title: Pulmonary hypertension in wild type mice and animals with genetic deficit in KCa2.3 and KCa3.1 channels.
abstract: OBJECTIVE
  In vascular biology, endothelial KCa2.3 and KCa3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of KCa2.3 and KCa3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of KCa2.3 and KCa3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension.
  
  
  RESULTS
  Male wild type and KCa3.1-/-/KCa2.3T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The KCa3.1-/-/KCa2.3T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the KCa2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the KCa2.3 and KCa3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of KCa2.3 and KCa3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype.
  
  
  CONCLUSIONS
  Despite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Christine
authors.initials: C
authors.lastname: Wandall-Frostholm
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Lykke Moran
authors.initials: LM
authors.lastname: Skaarup
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; Institute for Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Veeranjaneyulu
authors.initials: V
authors.lastname: Sadda
authors.affiliation: Institute for Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Gorm
authors.initials: G
authors.lastname: Nielsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Elise Røge
authors.initials: ER
authors.lastname: Hedegaard
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Susie
authors.initials: S
authors.lastname: Mogensen
authors.affiliation: Institute for Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark; Aragon Institute of Health Sciences I+CS and ARAID, Zaragoza, Spain.
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
mesh_terms: D000818:Animals; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000150:complications; D000860:Hypoxia / Q000150:complications; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496900:Kcnn3 protein, mouse; C496925:Kcnn4 protein, mouse; D012333:RNA, Messenger; D051640:Small-Conductance Calcium-Activated Potassium Channels; D004318:Doxycycline