ZFIN ID: ZDB-PUB-090616-52
Loss of M2 muscarinic receptor function inhibits development of hypoxic bradycardia and alters cardiac {beta}-adrenergic sensitivity in larval zebrafish Danio rerio
Steele, S.L., Lo, K.H., Li, V.W., Cheng, S.H., Ekker, M., and Perry, S.F.
Date: 2009
Source: American journal of physiology. Regulatory, integrative and comparative physiology   297(2): R412-R420 (Journal)
Registered Authors: Cheng, Shuk Han, Ekker, Marc, Perry, Steve F.
Keywords: none
MeSH Terms:
  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Antagonists
  • Adrenergic beta-Antagonists/pharmacology
  • Animal Structures/metabolism
  • Animals
  • Bradycardia/chemically induced
  • Bradycardia/etiology*
  • Bradycardia/metabolism
  • Bradycardia/physiopathology
  • Brain/metabolism
  • Carbachol/pharmacology
  • Embryo, Nonmammalian/metabolism
  • Gene Expression/genetics
  • Heart/drug effects
  • Heart/physiopathology*
  • Heart Rate/physiology
  • Hypoxia/complications*
  • Hypoxia/metabolism
  • Hypoxia/physiopathology
  • Larva/drug effects
  • Larva/metabolism
  • Myocardium/metabolism
  • Norepinephrine/pharmacology
  • Oligonucleotides, Antisense/administration & dosage
  • Oligonucleotides, Antisense/genetics
  • Receptor, Muscarinic M2/physiology*
  • Receptors, Adrenergic, beta/genetics
  • Receptors, Adrenergic, beta/metabolism*
  • Receptors, Adrenergic, beta-1/genetics
  • Receptors, Adrenergic, beta-2/genetics
  • Zebrafish/metabolism*
PubMed: 19515979 Full text @ Am. J. Physiol. Regul. Integr. Comp. Physiol.
Fish exposed to hypoxia develop decreased heart rate, or bradycardia, the physiological significance of which remains unknown. The general muscarinic receptor antagonist atropine abolishes the development of this hypoxic bradycardia, suggesting the involvement of muscarinic receptors. In this study, we tested the hypothesis that the hypoxic bradycardia is mediated specifically by stimulation of the M2 muscarinic receptor, the most abundant subtype in the vertebrate heart. Zebrafish (Danio rerio) were reared at two levels of hypoxia (PO2 = 30 and 40 Torr) from the point of fertilization. In hypoxic fish the heart rate was significantly lower than in normoxic controls from 2 to 10 days post fertilization (dpf). At the more severe level of hypoxia (30 Torr), there were significant increases in the relative mRNA expression of M2 and the cardiac type beta-adrenergic receptors (beta1AR, beta2aAR, and beta2bAR) at 4 dpf. The hypoxic bradycardia was abolished (at PO2 = 40 Torr) or significantly attenuated (at PO2 = 30 Torr) in larvae experiencing M2 receptor knockdown (using Morpholino antisense oligonucleotides). Sham injected larvae exhibited typical hypoxic bradycardia in both hypoxic regimes. The expression of beta1AR, beta2aAR, beta2bAR, and M2 mRNA were all altered at various stages between 1 and 4 dpf in larvae experiencing M2 knockdown. Interestingly, M2 receptor knockdown unveiled a cardioinhibitory role for the beta2-adrenergic receptor. This is the first study to demonstrate a specific role of the M2 muscarinic receptor in the initiation of hypoxic bradycardia in fish. Key words: bradycardia, muscarinic, adrenergic, hypoxia.