title: Analysis of responses to big endothelin in the hindquarters vascular bed of the cat.
abstract: OBJECTIVE
  To investigate vascular responses to the endothelin-1 (ET-1) precursor, human big endothelin 1-38 (big ET), in the peripheral vascular bed of the cat.
  
  
  METHODS
  These studies were designed to investigate the hypothesis that bit ET is converted to an active peptide with properties similar to ET-1.
  
  
  METHODS
  Hindquarters vascular bed of the cat under conditions of controlled bloodflow; changes in perfusion pressure reflect changes in vascular resistance.
  
  
  METHODS
  Fifty-four adult mongrel cats.
  
  
  METHODS
  Big ET, ET-1, the peptidases chymotrypsin, pepsin and cathepsin-D, and the metalloprotease inhibitor phosphoramidon.
  
  
  RESULTS
  Intra-arterial injections of big ET induced a slow-developing and sustained increase in hindquarters perfusion pressure which could be blocked by phosphoramidon. ET-1 (0.3 nmol), administered as a slow infusion over a 10-min period, produced a slowly developing increase in hindquarters perfusion pressure in a manner similar to that observed in response to injection of big ET. A bolus injection of ET-1 produced a biphasic response characterized by a transient decrease in pressure followed by an increase which was significantly greater in magnitude and more rapid in onset than the pressor response to big ET (0.3 nmol). After incubation of big ET with chymotrypsin, pepsin and cathepsin-D (each 5% weight/weight) for 30 mins at 37 degrees C, injection of activated big ET produced a biphasic response characteristic of the response to ET-1 with an initial transient decrease in pressure followed by a secondary increase in hindquarters perfusion pressure.
  
  
  CONCLUSIONS
  Big ET produces a phosphoramidon-sensitive pressor response which is similar to that produced by an infusion of ET-1. These data suggest that chymotrypsin, pepsin and cathepsin-D can convert big ET to an active peptide which elicits a biphasic response similar to that produced by ET-1.
authors: Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
authors: D Y
authors: DY
authors: Tamura
authors: R K
authors: RK
authors: Minkes
authors: J A
authors: JA
authors: Bellan
authors: T J
authors: TJ
authors: McMahon
authors: D B
authors: DB
authors: McNamara
authors: P J
authors: PJ
authors: Kadowitz
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000502:physiology; D002402:Cathepsin D / Q000494:pharmacology; D002415:Cats; D002918:Chymotrypsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply; D007261:Infusions, Intra-Arterial; D007269:Injections, Intra-Arterial; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010434:Pepsin A / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D004338:Drug Combinations; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D002918:Chymotrypsin; D010434:Pepsin A; D002402:Cathepsin D; D015260:Neprilysin; C008890:phosphoramidon