SIMULTANEOUS MANIPULATION OF THE NITRIC-OXIDE AND PROSTANOID PATHWAYSREDUCES MYOCARDIAL REPERFUSION INJURY

The effects of aspirin and L-arginine (biological precursor of nitric oxide) on the production of hydroxyl radicals, cyclic guanosine monoph osphate levels, vascular tone, and the recovery of the ischemic myocar dium were investigated in isolated rat hearts subjected to ischemia an d reperfusion. After 30 minutes of perfusion, hearts were arrested wit h St. Thomas' Hospital cardioplegic solution, global ischemia was indu ced at 37 degrees C for 45 minutes, and the hearts were then reperfuse d at 37 degrees C for 30 minutes. The percent change in recovery of pu lse pressure and maximal change of this pressure with time were better in the group perfused with Krebs-Henseleit solution containing aspiri n plus L-arginine (17% +/- 23%, p = 0.001, and 10% +/- 25%, p = 0.002, respectively) compared with these values in the control group perfuse d with Krebs-Henseleit solution alone (-7% +/- 14% and -11% + 16%, res pectively). Coronary vascular resistance before and after ischemia wer e lower in the aspirin plus L-arginine group (0.19 +/- 0.03 dynes sec/ cm(5), p = 0.001, and 0.23 +/- 0.04 dynes sec/cm(5), p = 0.01, respect ively) compared with those of the control group (0.24 +/- 0.02 and 0.2 8 +/- 0.07 dynes sec/cm(5), respectively). Cyclic guanosine monophosph ate levels increased from 22.5 +/- 6 pmol/100 mg of tissue in the cont rol group to 37.1 +/- 8.9 pmol/100 mg (p = 0.002) in the aspirin plus L-arginine group. Adding N omega-nitro-L-arginine methyl ester to the perfusion medium caused a deterioration in pulse pressure and maximal change of this pressure with time, a decrease in cyclic guanosine mono phosphate, and a rise in coronary vascular resistance. The addition of L-arginine tb the solution in the Krebs-Henseleit solution plus aspir in group increased the production of hydroxyl radicals from 0.32 +/- 0 .18 nmol/gm per 3 minutes to 0.75 +/- 0.33 nmol/gm per 3 minutes (p = 0.03). Despite the association of nitric oxide with increased hydroxyl radical production, it appears that nitric oxide has an overall benef icial effect on the recovery of the ischemic myocardium. The synergism between aspirin and arginine may be caused in part by the scavenging of hydroxyl radicals. Alternatively, by inhibiting the prostaglandin p athway, aspirin may reduce the generation of superoxide anion, a free radical that inactivates nitric oxide. The prolonged half-life of nitr ic oxide may explain the increased levels of cyclic guanosine monophos phate seen in the group perfused with Krebs-Henseleit solution plus as pirin plus L-arginine. Aspirin and L-arginine, both readily available, may be useful adjuncts to clinical cardioplegia strategy.