title: Effects of combined angiotensin II and endothelin receptor blockade with developing heart failure: effects on left ventricular performance.
abstract: BACKGROUND
  The goal of this study was to determine the comparative effects of angiotensin II type 1 (AT(1)) receptor inhibition alone, endothelin-1 (ET) receptor blockade alone, and combined receptor blockade on left ventricular (LV) function, contractility, and neurohormonal system activity in a model of congestive heart failure (CHF).
  
  
  RESULTS
  Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant AT(1) receptor blockade (valsartan, 3 mg/kg per day) and rapid pacing (n=8), (3) concomitant ET receptor blockade (bosentan, 50 mg/kg BID) and rapid pacing (n=8), (4) concomitant combined AT(1) and ET receptor inhibition and rapid pacing (n=8), and (5) sham-operated control (n=9). LV stroke volume was reduced from the control value after rapid pacing, was unchanged with either AT(1) or ET receptor blockade alone, but was improved with combination treatment. LV peak wall stress was reduced in both groups with ET receptor blockade compared with the rapid pacing group. Plasma norepinephrine levels were increased by >3-fold after rapid pacing, remained increased in the monotherapy groups, but were reduced after combination treatment. LV myocyte velocity of shortening was reduced after rapid pacing-induced CHF, remained reduced after AT(1) receptor blockade, increased after ET receptor blockade (compared with rapid pacing-induced CHF values), and returned to within control values after combined blockade.
  
  
  CONCLUSIONS
  Combined AT(1) and the ET receptor blockade in this model of CHF improved LV pump function, and contributory factors included the effects of LV loading conditions, neurohormonal system activity, and myocardial contractile performance. Thus, combined receptor blockade may provide a useful combinatorial therapeutic approach in CHF.
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: New
authors.forename: A C
authors.initials: AC
authors.lastname: Sampson
authors.forename: M K
authors.initials: MK
authors.lastname: King
authors.forename: J W
authors.initials: JW
authors.lastname: Hendrick
authors.forename: M J
authors.initials: MJ
authors.lastname: Clair
authors.forename: J H
authors.initials: JH
authors.lastname: McElmurray
authors.forename: J
authors.initials: J
authors.lastname: Mandel
authors.forename: R
authors.initials: R
authors.lastname: Mukherjee
authors.forename: M
authors.initials: M
authors.lastname: de Gasparo
authors.forename: F G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000077300:Bosentan; D002304:Cardiac Pacing, Artificial; D003131:Combined Modality Therapy; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D009200:Myocardial Contraction; D009638:Norepinephrine / Q000097:blood; D044022:Receptor, Endothelin A; D012083:Renin / Q000097:blood; D013449:Sulfonamides / Q000627:therapeutic use; D013552:Swine; D013777:Tetrazoles / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000503:physiopathology / Q000628:therapy*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D012083:Renin; D014633:Valine; D000077300:Bosentan; D009638:Norepinephrine