ADDITIVE EFFECTS OF L-ARGININE INFUSION AND LEUKOCYTE DEPLETION ON RECOVERY AFTER HYPOTHERMIC ISCHEMIA IN NEONATAL LAMB HEARTS

Prior experiments on hypothermic ischemia/reperfusion have shown that (1) leukocytes have an important role in the injury resulting from hyp othermic ischemia/reperfusion and (2) endothelial dysfunction with red uced release of nitric oxide occurs after hypothermic ischemia/reperfu sion. L-Arginine is a nitric oxide precursor, and the effects of nitri c oxide released from endothelial cells include vasorelaxation and inh ibition of leukocyte adhesion to endothelium. The potential roles of a n interaction between endothelial dysfunction and leukocyte-mediated i njury were examined in neonatal hearts. Thirty-two isolated, blood-per fused neonatal lamb hearts were subjected to 2 hours of 10 degrees C c ardioplegic ischemia. Group L-arginine received a 3 mmol/L dose of L-a rginine during the first 20 minutes of repeifusion. In group leukocyte depletion, leukocytes were depleted (Sepacell filler) from the perfus ate before reperfusion, In group L-arginine+leukocyte depletion, leuko cytes were depleted and a 3 mmol/L dose of L-arginine was infused duri ng early reperfusion. The control group had no intervention during rep erfusion. At 30 minutes of reperfusion, left ventricular maximum devel oped pressure, positive maximum and negative maximum first derivative of left ventricular pressure (dP/dt), developed pressure at V10 (volum e that produces a left ventricular end-diastolic pressure of 10 mm Hg at baseline measurement), and dP/dt at V10 were measured. Coronary blo od flow was continuously monitored and oxygen consumption was also mea sured to evaluate the metabolic recovery. In each heart, we also teste d coronary vascular resistance response to the endothelium-dependent v asodilator acetylcholine 10(-7) mol/L and the endothelium-independent vasodilator trinitroglycerin 3 x 10(-5) mol/L to assess endothelial fu nction. Results are given as mean percent recovery of baseline values a standard deviation Group L-arginine+leukocyte depletion showed signi ficantly greater recovery of left ventricular function than the other three groups, and groups L-arginine and leukocyte depletion also showe d better recovery than the control group (positive maximum dP/dt: cont rol group = 68.3% + 8.8%, group L-arginine = 88.8% +/- 3.8%, group L-a rginine+leukocyte depletion = 100.6% +/- 8.7%, group leukocyte depleti on = 79.3% +/- 8.1%; p < 0.05). Groups L-arginine and L-arginine+leuko cyte depletion had higher postischemic coronary blood flow than other groups (control group = 133.0% +/- 31.6%, group L-arginine = 203.2% +/ - 32.1%, group L-arginine+leukocyte depletion = 222.0% +/- 30.4%, grou p leukocyte depletion = 156.3% +/- 29.0%; p < 0.05), Group L-arginineleukocyte depletion showed higher oxygen consumption than the control group (control group = 76.1% +/- 19.22.1%, group L-arginine = 96.8% a 17.6%, group L-arginine+leukocyte depletion = 110.1% +/- 19.2%, group leukocyte depletion = 94.4% +/- 12.9%, p < 0.05). Groups L-arginine, L -arginine+leukocyte depletion, and leukocyte depletion showed greater recovery of the response to acetylcholine than the control group (cont rol group = 39.9% +/- 13.9%, group L-arginine = 61.0% +/- 14.8%, group L-arginine+leukocyte depletion = 53.5% +/- 14.1%, group leukocyte dep letion = 57.9% +/- 13.3%), but there were no intergroup differences in the response to trinitroglycerin (control group = 42.4% +/- 15.6%, gr oup L-arginine = 36.4% +/- 15.4%, group L-arginine+leukocyte depletion = 37.7% +/- 10. 2%, and group leukocyte depletion = 36.5% +/- 11.5%). Conclusion: Reperfusion with leukocyte depletion and L-arginine infus ion during reperfusion have additive effects on the recovery of mechan ical and endothelial function in neonatal lamb hearts. These results s uggest that the beneficial effects of L-arginine involve mechanisms be yond leukocyte inhibition, most likely increased endothelial nitric ox ide production.