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There is increasing evidence corroborating a protective role of carbon monoxide releasing molecules (CORMs) in injured tissues. Carbon monoxide (CO) carriers have been recently developed as a pharmacological tool to simulate the effect of heme oxygenase-1-derived CO. The effects of CORM-3, a water-soluble CO releaser, on the incidence of reperfusion-induced ventricular fibrillation (VF) and tachycardia (VT) were studied in isolated rat hearts. Hearts were treated with different doses of CORM-3 before the induction of 30 min global ischemia followed by 120 min reperfusion. We found that at concentrations of 25 microM and 50 microM of CORM-3 promoted a significant reduction in the incidence of VF and VT. Thus, the incidence of VF was reduced by 67% (p<0.05) and 92% (p<0.05) with 25 microM and 50 microM of CORM-3, respectively. The protective effect of CORM-3 on the incidence of VT followed the same pattern. The antiarrhythmic protection was associated with a marked attenuation in infarct size, significant decreases in cellular Na(+) and Ca(2+) gains and K(+) loss. Consequently, the recovery of post-ischemic function was significantly improved. In conclusion, CORM-3 exerts beneficial effects against ischemia/reperfusion-induced injury through its abilities to release CO which mediates a cardioprotective action by regulating tissue Na(+), K(+), and Ca(2+) levels.

We studied the effects of various cycles of preconditioning (PC) (one cycle, 1 x PC; two cycles, 2 x PC; three cycles, 3 x PC; and four cycles, 4 x PC) on cardiac function, infarct size, and the incidence of reperfusion-induced arrhythmias in isolated hearts obtained from rabbits with hypercholesterolemia. After 8 weeks of hypercholesterolemia, hearts were subjected to 30 min of ischemia followed by 120 min of reperfusion. Various cycles of PC resulted in a "cycle-dependent" reduction in infarct size in the age-matched nonhypercholesterolemic group. In the 8-week hypercholesterolemic group, increasing cycles of PC resulted in a significant increase in infarct size from their nonpreconditioned ischemic/reperfused control value of 44 +/- 5% to 45 +/- 6%, 49 +/- 5%, 59 +/- 6% (p < 0.05), and 58 +/- 5% (p < 0.05), respectively. PC increased the vulnerability of the myocardium to reperfusion-induced arrhythmias in hypercholesterolemics indicating that PC may be an "intact heart" phenomenon. The effects of PC appear currently to be a dilemma in laboratories and clinics. The solution to the problem of PC in intact and diseased myocardium requires further data from two different sources: (a) previously "diseased" animals, and (b) diseased human myocardium from clinics. Once these data are available, then the effects under which PC will be beneficial rather than harmful could be established and the dilemma solved.