Inherent variations in CO-H2S-mediated carotid body O2 sensing mediate hypertension and pulmonary edema

Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1174-9. doi: 10.1073/pnas.1322172111. Epub 2014 Jan 6.

Abstract

Oxygen (O2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Humans and animals exhibit substantial interindividual variation in this chemosensory reflex response, with profound effects on cardiorespiratory functions. However, the underlying mechanisms are not known. Here, we report that inherent variations in carotid body O2 sensing by carbon monoxide (CO)-sensitive hydrogen sulfide (H2S) signaling contribute to reflex variation in three genetically distinct rat strains. Compared with Sprague-Dawley (SD) rats, Brown-Norway (BN) rats exhibit impaired carotid body O2 sensing and develop pulmonary edema as a consequence of poor ventilatory adaptation to hypobaric hypoxia. Spontaneous Hypertensive (SH) rat carotid bodies display inherent hypersensitivity to hypoxia and develop hypertension. BN rat carotid bodies have naturally higher CO and lower H2S levels than SD rat, whereas SH carotid bodies have reduced CO and greater H2S generation. Higher CO levels in BN rats were associated with higher substrate affinity of the enzyme heme oxygenase 2, whereas SH rats present lower substrate affinity and, thus, reduced CO generation. Reducing CO levels in BN rat carotid bodies increased H2S generation, restoring O2 sensing and preventing hypoxia-induced pulmonary edema. Increasing CO levels in SH carotid bodies reduced H2S generation, preventing hypersensitivity to hypoxia and controlling hypertension in SH rats.

Keywords: cystathionine-γ-lyase; gasotransmitters; high-altitude hypoxia; sympathetic tone.

Publication types

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

MeSH terms

  • Animals
  • Body Weight
  • Carbon Monoxide / chemistry*
  • Carotid Body / physiology*
  • Catecholamines / metabolism
  • Cystathionine gamma-Lyase / metabolism
  • Heme Oxygenase (Decyclizing) / metabolism
  • Hydrogen Sulfide / chemistry*
  • Hypertension / metabolism*
  • Hypoxia
  • Immunohistochemistry
  • Male
  • Oxygen / chemistry*
  • Oxygen Consumption
  • Pulmonary Edema / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reproducibility of Results
  • Respiration
  • Signal Transduction
  • Species Specificity
  • Splanchnic Nerves / pathology

Substances

  • Catecholamines
  • Carbon Monoxide
  • Heme Oxygenase (Decyclizing)
  • heme oxygenase-2
  • Cystathionine gamma-Lyase
  • Oxygen
  • Hydrogen Sulfide