Heme oxygenase is necessary for the excitatory response of cultured neonatal rat rostral ventrolateral medulla neurons to hypoxia

Am J Physiol Regul Integr Comp Physiol. 2009 Jan;296(1):R102-18. doi: 10.1152/ajpregu.90325.2008. Epub 2008 Oct 29.


Heme oxygenase has been linked to the oxygen-sensing function of the carotid body, pulmonary vasculature, cerebral vasculature, and airway smooth muscle. We have shown previously that the cardiorespiratory regions of the rostral ventrolateral medulla are excited by local hypoxia and that heme oxygenase-2 (HO-2) is expressed in the hypoxia-chemosensitive regions of the rostral ventrolateral medulla (RVLM), the respiratory pre-Bötzinger complex, and C1 sympathoexcitatory region. To determine whether heme oxygenase is necessary for the hypoxic-excitation of dissociated RVLM neurons (P1) cultured on confluent medullary astrocytes (P5), we examined their electrophysiological responses to hypoxia (NaCN and low Po(2)) using the whole-cell perforated patch clamp technique before and after blocking heme oxygenase with tin protoporphyrin-IX (SnPP-IX). Following the electrophysiological recording, immunocytochemistry was performed on the recorded neuron to correlate the electrophysiological response to hypoxia with the expression of HO-2. We found that the responses to NaCN and hypoxia were similar. RVLM neurons responded to NaCN and low Po(2) with either depolarization or hyperpolarization and SnPP-IX blocked the depolarization response of hypoxia-excited neurons to both NaCN and low Po(2) but had no effect on the hyperpolarization response of hypoxia-depressed neurons. Consistent with this observation, HO-2 expression was present only in the hypoxia-excited neurons. We conclude that RVLM neurons are excited by hypoxia via a heme oxygenase-dependent mechanism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials
  • Animals
  • Animals, Newborn
  • Astrocytes / metabolism
  • Cell Hypoxia
  • Cells, Cultured
  • Chemoreceptor Cells / drug effects
  • Chemoreceptor Cells / enzymology*
  • Coculture Techniques
  • Enzyme Inhibitors / pharmacology
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Immunohistochemistry
  • Medulla Oblongata / cytology
  • Medulla Oblongata / drug effects
  • Medulla Oblongata / enzymology*
  • Metalloporphyrins / pharmacology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Oxygen / metabolism*
  • Patch-Clamp Techniques
  • Protoporphyrins / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction* / drug effects
  • Sodium Cyanide / pharmacology
  • Time Factors


  • Enzyme Inhibitors
  • Metalloporphyrins
  • Protoporphyrins
  • protoporphyrin IX
  • tin protoporphyrin IX
  • Heme Oxygenase (Decyclizing)
  • heme oxygenase-2
  • Sodium Cyanide
  • Oxygen