Hypoxic pulmonary vasodilation: a paradigm shift with a hydrogen sulfide mechanism

Am J Physiol Regul Integr Comp Physiol 298: R51-R60, 2010. First published November 4, 2009; doi: 10.1152/ajpregu.00576.2009.--Hypoxic pulmonary vasoconstriction (HVC), an intrinsic and assumed ubiquitous response of mammalian pulmonary blood vessels, matches regional ventilation to perfusion via an unknown O2-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.sub.2]-sensing mechanism. In both animals, exogenous [H.sub.2]S mimicked the vasoactive effects of hypoxia in isolated PA. [H.sub.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.sub.2]S production/consumption and [O.sub.2] was examined in real time by use of amperometric [H.sub.2]S and [O.sub.2] sensors. H2S was produced by sea lion and cow lung homogenate in the absence of [O.sub.2], but it was rapidly consumed when [O.sub.2] was present. Furthermore, consumption of exogenous [H.sub.2]S by cow lung homogenate, PA smooth muscle cells, and heart mitochondria was [O.sub.2] dependent and exhibited maximal sensitivity at physiologically relevant [Po.sub.2] levels. These studies show that HVC is not an intrinsic property of PA and provide further evidence for [O.sub.2]-dependent [H.sub.2]S metabolism in [O.sub.2] sensing. hypoxic vasoconstriction; pinniped; pulmonary hypertension