Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs.

Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca(2+) entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin.

Maternal caffeine administration and cerebral oxygenation in near-term fetal sheep.

The authors test the null hypothesis that maternal caffeine administration will not significantly alter fetal cerebral oxygenation. The authors measured fetal arterial blood gases, cortical tissue O(2) tension (tPO(2)), sagittal sinus blood gases, and laser Doppler cerebral blood flow in response to a 30-minute caffeine infusion (400 mg intravenously) into 7 near-term pregnant ewes, and they calculated fractional O(2) extraction and relative cerebral metabolic rate for O(2) (CMRO(2)). Following maternal caffeine infusion, both fetal cortical tPO(2) and sagittal sinus (HbO(2)) decreased significantly, from 10.7 +/- 0.9 to 6.8 +/- 1.1 Torr and from 46% +/- 2% to 37% +/- 6%, respectively. This was associated with significant 20% to 30% increases in fractional O(2) extraction and CMRO( 2). Fetal arterial blood gas values did not change significantly. In conclusion, maternal caffeine administration significantly decreases cerebral oxygenation without affecting systemic oxygenation in fetal sheep. The authors speculate that for a fetus that may be otherwise compromised, this increase in CMRO(2) with decreased cortical tPO(2) could present a problem.