to the development of a new approach to the understanding and pharmacological control of life threatening reperfusion-induced arrhythmias.
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