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The increase in cerebral blood flow (CBF) during hypoxia in fetal sheep at 0.6 gestation is less than the increase at 0.9 gestation when normalized for differences in baseline CBF and oxygen consumption. Nitric oxide (NO) synthase (NOS) catalytic activity increases threefold during this period of development. We tested the hypothesis that administration of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) decreases the CBF response to systemic hypoxia selectively at 0.9 gestation. We also tested whether any peripheral vasoconstriction during hypoxia is potentiated by L-NAME at 0.9 gestation. Administration of L-NAME increased arterial blood pressure and decreased microsphere-determined CBF during normoxia in fetal sheep at both 0.6 and 0.9 gestation. With subsequent reduction of arterial oxygen content by approximately 50%, the percent increase in forebrain CBF in a control group (57 +/- 11%; +/- SE) and L-NAME-treated group (51 +/- 6%) was similar at 0.6 gestation. Likewise, at 0.9 gestation, the increase in CBF was similar in control (90 +/- 25%) and L-NAME (80 +/- 28%) groups. At 0.9 gestation, L-NAME treatment attenuated the increase in coronary blood flow and increased gastrointestinal vascular resistance during hypoxia. We conclude that NO exerts a basal vasodilatory influence in brain as early as 0.6 gestation in fetal sheep but is not an important mechanism for hypoxic vasodilation in brain at either 0.6 or 0.9 gestation. Thus the developmental increase in NOS catalytic capacity does not appear to be responsible for developmental increases in the CBF response to hypoxia during this period. In contrast, NO modulates the vascular response to hypoxia in heart and gastrointestinal tract.

Dopamine is often used as a pressor agent in sick newborn infants, but an increase in arterial blood pressure could disrupt the blood-brain barrier (BBB), especially in the preterm newborn. Using time-dated pregnant sheep, we tested the hypothesis that dopamine-induced hypertension increases fetal BBB permeability and cerebral water content. Barrier permeability was assessed in nine brain regions, including cerebral cortex, caudate, thalamus, brain stem, cerebellum, and spinal cord, by intravenous injection of the small tracer molecule [(14)C]aminoisobutyric acid at 10 min after the start of dopamine or saline infusion. We studied 23 chronically catheterized fetal sheep at 0.6 (93 days, n = 10) and 0.9 (132 days, n = 13) gestation. Intravenous infusion of dopamine increased mean arterial pressure from 38 +/- 3 to 53 +/- 5 mmHg in 93-day fetuses and from 55 +/- 5 to 77 +/- 8 mmHg in 132-day fetuses without a decrease in arterial O(2) content. These 40% increases in arterial pressure are close to the maximum hypertension reported for physiological stresses at these ages in fetal sheep. No significant increases in the brain transfer coefficient of aminoisobutyric acid were detected in any brain region in dopamine-treated fetuses compared with saline controls at 0.6 or 0.9 gestation. There was also no significant increase in cortical water content with dopamine infusion at either age. We conclude that a 40% increase in mean arterial pressure during dopamine infusion in normoxic fetal sheep does not produce substantial BBB disruption or cerebral edema even as early as 0.6 gestation.

