Chronic AT1 receptor blockade and angiotensin-converting enzyme (ACE) inhibition in (CHF 146) cardiomyopathic hamsters: effects on cardiac hypertrophy and survival.
OBJECTIVE
We have reported that angiotensin II AT1 receptors are upregulated and that there are no AT2 receptors in the ventricles of cardiomyopathic hamsters. Since the upregulation was present even when no histological lesions were detectable, these results suggested that angiotensin II plays a role in the genesis/maintenance of this pathology. A survival study was conducted to compare the effects of an angiotensin II AT1 receptor antagonist, losartan (L), to those of a placebo (P). Since the angiotensin-converting enzyme (ACE) inhibitor quinapril (Q) has been shown to have beneficial effects in this animal model, a Q group was included.


METHODS
Male Syrian cardiomyopathic hamsters (CHF 146, n = 360) were orally administered P, low- (30 mg/kg/day) or high-dose (100 mg/kg/day) L, or Q (100 mg/kg/day), starting at day 50 of life. Inbred control hamsters (CHF 148, n = 180) were treated with P or L (100 mg/kg/day) as controls. Animals were sacrificed at intervals to evaluate cardiac hypertrophy. Kaplan-Meier analysis was performed to assess differences in survival.


RESULTS
High-dose L had no effects on the survival of control hamsters. There was an unexpected dose-dependent decrease in the survival of cardiomyopathics treated with L (low-dose, P = 0.14; high-dose, P = 0.0015) compared to an increase with Q (P = 0.0003). Cardiac hypertrophy compared to P was increased with L but significantly decreased with Q in cardiomyopathics.


CONCLUSIONS
In this model, losartan did not improve survival compared to placebo and quinapril and, if anything, increased mortality. Our results suggest that AT1 receptor antagonists and ACE inhibitors are not necessarily equivalent or interchangeable in terms of their effects on cardiac hypertrophy and survival in selected progressive heart failure models.
Bastien
N R
NR
Department of Pharmacology, Faculty of Medicine, Université de Montréal, C.P. 6128, Québec, Canada.
Juneau
A V
AV
Ouellette
J
J
Lambert
C
C
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D003404:Creatinine / Q000097:blood; D006224:Cricetinae; D005069:Evaluation Studies as Topic; D007546:Isoquinolines / Q000627:therapeutic use*; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008647:Mesocricetus; D009206:Myocardium / Q000473:pathology; D011188:Potassium / Q000097:blood; D000077583:Quinapril; D012964:Sodium / Q000097:blood; D044005:Tetrahydroisoquinolines
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000804:Angiotensin II; D012964:Sodium; D003404:Creatinine; D000410:Alanine Transaminase; D019808:Losartan; D000077583:Quinapril; D011188:Potassium