title: Respective role of humoral factors and blood pressure in cardiac remodeling of DOCA hypertensive rats.
abstract: OBJECTIVE
  Recent studies have shown that beside elevated arterial blood pressure, humoral factors such as angiotensin II, aldosterone, endothelin or bradykinin might play a role in the cardiac hypertrophy and fibrosis secondary to hypertension. In addition, it seems that perivascular fibrosis and interstitial fibrosis are controlled by independent mechanisms. Therefore, the goal of our study was to evaluate the respective role of the increased arterial pressure and of humoral factors on cardiac remodeling in an experimental hypertension model.
  
  
  METHODS
  Uninephrectomized rats received DOCA, a high salt diet, and when hypertension was installed, they were treated for 6 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg day-1), an ACE inhibitor, enalapril (3 mg/kg day-1), or a mixed ETA-ETB endothelin receptor antagonist, bosentan (100 mg/kg day-1). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and interstitial as well as perivascular fibrosis were evaluated by quantitative morphometry.
  
  
  RESULTS
  DOCA-salt hypertensive rats exhibited a marked cardiac hypertrophy associated with a decrease of maximal coronary blood flow and interstitial and perivascular fibrosis. The calcium antagonist nearly normalized arterial pressure and suppressed all these changes. Enalapril had no effect on arterial pressure and perivascular fibrosis but decreased subendocardial fibrosis. Bosentan had a very small effect on arterial pressure but decreased cardiac hypertrophy and both perivascular and subendocardial fibrosis.
  
  
  CONCLUSIONS
  We conclude that in DOCA salt hypertension, humoral factors such as endothelin may play a role beside high blood pressure in cardiac remodeling. In addition, the different components of this remodeling (decrease of vascular reserve, cardiac hypertrophy and cardiac fibrosis) are controlled independently.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Karam
authors.forename: D
authors.initials: D
authors.lastname: Heudes
authors.forename: P
authors.initials: P
authors.lastname: Hess
authors.forename: M F
authors.initials: MF
authors.lastname: Gonzales
authors.forename: B M
authors.initials: BM
authors.lastname: Löffler
authors.forename: M
authors.initials: M
authors.lastname: Clozel
authors.forename: J P
authors.initials: JP
authors.lastname: Clozel
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D000077300:Bosentan; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000032:analysis; D003326:Coronary Circulation / Q000187:drug effects; D003900:Desoxycorticosterone; D004656:Enalapril / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D005355:Fibrosis; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020748:Mibefradil; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D003900:Desoxycorticosterone; D004656:Enalapril; D003094:Collagen; D000077300:Bosentan