Fetal head compression during labor may increase intracranial pressure (ICP) and decrease cerebral perfusion pressure (CPP). An increase in mean arterial pressure (MAP) associated with the Cushing response normally acts to mitigate an ischemic insult when the increase in ICP approaches MAP. However, the premature fetus may be limited in its ability to increase MAP. We compared the efficacy of the pressor response in sustaining CPP, cerebral blood flow (CBF), and cerebral O2 consumption (CMRO2) in chronically catheterized fetal sheep at 0.6 gestation (92 d; n = 7) and 0.9 gestation (133 d; n = 7). When fetal ICP was increased to baseline MAP (41 +/- 3 mm Hg; +/-SEM) in 92-d fetuses, MAP increased by 7 +/- 2 mm Hg and remained stable during 30 min of constant ICP elevation; CBF decreased by 72% and CMRO2 decreased by 46%. In 133-d fetuses, MAP increased from 53 +/- 2 to 65 +/- 4 mm Hg at 3 min of elevated ICP; CBF decreased by 62% and CMRO2 decreased 30%. However, MAP continued to increase after 3 min and reached a stable level of 75 +/- 3 mmHg at 30 min in 133-d fetuses. The additional increase in MAP restored CBF and CMRO2 to baseline values. Plasma epinephrine and vasopressin concentrations increased between 6 and 33 min of elevated ICP to levels, exceeding those in 92-d fetuses. We conclude that the arterial pressure response to intracranial hypertension is present at 0.6 gestation but is less well developed than at 0.9 gestation in fetal sheep, possibly due to immaturity of the sympathoadrenal and vasopressin systems. Consequently, CBF and CMRO2 are not as well defended at mid-gestation against elevated ICP as might occur during difficult labor.

The human fetal head is periodically compressed during labor. The resulting increase in intracranial pressure (ICP) may exceed the hydrostatic increase in mean arterial pressure (MAP), thereby decreasing cerebral perfusion pressure (CPP). We determined whether the cardiovascular system of near-term fetal sheep is capable of rapidly increasing MAP during periodic increases in ICP. In 12 chronically instrumented fetuses, we produced sinusoidal oscillations in ICP with a maximum of 52 +/- 1 mmHg (baseline MAP) and a minimum of 4 +/- 1 mmHg at a 3-min periodicity by ventricular fluid infusion and withdrawal. Phasic increases in MAP and decreases in electromagnetically determined renal blood flow tracked behind ICP by 0.3-0.5 min. By the sixth cycle, tonic peripheral vasoconstriction that occurred attenuated by the reduction in CPP during subsequent ICP oscillations. By the 10th cycle, plasma catecholamines and vasopressin increased 20-fold. To more closely simulate the pattern during labor, we produced an ICP triangular pulse train with 5-min periodicity and pulse duration of 1.5 min in six other fetuses. The MAP response was nearly out of phase with this more rapid rise of ICP. Thus the phasic component of the fetal pressor response is inadequate for maintaining CPP when ICP is increased to baseline MAP in less than 0.75 min. However, when the ICP pulse duration and frequency are sufficiently high, a tonic pressor response that may be humorally mediated acts to minimize transient cerebral ischemia.

Fetal head compression during normal labor can increase intracranial pressure (ICP). We studied the cerebral and peripheral blood flow responses to ICP elevation in utero in chronically catheterized fetal sheep using the radiolabeled microsphere technique. ICP was elevated, stepwise, in increments of 6 +/- 1 mm Hg by infusion of artificial cerebrospinal fluid into a lateral ventricle. When ICP was raised to within 28 mm Hg of baseline mean arterial blood pressure (i.e., ICP above 22 mm Hg), arterial pressure began to increase. Above this ICP level, up to 41 mm Hg, mean cerebral perfusion pressure was maintained by equivalent increases in arterial pressure. Cerebral blood flow and O2 uptake at the highest ICP levels were not different from baseline values. Changes in peripheral organ blood flow were graded according to the level of ICP. At the highest level (ICP = 41 mm Hg), renal, gastrointestinal, and skin blood flow decreased by 68%, 69%, and 65%, respectively. Myocardial and adrenal blood flow doubled, whereas heart rate and cardiac output were unchanged. Placental blood flow increased in proportion to arterial pressure. Arterial plasma epinephrine, norepinephrine and arginine vasopressin increased by nearly two orders of magnitude. Therefore, as ICP approaches baseline mean arterial pressure, fetal lambs are capable of sustaining cerebral perfusion by initiating profound visceral vasoconstriction without curtailing placental blood flow. Since cerebral O2 uptake was maintained, there is no evidence that stimulation of the peripheral response requires pronounced cerebral ischemia. This highly developed Cushing response may be important for ensuring cerebral viability when the fetal head is compressed during parturition.