Beta1-adrenergic receptors maintain fetal heart rate and survival.
Beta-adrenergic receptor (betaAR) activation has been shown to maintain heart rate during hypoxia and to rescue the fetus from the fetal lethality that occurs in the absence of norepinephrine. This study examines whether the same subtype of betaAR is responsible for survival and heart rate regulation. It also investigates which betaARs are located on the early fetal heart and whether they can be directly activated during hypoxia. Cultured E12.5 mouse fetuses were treated with subtype-specific betaAR antagonists to pharmacologically block betaARs during a hypoxic insult. Hypoxia alone reduced heart rate by 35-40% compared to prehypoxic levels. During hypoxia, heart rate was further reduced by 31% in the presence of a beta(1)AR antagonist, CGP20712A, at 100 nM, but not with a beta2 (ICI118551)- or a beta3 (SR59230A)-specific antagonist at 100 nM. Survival in utero was also mediated by beta1ARs. A beta1 partial agonist, xamoterol, rescued 74% of catecholamine-deficient (tyrosine-hydroxylase-null) pups to birth, a survival rate equivalent to that with a nonspecific betaAR agonist, isoproterenol (87%). Receptor autoradiography showed that beta1ARs were only found on the mouse heart at E12.5, while beta2ARs were localized to the liver and vasculature. To determine if the response to hypoxia was intrinsic to the heart, isolated fetal hearts were incubated under hypoxic conditions in the presence of a betaAR agonist. Heart rate was reduced to 25-30% by hypoxia alone, but was restored to 63% of prehypoxic levels with 100 nM isoproterenol. Restoration was completely prevented if beta1ARs were blocked with CGP20712A at 300 nM, a concentration that blocks beta1ARs, but not beta2- or beta3ARs. Our results demonstrate that beta1ARs are located on the heart of early fetal mice and that beta1AR stimulation maintains fetal heart rate during hypoxia and mediates survival in vivo.
Chandra
Rashmi
R
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Portbury
Andrea L
AL
Ray
Alisa
A
Ream
Margie
M
Groelle
Marybeth
M
Chikaraishi
Dona M
DM
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D005318:Fetal Heart / Q000503:physiopathology; D005311:Fetal Hypoxia / Q000401:mortality*; D006340:Heart Rate, Fetal / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010100:Oxygen / Q000032:analysis; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D015996:Survival Rate; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency
D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D018342:Receptors, Adrenergic, beta-1; C049763:CGP 20712A; D014446:Tyrosine 3-Monooxygenase; D007545:Isoproterenol; D010100:Oxygen