title: Differential effects of angiotensin II versus endothelin-1 inhibitions in hypertrophic left ventricular myocardium during transition to heart failure.
abstract: BACKGROUND
  In view of their mutual crosstalk, the roles of angiotensin II (Ang II) and endothelin-1 (ET-1) in the myocardium are assumed to be synergistic and supplemental.
  
  
  RESULTS
  In the phase of compensated left ventricular (LV) hypertrophy of Dahl salt-sensitive rats, Ang II peptide and the ACE mRNA in the LV were increased by 1.6- and 3.8-fold, respectively. In contrast, ET-1 peptide and the preproET-1 mRNA remained unchanged. In subsequent congestive heart failure (CHF), Ang II and ACE mRNA did not show further increases. But ET-1 and the mRNA were increased de novo by 5.3- and 4.1-fold, respectively. In ascending aorta-banded rats, the local activations of Ang II and ET-1 also showed a differential time course between LV hypertrophy and CHF. Long-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhibitor) and with bosentan (a mixed ET receptor blocker) equally improved long-term survival. Temocapril reduced the LV/body weight ratio and ameliorated LV fractional shortening. Conversely, although bosentan equally improved fractional shortening, it did not reduce the increase in LV mass. Combined treatment with these 2 drugs further ameliorated the animal's survival without additional decreases in systolic pressure.
  
  
  CONCLUSIONS
  The pathophysiological roles in the myocardium during the transition to CHF differ qualitatively between Ang II and ET-1. Thus, long-term therapy with a combination of ACE inhibition and ET antagonism may provide a new approach for heart failure in humans.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Y
authors.initials: Y
authors.lastname: Kihara
authors.forename: K
authors.initials: K
authors.lastname: Inagaki
authors.forename: Y
authors.initials: Y
authors.lastname: Onozawa
authors.forename: T
authors.initials: T
authors.lastname: Yoneda
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.forename: S
authors.initials: S
authors.lastname: Sasayama
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D018450:Disease Progression; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016232:Endothelins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D016019:Survival Analysis; D013841:Thiazepines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D013449:Sulfonamides; D013841:Thiazepines; D000808:Angiotensinogen; D000804:Angiotensin II; C055603:temocapril hydrochloride; D007703:Peptidyl-Dipeptidase A; D000077300:Bosentan