Role of nitric oxide in hypoxic cerebral vasodilatation in the ovine fetus

Abstract

To investigate the role of nitric oxide (NO) in fetal cerebral circulatory responses to acute hypoxia, near-term fetal sheep were instrumented with laser Doppler probes placed in the parasagittal parietal cortices and vascular catheters in the sagittal sinus and brachiocephalic artery. After a 3 day recovery period, responses of cortical blood flow (CBF) to hypoxia were compared with and without inhibition of nitric oxide synthase (NOS). After an initial 30 min baseline period, fetuses were given a bolus followed by a continuous infusion of Nomega-nitro-L-arginine methyl ester (L-NAME), or saline vehicle as control. After administration of L-NAME, CBF decreased by 14 +/- 6 % (P < 0.01) despite increases in arterial blood pressure of 15 mmHg, resulting in an ~60 % increase in cerebrovascular resistance. Thirty minutes following initiation of L-NAME or vehicle infusion, fetal systemic hypoxia was induced by allowing the ewes to breathe 10-11 % oxygen. In control fetuses CBF increased progressively to 145 +/- 9 % of baseline (P < 0.01) after 30 min, while cortical release of cyclic guanylate cyclase (cGMP), an index of NOS activity, increased 26 +/- 8 % (P < 0.05). In contrast, CBF in L-NAME-treated fetuses increased to only 115 % of the reduced CBF baseline, whereas cortical release of cGMP did not change significantly. In summary, basal levels of NO lower resting cortical vascular resistance by ~15 % in the fetal sheep. Inhibition of NO synthesis attenuates hypoxic cerebral relaxation but does not completely prevent the characteristic increases in CBF. Hypoxic increases in NO directly increase cortical production of cGMP and inhibition of NO synthesis ablates these changes in cGMP.

Figure 1. Protocol

Time sequence of vehicle or l-NAME infusion, hypoxia and recovery stimulated by l-arginine is shown.

Figure 2. Comparison of CBF (top panel) and cortical vascular resistance (bottom panel) responses in untreated and NOS-inhibited late-gestation fetal sheep

Results (means ±s.e.m.) are shown for eight control and eight l-NAME-treated fetuses. ^* Significantly different from initial baseline; § significantly different between groups. The rise in CBF in NOS-inhibited fetuses from the lowered baseline after l-NAME infusion was not significantly different.

Figure 3. Changes in mean arterial blood pressure (top panel) and heart rate (bottom panel)

Results (means ±s.e.m.) are shown for eight control and eight l-NAME-treated fetuses. ^* Significantly different from initial baseline; § significantly different between groups.

Figure 4. Changes in cortical production of cGMP

Results (means ±s.e.m.) are shown for five control and five l-NAME-treated fetuses. ^* Significantly different from initial baseline; § significantly different between groups.

Figure 5. Changes in blood gases and pH

Results (means ±s.e.m.) are shown for eight control and eight l-NAME-treated fetuses. ^* Significantly different from initial baseline; § significantly different between groups.

Figure 6. Changes in glucose and lactate

Results (means ±s.e.m.) are shown for eight control and eight l-NAME-treated fetuses. ^* Significantly different from initial baseline; § significantly different between groups.