title: Acute hypertension after nitric oxide synthase inhibition is mediated primarily by increased endothelin vasoconstriction.
abstract: OBJECTIVE
  To determine the quantitative roles played by the different vasoconstrictor systems in the acute pressor response in conscious rats before and after inhibition of nitric oxide synthase with Nw-nitro-L-arginine methyl ester (L-NAME).
  
  
  METHODS
  In conscious male Sprague-Dawley rats, previously instrumented with aortic and venous catheters, the contributions of the different systems were assessed by maximal cumulative pharmacological blockade of alpha 1-adrenoceptors (1 mg/kg prazosin intraperitoneally), AT1 receptors (30 mg/kg losartan intraperitoneally) and V1/V2 receptors (10 mg/kg [beta-mercapto-beta, beta-cyclopenta-methylenepropionyl1, O-Et-Tyr2-Val4-Arg8]-vasopressin per min intravenously). In addition, the contribution of endothelin-1-induced vasoconstriction in response to 100 mg/kg L-NAME intraperitoneally to the hypertension was assessed by administering 5-100 mg/kg ETA/ETB receptor antagonist PD 145 065 intravenously under three different conditions: as the last step of a series of antagonists in the cumulative pharmacological blockade after having induced the L-NAME pressor response; alone before L-NAME treatment; and alone after the full development of the L-NAME pressor response. A separate group of rats was treated acutely with 30 mg/kg losartan intraperitoneally or pretreated for 3 days with 30 mg/kg angiotensin I converting enzyme inhibitor enalapril via drinking water alone or in combination with 1% salt was used to assess the role of the renin-angiotensin system in the L-NAME-induced hypertension.
  
  
  RESULTS
  Short-term administration of the combined ETA/ETB receptor antagonist PD 145065 did not change the arterial pressure under control conditions. Inhibition of the renin-angiotensin system, alpha 1-adrenoceptors or vasopressin receptors alone or in combination did not alter the magnitude of the L-NAME pressor response. In contrast, our results show that both treatments before and during acute nitric oxide synthase blockade hypertension using the ETA/ETB receptor antagonist PD 145065 abolished almost completely (approximately 85%) the pressor response.
  
  
  CONCLUSIONS
  These studies indicate that the predominant mechanism of hypertension, at least in the acute phase, after acute nitric oxide synthase blockade with L-NAME is associated with a marked increase in ETA/ETB receptor activation rather than with increases in alpha 1, AT1 and V1/V2 receptor activation. It remains to be determined whether endothelin participates also in the chronic phase of nitric oxide-deficient hypertension.
authors.affiliation: Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: J D
authors.initials: JD
authors.lastname: Banting
authors.forename: P
authors.initials: P
authors.lastname: Friberg
authors.forename: M A
authors.initials: MA
authors.lastname: Adams
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D016232:Endothelins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D016232:Endothelins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D017466:Receptors, Endothelin; C082887:PD 145065; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester