Dose dependency of L-arginine in neonatal myocardial protection: the nitric oxide paradox.
OBJECTIVE
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.
Kronon
M T
MT
Division of Cardiovascular Surgery, The Heart Institute for Children, Hope Children's Hospital, Oak Lawn, Illinois, USA.
Allen
B S
BS
Halldorsson
A
A
Rahman
S
S
Wang
T
T
Ilbawi
M
M
D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000008:administration & dosage / Q000627:therapeutic use*; D001769:Blood; D001794:Blood Pressure / Q000187:drug effects; D002306:Cardiac Volume / Q000187:drug effects; D002314:Cardioplegic Solutions / Q000008:administration & dosage / Q000627:therapeutic use; D002315:Cardiopulmonary Bypass; D003331:Coronary Vessels / Q000187:drug effects; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects; D013312:Stress, Physiological / Q000503:physiopathology; D013318:Stroke Volume / Q000187:drug effects; D013552:Swine; D013599:Systole; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000378:metabolism*
D002314:Cardioplegic Solutions; D016166:Free Radical Scavengers; D009566:Nitrates; D016877:Oxidants; D014665:Vasodilator Agents; C039642:peroxynitric acid; D009569:Nitric Oxide; D001120:Arginine; D009195:Peroxidase