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J Thorac Cardiovasc Surg 1999;118:655-664
© 1999 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

DOSE DEPENDENCY OF L-ARGININE IN NEONATAL MYOCARDIAL PROTECTION: THE NITRIC OXIDE PARADOX

From the Division of Cardiovascular Surgery, The Heart Institute for Children, Hope Children’s Hospital, Oak Lawn, Ill.

M.T.K is supported in part by the Pillsbury Fellowship.

Address for reprints: Bradley S. Allen, MD, The Heart Institute for Children, Hope Children’s Hospital, 4440 West 95th St, Oak Lawn, IL 60453.

Objectives: 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.
Methods: 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.
Results: 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).
Conclusions: 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.

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