title: BQ-123, a selective endothelin subtype A-receptor antagonist, lowers blood pressure in different rat models of hypertension.
abstract: OBJECTIVE
  To investigate the role of endothelin-1 in the pathogenesis of hypertension directly by using the selective endothelin subtype A-receptor antagonist BQ-123.
  
  
  METHODS
  The antihypertensive and hemodynamic effects of sustained BQ-123 administration were examined in conscious, unrestrained spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) rats and renin hypertensive rats.
  
  
  RESULTS
  Sustained infusions of BQ-123 (0.16-164 nmol/kg per min, intravenously, for 6 h) produced dose-dependent reductions in mean arterial pressure in SHR, the maximal reduction being obtained with a dose of 16 nmol/kg per min. This reversible response was evident up to 14 h after the cessation of antagonist infusion. The antihypertensive response to a maximal dose of BQ-123 was associated with bradycardia, but only a minimal reduction in cardiac output (since the stroke volume was elevated) in the SHR. Therefore, the antihypertensive effect of BQ-123 resulted from a decrease in total peripheral resistance. In contrast, in WKY rats the infusion of the high dose (164 nmol/kg per min, intravenously for 6 h) produced a small but significant reduction in mean arterial pressure. BQ-123 did not alter the pressor response or tachycardia observed in pithed SHR following stimulation of the thoracolumbar sympathetic outflow. BQ-123 was also antihypertensive in renin hypertensive rats, lowering the blood pressure to an extent similar to that observed in SHR.
  
  
  CONCLUSIONS
  The data presented indicate a role for endothelin in the pathophysiology of hypertension.
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
authors.forename: S A
authors.initials: SA
authors.lastname: Douglas
authors.forename: M
authors.initials: M
authors.lastname: Gellai
authors.forename: M
authors.initials: M
authors.lastname: Ezekiel
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D003655:Decerebrate State; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D065128:Endothelin Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012083:Renin / Q000502:physiology; D013564:Sympathetic Nervous System / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D012083:Renin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)