Nitric oxide synthase inhibition attenuates delayed vasodilation and increases injury after cerebral ischemia in fetal sheep

K. A. Marks, C. E. Mallard, I. Roberts, C. E. Williams, P. D. Gluckman, A. D. Edwards

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76 Scopus citations


Transient cerebral ischemia in fetal sheep is followed by a period of delayed cerebral injury associated with cerebral vasodilation. As nitric oxide (NO) can mediate both vasodilation and neuronal death, this study investigated whether inhibition of NO synthesis would attenuate the vasodilation and decrease cerebral injury. Eleven late gestation (range 122- 133 d) fetal sheep were subjected to 30 min of transient cerebral ischemia in utero. Two hours later, treatment group (n = 5) received a continuous infusion of N(G)-nitro-L-arginine (L-NNA) at a dose of 50 mg · h-1 for 4 h followed by 20 mg · h-1 for the subsequent study period, a competitive inhibitor of NO synthase (NOS), whereas a control group (n = 6) received PBS. Inhibition of NOS activity was confirmed in the treatment group by 1) suppression of the fall in mean arterial blood pressure (MAP) associated with acetylcholine (p < 0.01), and 2) persistent increase in MAP after commencement of L-NNA (p < 0.05). Changes in cerebral blood volume (CBV) were observed for 3 d by measuring changes in concentration of total cerebral Hb ([tHb]) using near infrared spectroscopy. The delayed increase in CBV commenced at 13.1 ± 1.0 h postischemia in the control and 12.7 ± 2.3 h in the treatment group. Maximum increase at 30-36 h was 0.5 ± 0.1 mL · 100 g- 1 in the treatment group and 1.2 ± 0.2 mL · 100 g-1 in the control (p < 0.05). Final CBV was depressed below preischemic baseline in the treatment (- 0.7 ± 0.2 mL · 100 g-1) but not the control group (-0.1 ± 0.3 mL · 100 g-1) (p < 0.05). Neuronal loss, quantified histologically 3 d postischemia, indicated that cerebral injury was increased in the treatment group (p < 0.05). The results indicate that after transient cerebral ischemia in fetal sheep, NOS inhibition attenuates the delayed rise in CBV but does not decrease the extent of cerebral injury.

Original languageEnglish
Pages (from-to)185-191
Number of pages7
JournalPediatric Research
Issue number2
StatePublished - 1 Jan 1996
Externally publishedYes

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


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