This proposal aims to determine why catecholamines are essential for embryonic survival and, specifically, how they regulate embryonic cardiovascular function. Previous studies failed to show a need for catecholamines during embryonic development. However, mice which are deficient in catecholamines die at midgestation (E11-15), apparently from cardiovascular failure. We hypothesize that catecholamines are released in the embryo during transient decreases in PO2 in utero and directly stimulate beta-adrenergic receptors (beta-ARs) to increase heart rate, an effect well characterized in postnatal animals. We believe this effect was missed in earlier experiments since control heart rate is not dependent on catecholamines under non-hypoxic conditions.
Specific Aims : 1A). To determine the effect of combined catecholamine blockade and hypoxia on heart function in midgestational embryos in culture and to identify the relevant catecholamine receptor responsible for maintaining heart rate during hypoxia.
Specific Aims : 1B). To determine if the heart is the primary site of action of catecholamines during hypoxia. Since the pilot studies this proposal is based on involved whole embryos in culture, it is not known whether hypoxia or beta-AR antagonists work directly on the heart or on some other effector tissue. Likewise, it is not clear where the essential catecholamines are being produced, i.e. actually in the heart or in primitive sympathetic neurons, Specific Aims: 2). To examine the effect that in utero hypoxia has on the survival of catecholamine deficient (tyrosine hydroxylase (TH) knockout) mice. If our hypothesis that catecholamines are needed to survive an hypoxic event in utero is correct, then catecholamines deficient animals should be more susceptible to induced hypoxia than in wild type litter mates.
Chandra, Rashmi; Portbury, Andrea L; Ray, Alisa et al. (2006) Beta1-adrenergic receptors maintain fetal heart rate and survival. Biol Neonate 89:147-58 |
Portbury, Andrea L; Chandra, Rashmi; Groelle, Marybeth et al. (2003) Catecholamines act via a beta-adrenergic receptor to maintain fetal heart rate and survival. Am J Physiol Heart Circ Physiol 284:H2069-77 |