Dose dependency of L-arginine in neonatal myocardial protection: The nitric oxide paradox

Objectives: Recent experimental studies have suggested that enriching cardi oplegic solution with L-arginine improves myocardial protection by increasi ng nitric oxide production. Nitric oxide, however, also generates the toxic oxygen-derived free radical peroxynitrite; thus these beneficial effects m ay be dose dependent, especially in vulnerable (stressed) hearts. Methods: Fifteen neonatal piglets underwent 60 minutes of ventilator hypoxia (inspir ed oxygen fraction 8%-10%) followed by 20 minutes of normothermic ischemia on cardiopulmonary bypass (stress). They were then protected for 70 minutes with multiple doses of blood cardioplegic solution. In 5 (group 1), the ca rdioplegic solution contained no L-arginine, in 5 (group 2), it was enriche d with a 4 mmol/L concentration of L-arginine, and in 5 (group 3), a 10 mmo l/L concentration of L-arginine. Myocardial function was assessed by means of pressure volume loops and expressed as a percentage of control, and coro nary vascular resistance and conjugated diene production mere measured duri ng infusions of cardioplegic solution. Results: Compared with the protectio n afforded by blood cardioplegic solution without L-arginine (group 1), the addition of a 4 mmol/L concentration of L-arginine (group 2) significantly improved myocardial protection, resulting in complete return of systolic f unction tend-systolic elastance 38% vs 100%; P < .001 vs 4 mmol/L L-arginin e) and preload recruitable stroke work (40% vs 100%; P < .001 vs 4 mmol/L L -arginine; minimal increase in diastolic stiffness (239% vs 158%; P < .001 vs 4 mmol/L L-arginine); and lower coronary vascular resistance, conjugated diene production, and myeloperoxidase activity (P < .001 vs 4 mmol/L L-arg inine in each casei. Conversely, supplementing the cardioplegic solution wi th a 10 mmol/L dose of L-arginine (group 3) negated these beneficial effect s, resulting in depressed systolic function tend-systolic elastance 41% +/- 2%; P < .001 vs 4 mmol/L L-arginine) and preload recruitable stroke work ( 40% +/- 2%; P < .001 vs 4 mmol/L L-arginine); increased diastolic stiffness (246% +/- 7%; P < .001 vs 4 mmol/L L-arginine); and higher conjugated dien e production, myeloperoxidase activity, and coronary vascular resistance (P < .001 vs 4 mmol/L L-arginine in each case). Conclusions: Enriching cardio plegic solution with a 4 mmol/L concentration of L-arginine significantly i mproves myocardial protection by reducing oxygen-derived free radical forma tion by white blood cells, thus preserving vascular and myocardial function . However, these beneficial effects are dose dependent because 10 mmol/L co ncentrations of L-arginine increase oxygen-derived free radical production resulting in vascular and myocardial dysfunction.