title: Effects of dimethylarginine dimethylaminohydrolase-1 overexpression on the response of the pulmonary vasculature to hypoxia.
abstract: Acute and sustained hypoxic pulmonary vasoconstriction (HPV), as well as chronic pulmonary hypertension (PH), is modulated by nitric oxide (NO). NO synthesis can be decreased by asymmetric dimethylarginine (ADMA), which is degraded by dimethylarginine dimethylaminohydrolase-1 (DDAH1). We investigated the effects of DDAH1 overexpression (DDAH1(tg)) on HPV and chronic hypoxia-induced PH. HPV was measured during acute (10 min) and sustained (3 h) hypoxia in isolated mouse lungs. Chronic PH was induced by the exposure of mice to 4 weeks of hypoxia. ADMA and cyclic 3',5'-guanosine monophosphate (cGMP) were determined by ELISA, and NO generation was determined by chemiluminescence. DDAH1 overexpression exerted no effects on acute HPV. However, DDAH1(tg) mice showed decreased sustained HPV compared with wild-type (WT) mice. Concomitantly, ADMA was decreased, and concentrations of NO and cGMP were significantly increased in DDAH1(tg). The administration of either Nω-nitro-l-arginine or 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one potentiated sustained HPV and partly abolished the differences in sustained HPV between WT and DDAH1(tg) mice. The overexpression of DDAH1 exerted no effect on the development of chronic hypoxia-induced PH. DDAH1 overexpression selectively decreased the sustained phase of HPV, partly via activation of the NO-cGMP pathway. Thus, increased ADMA concentrations modulate sustained HPV, but not acute HPV or chronic hypoxia-induced PH.
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors: Adel
authors: A
authors: Bakr
authors: Oleg
authors: O
authors: Pak
authors: Ashraf
authors: A
authors: Taye
authors: Farid
authors: F
authors: Hamada
authors: Ramadan
authors: R
authors: Hemeida
authors: Wiebke
authors: W
authors: Janssen
authors: Mareike
authors: M
authors: Gierhardt
authors: Hossein A
authors: HA
authors: Ghofrani
authors: Werner
authors: W
authors: Seeger
authors: Friedrich
authors: F
authors: Grimminger
authors: Ralph T
authors: RT
authors: Schermuly
authors: Martin
authors: M
authors: Witzenrath
authors: Ralf P
authors: RP
authors: Brandes
authors: Ngan
authors: N
authors: Huang
authors: John P
authors: JP
authors: Cooke
authors: Norbert
authors: N
authors: Weissmann
authors: Natascha
authors: N
authors: Sommer
mesh_terms: D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism*; D001808:Blood Vessels / Q000187:drug effects / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D015870:Gene Expression; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D009924:Organ Culture Techniques; D010069:Oxadiazoles / Q000494:pharmacology; D015398:Signal Transduction; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D010069:Oxadiazoles; D019335:Nitroarginine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase; D006152:Cyclic GMP
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