Hypoxic pulmonary vasodilation: a paradigm shift with a hydrogen sulfide mechanism.
Hypoxic pulmonary vasoconstriction (HVC), an intrinsic and assumed ubiquitous response of mammalian pulmonary blood vessels, matches regional ventilation to perfusion via an unknown O(2)-sensing mechanism. Global pulmonary hypoxia experienced by individuals suffering from chronic obstructive pulmonary disease or numerous hypoventilation syndromes, including sleep apnea, often produces maladaptive pulmonary hypertension, but pulmonary hypertension is not observed in diving mammals, where profound hypoxia is routine. Here we examined the response of cow and sea lion pulmonary arteries (PA) to hypoxia and observed the expected HVC in the former and a unique hypoxic vasodilation in resistance vessels in the latter. We then used this disparate response to examine the O(2)-sensing mechanism. In both animals, exogenous H(2)S mimicked the vasoactive effects of hypoxia in isolated PA. H(2)S-synthesizing enzymes, cystathionine beta-synthase, cystathionine gamma-lyase, and 3-mercaptopyruvate sulfur transferase, were identified in lung tissue from both animals by one-dimensional Western blot analysis and immunohistochemistry. The relationship between H(2)S production/consumption and O(2) was examined in real time by use of amperometric H(2)S and O(2) sensors. H(2)S was produced by sea lion and cow lung homogenate in the absence of O(2), but it was rapidly consumed when O(2) was present. Furthermore, consumption of exogenous H(2)S by cow lung homogenate, PA smooth muscle cells, and heart mitochondria was O(2) dependent and exhibited maximal sensitivity at physiologically relevant Po(2) levels. These studies show that HVC is not an intrinsic property of PA and provide further evidence for O(2)-dependent H(2)S metabolism in O(2) sensing.
Olson
Kenneth R
KR
Indiana Univ. School of Medicine-South Bend, 131 Raclin Carmichael Hall, South Bend, IN 46617, USA. kolson@nd.edu
Whitfield
Nathan L
NL
Bearden
Shawn E
SE
St Leger
Judy
J
Nilson
Erika
E
Gao
Yan
Y
Madden
Jane A
JA
D000818:Animals; D002417:Cattle; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D005260:Female; D006862:Hydrogen Sulfide / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000098:blood supply* / Q000201:enzymology / Q000502:physiology; D023421:Models, Animal; D010100:Oxygen / Q000378:metabolism*; D011651:Pulmonary Artery / Q000502:physiology*; D046070:Sea Lions; D015398:Signal Transduction / Q000502:physiology; D013466:Sulfurtransferases / Q000378:metabolism; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology*
D013466:Sulfurtransferases; C021550:3-mercaptopyruvate sulphurtransferase; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D010100:Oxygen; D006862:Hydrogen Sulfide