Free radicals and reperfusion-induced arrhythmias: protection by spin trap agent PBN in the rat heart.
Using the isolated perfused rat heart with transient (10-minute) regional ischemia induced by coronary artery ligation, we have shown that PBN (N-tert-butyl-alpha-phenylnitrone), an organic spin trap agent designed specifically to form "stable" adducts with free radicals in electron spin resonance studies, can dramatically reduce the vulnerability of the myocardium to reperfusion-induced ventricular fibrillation. Studied in the concentration range of 5-1,000 microM/L, PBN added to the perfusate 5 minutes prior to ischemia exerted a dose-dependent protective effect. At the optimum concentration of 30 microM/L PBN reduced the incidence of ventricular fibrillation to 50% (6 of 12) from its control value of 100% (12 of 12). The antiarrhythmic effect was achieved without any substantial effect on coronary flow or heart rate. Investigating whether this was a direct antiarrhythmic effect, operating during reperfusion, or an indirect effect arising from the action of PBN on the heart during ischemia, PBN (30 microM/L) was added to the perfusion fluid 2 minutes before reperfusion. In the control group, 100% of the hearts fibrillated whereas only 50% fibrillated in the PBN group. Additional studies were designed to ascertain whether the drug caused an absolute reduction in vulnerability to reperfusion-induced arrhythmias (irrespective of the duration of ischemia) or whether it only shifted the ischemic time-reperfusion vulnerability curve to the right (i.e., delayed the onset of vulnerability). Thus, studies were undertaken to define the relation between the duration of ischemia and the incidence of reperfusion-induced arrhythmias in control hearts and hearts treated with PBN.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000150:complications* / Q000503:physiopathology; D003497:Cyclic N-Oxides; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013113:Spin Labels / Q000627:therapeutic use*; D013997:Time Factors
D003497:Cyclic N-Oxides; D005609:Free Radicals; D009589:Nitrogen Oxides; D013113:Spin Labels; C029217:phenyl-N-tert-butylnitrone; D010100:Oxygen