Fetal swallowing activity is markedly different from the adult, as spontaneous fetal swallowing occurs markedly higher rate when compared to spontaneous adult drinking. This high rate of fetal swallowing is critical for the regulation of amniotic fluid. Disordered fetal swallowing has been associated with both a decrease and increase in amniotic fluid volume. Both conditions are associated with a significant increase in perinatal morbidity and mortality, and limited treatment modalities are currently available. The mechanisms underlying the high rate of fetal swallowing have not been previously explored. Understanding these mechanisms may facilitate the discovery of an effective and safe treatment for amniotic fluid disorders via regulation of fetal swallowing, potent reducing perinatal morbidity and mortality. Behavioral studies in the adult rat have demonstrated important roles for the central angiotensin II (AngII) receptor subtype I (ATI), glutamate N-methyl-D-aspartate receptor subtype 1 (NMDA-NR1), and neuronal nitric oxide synthase (nNOS) in the regulation of stimulated, though not basal adult drinking. Our behavioral studies in the ovine fetus are the first to demonstrate an important role for nitric oxide (NO) in regulating both spontaneous and stimulated fetal swallowing. Moreover, our preliminary data suggest AngII and NMDA receptors are also involved in the regulation of fetal swallowing. We hypothesize that the very high rate of spontaneous fetal swallowing is regulated similarly to stimulated adult drinking, both requiring upregulation of AngII, glutamate, and NO pathway within the dipsogenic neurons to maintain high rate of neuronal firing. We also hypothesize that the fundamental difference in the rate of spontaneous swallowing between the fetus and adult is due to overexpression of the above receptors and enzyme within the dipsogenic neurons of the fetus. Furthermore, we hypothesize that the negative feedback mechanism between the receptor and its ligand observed in the adult in response to osmotic stimulation, is not functional in the fetus. To prove these hypothesis, we perform both in vivo and in vitro studies in the ovine fetus and ewe. First, utilizing an in vivo ovine model of fetal swallowing, we will expand our current physiological behavioral studies to determine the role of selective AngII receptors (type I and type 2) and n-NOS in fetal swallowing. Second, utilizing qualitative in vitro techniques (immunohistochemistry and in-situ hybridization), we will determine the anatomical localization of ATI, AT2 and NMDA receptors, and nNOS enzyme within the dipsogenic centers of both the fetus and mother. Third, we will utilize western and northern blotting to determine the quantitative differences between the fetus and the mother in the expression ofAT1, AT2 and NMDA receptors, and nNOS enzyme under basal and stimulated conditions.
| El-Haddad, Mostafa A; Chao, Conrad R; Ross, Michael G (2005) N-methyl-D-aspartate glutamate receptor mediates spontaneous and angiotensin II-stimulated ovine fetal swallowing. J Soc Gynecol Investig 12:504-9 |
| El-Haddad, Mostafa A; Ismail, Yaser; Gayle, Dave et al. (2005) Central angiotensin II AT1 receptors mediate fetal swallowing and pressor responses in the near-term ovine fetus. Am J Physiol Regul Integr Comp Physiol 288:R1014-20 |
| Beall, Marie H; El Haddad, Mostafa; Gayle, Dave et al. (2004) Adult obesity as a consequence of in utero programming. Clin Obstet Gynecol 47:957-66; discussion 980-1 |
