title: Role of endothelin-1 in the hyper-responsiveness to nitrovasodilators following acute NOS inhibition.
abstract: OBJECTIVE
  Acute NOS inhibition in humans and animals is associated with hypersensitivity to NO donors. The mechanisms underlying this phenomenon have not been fully elucidated. The purpose of the present study was to assess whether hypersensitivity to NOS-blockade is linked to endothelin-1 (ET-1) signalling.
  
  
  METHODS
  Sprague Dawley rats were instrumented with indwelling arterial and venous catheters for continuous assessments of haemodynamic parameters and drug delivery, respectively. Mesenteric arteries were isolated and tested for reactivity by wire myography.
  
  
  RESULTS
  NOS blockade with L-N(G)-nitroarginine methyl ester (L-NAME) caused a pronounced increase in arterial blood pressure (BP) (∼40 mmHg). In L-NAME-treated animals, the dose of sodium nitroprusside (SNP) required to cause a significant reduction in arterial BP was lower than in vehicle-treated rats (P < 0.001), and the magnitude of the reduction in BP was greater. Similar results were obtained with other NO mimetics, but not isoprenaline; moreover, decreasing the BP back to baseline levels with prazosin after L-NAME treatment did not attenuate the hyper-responsiveness to NO donors. The increased responsiveness to NO donors was abolished by pretreatment with the ET(A/B) receptor antagonist, PD145065, or the ET(A) receptor-specific antagonist ABT627. Ex vivo, L-NAME treatment potentiated the constriction induced by big endothelin-1 (bET-1), the precursor to active ET-1, but had no effect on the ET-1-mediated constriction.
  
  
  CONCLUSIONS
  These data suggest that the increased sensitivity to NO donors is mediated, at least in part, by ET-1 in vivo, and the mechanism may involve the conversion of bET-1 to ET-1.
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, CanadaDepartment of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Stephane L
authors.initials: SL
authors.lastname: Bourque
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, CanadaDepartment of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Whittingham
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, CanadaDepartment of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Brien
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, CanadaDepartment of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, CanadaDepartment of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Adams
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009842:Oligopeptides; D014665:Vasodilator Agents; C082887:PD 145065; D009599:Nitroprusside; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester