Effect of post-hypoxic-ischemic inhibition of nitric oxide synthesis on cerebral blood flow, metabolism and electrocortical brain activity in newborn lambs.
Since an excessive production of nitric oxide upon reperfusion/reoxygenation may play an important role in post-hypoxic-ischemic (HI) brain injury, we investigated whether immediate post-HI blockade of nitric oxide synthesis by N-omega-nitro-L-arginine (NLA) may reduce this injury. In 18 newborn lambs, subjected to severe HI, changes from pre-HI values were measured for carotid blood flow (Qcar [ml/min]) as a measure of changes in brain blood flow, (relative) cerebral metabolic rate of oxygen (CMRO2), and electrocortical brain activity (ECBA) at 15, 60, 120 and 180 min after HI. Upon completion of HI, at the onset of reperfusion and reoxygenation, 6 lambs received a placebo (control group), 6 low-dose NLA (10 mg/kg i.v., NLA-10 group), and 6 high-dose NLA (40 mg/kg i.v., NLA-40 group). Histological damage to cerebellar Purkinje cells was assessed after termination of the experiment. Only the control group showed a distinct initial post-HI cerebral hyperperfusion. From 60 min after HI onward Qcar was decreased to about 75% of pre-HI Qcar in all 3 groups, although none of these changes in Qcar reached statistical significance. Despite the decreased Qcar in all 3 groups, only the control group showed a significantly decreased CMRO2. ECBA and its bandwidth decreased in all groups, but only recovered in the NLA-10 group 180 min after HI. The brain to body mass ratio (%) and percentage necrotic Purkinje cells were, respectively: 15.3 +/- 0.8 and 56 +/- 10 (control group); 12.5 +/- 1.2 and 36 +/- 9 (NLA-10 group), and 11.3 +/- 1.0 (p < 0.05 vs. the control group) and 35 +/- 14 (NLA-40 group). Since post-HI reperfusion injury of the brain has been characterized by a decreased CMRO2 and electrical brain activity, we conclude that preservation of CMRO2 in both NLA groups, but a recovery of ECBA and its bandwidth only in the NLA-10 group, suggests that NLA, and especially low-dose NLA, may reduce post-HI brain injury.
Dorrepaal
C A
CA
Department of Pediatrics, Leiden University Hospital, The Netherlands.
Shadid
M
M
Steendijk
P
P
Van der Velde
E T
ET
Van de Bor
M
M
Baan
J
J
Van Bel
F
F
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002534:Hypoxia, Brain / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control*; D012756:Sheep; D013997:Time Factors
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase