title: Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide.
abstract: Exposing mice to a chronic hypoxic treatment (10% oxygen, 21 days) that promotes pulmonary hypertension was observed to attenuate the pulmonary vasoconstriction response to acute hypoxia (HPV) both in vivo and in isolated pulmonary arteries. Since catalase restored the HPV response in isolated arteries, it appeared to be attenuated by extracellular hydrogen peroxide. Chronic hypoxia promoted the detection of elevated lung superoxide, extracellular peroxide, extracellular SOD expression, and protein kinase G (PKG) activation [based on PKG dimerization and vasodilator-stimulated phosphoprotein (VASP) phosphorylation], suggesting increased generation of extracellular peroxide and PKG activation may contribute to the suppression of HPV. Aorta from mice exposed to 21 days of hypoxia also showed evidence for extracellular hydrogen peroxide, suppressing the relaxation response to acute hypoxia. Peroxide appeared to partially suppress contractions to phenylephrine used in the study of in vitro hypoxic responses. Treatment of mice with the heme precursor δ-aminolevulinic acid (ALA; 50 mg·kg(-1)·day(-1)) during exposure to chronic hypoxia was examined as a pulmonary hypertension therapy because it could potentially activate beneficial cGMP-mediated effects through promoting a prolonged protoporphyrin IX (PpIX)-elicited activation of soluble guanylate cyclase. ALA attenuated pulmonary hypertension, increases in both superoxide and peroxide, and the suppression of in vitro and in vivo HPV responses. ALA generated prolonged detectible increases in PpIX and PKG-associated phosphorylation of VASP, suggesting PKG activation may contribute to suppression of pulmonary hypertension and prevention of alterations in extracellular peroxide that appear to be attenuating HPV responses caused by chronic hypoxia.
authors.affiliation: Department of Physiology and Pulmonary Hypertension Center, New York Medical College, Valhalla, New York.
authors.forename: Dhara
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Physiology and Pulmonary Hypertension Center, New York Medical College, Valhalla, New York.
authors.forename: Raed
authors.initials: R
authors.lastname: Alhawaj
authors.affiliation: Department of Physiology and Pulmonary Hypertension Center, New York Medical College, Valhalla, New York mike_wolin@nymc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
mesh_terms: D000208:Acute Disease; D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002908:Chronic Disease; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D065627:Familial Primary Pulmonary Hypertension; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011524:Protoporphyrins / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000959:Antihypertensive Agents; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D011524:Protoporphyrins; D000098662:Vasodilator-Stimulated Phosphoprotein; D013481:Superoxides; D000622:Aminolevulinic Acid; D006861:Hydrogen Peroxide; C028025:protoporphyrin IX; D013482:Superoxide Dismutase; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP
keywords: aminolevulinic acid; hypoxic pulmonary vasoconstriction; protein kinase G; pulmonary hypertension