In this project period experimental protocols will attempt to establish that moderate levels of fetal hypoxia (oxygen tension 13-15 torr) cause a transient depression of fetal breathing by inhibiting a tonic facilitation which arises in the ventral lateral medullary chemoreceptive areas. It is proposed that adenosine acting at the A1 receptor subtype causes this depression by inhibiting glutamate release. The effects of excitatory amino acid antagonists: 2-amino-5-phosphonopentanoate and 6-cyano-7- nitroquinoxaline-2,3-dione; instilled in the fourth ventricle on fetal breathing will be examined. Having established that either N-methyl-D- aspartate (NMDA) or non-NMDA receptors are important for the tonic facilitation of fetal breathing movements, simultaneous injections of NMDA or glutamate will be made with adenosine to determine if adenosine acts presynaptically or postsynaptically to inhibit fetal breathing. In separate experiments, adenosine will be instilled in the fourth ventricle of fetal sheep who have a rostral pontine brain stem transection to establish that adenosine acting at the medulla alone is capable of inhibiting fetal breathing. Blood flow to the medulla and pons will be measured after adenosine administration to the fourth ventricle to demonstrate that changes in local blood flow are not responsible for the inhibitory effects. The mechanism for respiratory adaptation to sustained hypoxia will be studied using quantitative receptor autoradiography to determine if adenosine A1 receptors are depleted in respiratory related neuron groups of the brain stem. In additional studies, the amount of guanine nucleotide-binding protein (G proteins) will be quantitated using Western analysis of Gi and Go alpha-subunits in cell membranes from the ventral lateral medulla. Depletion of adenosine A1 receptor coupled G- proteins would also lead to adaptation to hypoxia. Fetal breathing movements are used as an index of fetal well being in clinical obstetrics. These studies will add to the understanding of the regulation of this activity in the fetus.
| Bissonnette, John M; Hohimer, A Roger; Knopp, Sharon J (2010) Effect of hypoxia on expiratory muscle activity in fetal sheep. Respir Physiol Neurobiol 171:110-4 |
| Bissonnette, J M; Hohimer, A R; Knopp, S J (1997) Non-NMDA receptors modulate respiratory drive in fetal sheep. J Physiol 501 ( Pt 2):415-23 |
| Bissonnette, J M; Hohimer, A R; Knopp, S J (1995) GABAergic and glutamatergic effects on behaviour in fetal sheep. J Physiol 487 ( Pt 3):677-84 |
| Bissonnette, J M; Hohimer, A R; Knopp, S J (1994) A cholinergic mechanism involved in fetal breathing during the high voltage ECoG state. Respir Physiol 96:151-62 |
| Egerman, R S; Bissonnette, J M; Hohimer, A R (1993) The effects of centrally administered adenosine on fetal sheep heart rate accelerations. Am J Obstet Gynecol 169:866-9 |
| Bissonnette, J M; Hohimer, A R; Knopp, S J (1991) The effect of centrally administered adenosine on fetal breathing movements. Respir Physiol 84:273-85 |
| Hohimer, A R; Bissonnette, J M (1991) Vascular lactic acid infusions do not alter the incidence of fetal breathing movements or their inhibition by acute hypoxemia. Pediatr Res 29:483-6 |
| Bissonnette, J M; Reddington, M (1991) Autoradiographic localization of adenosine A1 receptors in brainstem of fetal sheep. Brain Res Dev Brain Res 61:111-5 |
| Bissonnette, J M; Hohimer, A R; Chao, C R et al. (1990) Theophylline stimulates fetal breathing movements during hypoxia. Pediatr Res 28:83-6 |
| Bissonnette, J M; Hohimer, A R; Willeke, G B (1989) Effect of asphyxia on respiratory activity in fetal sheep. J Dev Physiol 12:157-61 |
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