15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Fetal-Hypoxia

We aimed to develop a model of fetal hypoxia-ischemia (HI) preconditioning that reflects the pathophysiological conditions of perinatal asphyxia more closely than the existing neonatal stroke models. Fetal asphyxia (FA) was induced by clamping the uterine vasculature on embryonic day E17. At birth (P0), severe perinatal asphyxia (SPA) was induced during cesarean section. At P4, carotid arteries were studied in a wire myograph and at P8 brains were analyzed for apoptotic cell death in the prefrontal cortex and striatum. The contraction induced by K+ was significantly reduced in the carotid arteries from the SPA group and endothelium-dependent relaxation (mediated by acetylcholine) was augmented in the FA group. These changes in vascular responsiveness were not present in the animals exposed to both insults (FA + SPA). Additionally, FA+SPA animals showed lower numbers of apoptotic cells compared to SPA animals in both the prefrontal cortex and striatum. Exposure to a global fetal asphyctic insult seems to protect against the vascular alterations and the increase of apoptosis in striatum and prefrontal cortex induced by severe asphyxia at birth.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Apoptosis; Brain; Carotid Arteries; Disease Models, Animal; Fetal Hypoxia; Hypoxia-Ischemia, Brain; In Situ Nick-End Labeling; Ischemic Preconditioning; Rats; Rats, Sprague-Dawley; Vasoconstriction

The purpose of this study was to investigate the mechanisms of tension and intracellular calcium regulation following stimulation with the thromboxane A(2) receptor agonist U46619 in the left anterior descending coronary artery of fetal sheep exposed to long-term hypoxia. We hypothesized that there would be a reduction in intracellular calcium responses in long-term hypoxic left anterior descending coronary artery accompanied by an increase in calcium sensitivity of the contractile mechanism.. Pregnant sheep were kept at altitude (3820 m) from day 30 of gestation until day 140. Fetal hearts from long-term hypoxic and from a control, normoxic group were obtained and the left anterior descending coronary artery of the fetus was dissected, cleaned, and mounted in a bath (Jasco) in which tension and intracellular calcium [Ca(2+)](i), using Fura-2, could be measured simultaneously following stimulation of the thromboxane A(2) receptor with U46619. The role of intracellular calcium and the Rho kinase and protein kinase C pathways in the tension responses were investigated by maintaining intracellular calcium constant or by using the Rho kinase blocker, Y27632, or the protein kinase C blocker, GF109203-X.. There was no difference in the tension dose-response to U46619 between the normoxic fetal and hypoxic fetal left anterior descending, although [Ca(2+)](i) was lower in the hypoxic fetal than normoxic fetal at the highest doses. When [Ca(2+)]( i) was maintained constant at baseline levels, U46619 produced the same tension dose-response in both normoxic fetal and hypoxic fetal left anterior descending as when [Ca(2+)](i) was allowed to rise. The tension response was abolished in both groups when the Rho kinase inhibitor, Y27632, was given either during or before stimulation with U46619. The protein kinase C blocker, GF109203-X, had no effect on the tension response in either group.. Long-term hypoxia did not alter the tension response to thromboxane A(2) receptor stimulation in fetal left anterior descending. The contractions in response to U46619 were produced apparently completely by changes in calcium sensitivity through the Rho kinase pathway.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Altitude; Animals; Calcium; Coronary Vessels; Female; Fetal Hypoxia; Muscle Contraction; Muscle, Smooth, Vascular; Pregnancy; Protein Kinase C; Receptors, Thromboxane A2, Prostaglandin H2; rho-Associated Kinases; Sheep