title: Catecholamines act via a beta-adrenergic receptor to maintain fetal heart rate and survival.
abstract: Mice lacking catecholamines die before birth, some with cardiovascular abnormalities. To investigate the role of catecholamines in development, embryonic day 12.5 (E12.5) fetuses were cultured and heart rate monitored. Under optimal oxygenation, wild-type and catecholamine-deficient fetuses had the same initial heart rate (200-220 beats/min), which decreased by 15% in wild-type fetuses during 50 min of culture. During the same culture period, catecholamine-deficient fetuses dropped their heart rate by 35%. Hypoxia reduced heart rate of wild-type fetuses by 35-40% in culture and by 20% in utero, assessed by echocardiography. However, catecholamine-deficient fetuses exhibited greater hypoxia-induced bradycardia, reducing their heart rate by 70-75% in culture. Isoproterenol, a beta-adrenergic receptor (beta-AR) agonist, reversed this extreme bradycardia, restoring the rate of catecholamine-deficient fetuses to that of nonmutant siblings. Moreover, isoproterenol rescued 100% of catecholamine-deficient pups to birth in a dose-dependent, stereo-specific manner when administered in the dam's drinking water. An alpha-AR agonist was without effect. When wild-type fetuses were cultured with adrenoreceptor antagonists to create pharmacological nulls, blockade of alpha-ARs with 10 microM phentolamine or beta-ARs with 10 microM bupranolol alone or in combination did not reduce heart rate under optimal oxygenation. However, when combined with hypoxia, beta-AR blockade reduced heart rate by 35%. In contrast, the muscarinic blocker atropine and the alpha-AR antagonist phentolamine had no effect. These data suggest that beta-ARs mediate survival in vivo and regulate heart rate in culture. We hypothesize that norepinephrine, acting through beta-ARs, maintains fetal heart rate during periods of transient hypoxia that occur throughout gestation, and that catecholamine-deficient fetuses die because they cannot withstand hypoxia-induced bradycardia.
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Portbury
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chandra
authors.forename: Marybeth
authors.initials: M
authors.lastname: Groelle
authors.forename: Michael K
authors.initials: MK
authors.lastname: McMillian
authors.forename: Alana
authors.initials: A
authors.lastname: Elias
authors.forename: James R
authors.initials: JR
authors.lastname: Herlong
authors.forename: Maribel
authors.initials: M
authors.lastname: Rios
authors.forename: Suzanne
authors.initials: S
authors.lastname: Roffler-Tarlov
authors.forename: Dona M
authors.initials: DM
authors.lastname: Chikaraishi
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000473:pathology; D002395:Catecholamines / Q000502:physiology*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics / Q000502:physiology; D015150:Echocardiography, Doppler; D004837:Epinephrine / Q000502:physiology; D005260:Female; D005333:Fetus / Q000502:physiology*; D006340:Heart Rate, Fetal / Q000502:physiology*; D000860:Hypoxia / Q000503:physiopathology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009638:Norepinephrine / Q000502:physiology; D009924:Organ Culture Techniques; D011247:Pregnancy; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013534:Survival / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000502:physiology
chemical_list: D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine; D004837:Epinephrine