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

Recent experimental studies have suggested that enriching cardioplegic solution with L-arginine improves myocardial protection by increasing nitric oxide production. Nitric oxide, however, also generates the toxic oxygen-derived free radical peroxynitrite; thus these beneficial effects may be dose dependent, especially in vulnerable (stressed) hearts.

Fifteen neonatal piglets underwent 60 minutes of ventilator hypoxia (inspired 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 cardioplegic solution contained no L-arginine, in 5 (group 2), it was enriched with a 4 mmol/L concentration of L-arginine, and in 5 (group 3), a 10 mmol/L concentration of L-arginine. Myocardial function was assessed by means of pressure volume loops and expressed as a percentage of control, and coronary vascular resistance and conjugated diene production were measured during infusions of cardioplegic solution.

Compared with the protection 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 function (end-systolic elastance 38% vs 100%; P <.001 vs 4 mmol/L L-arginine) 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-arginine in each case). Conversely, supplementing the cardioplegic solution with a 10 mmol/L dose of L-arginine (group 3) negated these beneficial effects, resulting in depressed systolic function (end-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 diene production, myeloperoxidase activity, and coronary vascular resistance (P <.001 vs 4 mmol/L L-arginine in each case).

Enriching cardioplegic solution with a 4 mmol/L concentration of L-arginine significantly improves myocardial protection by reducing oxygen-derived free radical formation by white blood cells, thus preserving vascular and myocardial function. However, these beneficial effects are dose dependent because 10 mmol/L concentrations of L-arginine increase oxygen-derived free radical production, resulting in vascular and myocardial dysfunction.