title: Bkca opener, NS1619 pretreatment protects against shock-induced vascular hyporeactivity through PDZ-Rho GEF-RhoA-Rho kinase pathway in rats.
abstract: BACKGROUND
  Our previous study showed that the ischemic preconditioning and pretreatment of adenosine triphosphate-sensitive potassium channel (KATP) opener, pinacidil, may induce a good protective effect on shock-induced vascular hyporeactivity. Whether the pretreatment of opener/activator of the large-conductance calcium-activated potassium channel (Bkca), NS1619, can also induce a protective effect on vascular reactivity and play a beneficial effect on subsequent hemorrhagic shock is not clear.
  
  
  METHODS
  With Sprague-Dawley rats subjected to hemorrhagic shock and their isolated superior mesenteric artery, the protective effect of NS1619 (0.5, 1, 2, and 4 mg/kg) pretreatment (30 minutes before hemorrhage shock) on vascular reactivity and the underlying mechanisms were observed.
  
  
  RESULTS
  NS1619 pretreatment significantly improved the 72-hour survival of hemorrhagic shock rats, alleviated shock-induced decrease of vascular reactivity and calcium sensitivity, and increased the cardiac output and oxygen delivery. NS1619 2 mg/kg had the best effect. These protective effects of NS1619 pretreatment on vascular reactivity and calcium sensitivity were antagonized by RhoA inhibitor, C3 transferase, and Rho kinase antagonist, Y-27632. NS1619 pretreatment up-regulated the activities of RhoA, Rho-kinase, and PDZ-Rho GEF (guanine nucleotide exchange factor). These effects of NS1619 pretreatment were eliminated by RhoA inhibitor, C3 transferase.
  
  
  CONCLUSIONS
  Bkca opener, NS1619 pretreatment has good protective effect on vascular reactivity and calcium sensitivity, which plays a good beneficial effect on hemorrhagic shock. The mechanism may be mainly through PDZ-Rho GEF-RhoA-Rho kinase pathway. Bkca channel may be a potential target for the treatment of shock-induced vascular hyporeactivity.
authors.affiliation: From the State Key Laboratory of Trauma, Burns and Combined Injury (Y.H., G.Y., X.X., L.L., T.L.), Second Department of Research Institute of Surgery, and Department of Anesthesiology (Y.H.), Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.forename: Guangming
authors.initials: G
authors.lastname: Yang
authors.forename: Xudong
authors.initials: X
authors.lastname: Xiao
authors.forename: Liangming
authors.initials: L
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Li
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004108:Dilatation, Pathologic / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D019194:Ischemic Preconditioning / Q000379:methods; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects* / Q000503:physiopathology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity; D012771:Shock, Hemorrhagic / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D015398:Signal Transduction; D015996:Survival Rate; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000577:Amides; D001562:Benzimidazoles; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D015221:Potassium Channels; D011725:Pyridines; C108830:Y 27632; C086491:NS 1619; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D002118:Calcium