title: NS1619-induced vasodilation is enhanced and differentially mediated in chronically hypoxic lungs.
abstract: OBJECTIVE
  To identify the effect of the benzimidazalone derivative, NS1619, on modulating pulmonary vascular tone in lungs from rats exposed to normoxia (21% FiO2) or chronic hypoxia (10% FiO2) for three weeks.
  
  
  METHODS
  Isolated perfused lungs were preconstricted (U46619), and dose-dependent vasodilation to NS1619 was assessed. To elucidate the mechanisms responsible, NS1619 vasodilatory responses were assessed following inhibition of large-conductance Ca(2+)-activated (BKCa; iberiotoxin and paxilline), L-type Ca2+ (nifedipine), K+ (tetraethylammonium), Cl- (niflumic acid), and cation/TRP (lanthanum) channels, as well as nitric oxide synthase (L-NAME).
  
  
  RESULTS
  Compared to normoxia, NS1619-induced vasodilation was significantly greater following hypoxia; however, NO-dependent vasodilation and BKCa-mediated vasodilation, in response to NS1619, were similar in the normoxic and hypoxic lungs. In contrast, direct activation of L-type Ca2+ and non-BKCa K+ channel was involved in the NS1619-induced vasodilation only in hypoxic lungs.
  
  
  CONCLUSIONS
  NS1619 causes pulmonary vasodilation by affecting multiple complementary pathways, including stimulation of NO production, activation of BKCa channels, other TEA-sensitive K+ channels, and L-type Ca2+ channels, and could be considered as a therapeutic agent in hypoxic PH.
authors.affiliation: Vascular Research Laboratory, Providence VA Medical Center, 830 Chalkstone Avenue, Providence, RI, 02908, USA.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: McCullough
authors.forename: Alexander
authors.initials: A
authors.lastname: Vang
authors.forename: Gaurav
authors.initials: G
authors.lastname: Choudhary
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D014665:Vasodilator Agents; C086491:NS 1619; D009569:Nitric Oxide
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