Related Experiment Videos
Beneficial effects of trandolapril on experimentally induced congestive heart failure in rats
P Fornes1, C Richer, E Pussard
1Département de Pharmacologie, Faculté de Médecine, Paris-Sud, Le Kremlin-Bicêtre, France.
Insights
Angiotensin-converting enzyme (ACE) inhibitors like trandolapril improve survival in heart failure by reducing blood pressure and limiting cardiac remodeling. These benefits are seen both early and long-term.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Congestive heart failure (CHF) is a debilitating condition associated with reduced life expectancy.
- Angiotensin-converting enzyme (ACE) inhibitors are known to improve outcomes in CHF patients.
- The specific mechanisms and timing of ACE inhibitor benefits require further elucidation.
Purpose of the Study:
- To investigate the time-dependent development of cardiac dysfunction after myocardial infarction in a rat model.
- To evaluate the short- and long-term effects of the novel ACE inhibitor trandolapril on hemodynamic, biologic, and morphologic parameters in this model.
Main Methods:
- Induction of myocardial infarction in rats, followed by hemodynamic, biologic, and morphologic assessments over 9-12 months.
- Administration of oral trandolapril for 1 year to assess its therapeutic effects.
- Measurement of systolic blood pressure, cardiac index, left ventricular pressures, cardiac remodeling markers, plasma atrial natriuretic factor (ANF), and urinary cyclic guanosine monophosphate (cGMP).
Main Results:
- Post-infarction, rats exhibited persistent alterations in blood pressure, ventricular pressures, and cardiac remodeling (dilation, hypertrophy, fibrosis).
- Trandolapril treatment rapidly improved hemodynamic function and reduced plasma ANF levels.
- Long-term trandolapril administration led to a delayed reversal of cardiac structural changes, mitigating remodeling.
Conclusions:
- Trandolapril demonstrates early hemodynamic benefits and later beneficial effects on cardiac morphology in post-infarction heart failure.
- The enhanced survival associated with trandolapril is attributed to both immediate hemodynamic improvements and long-term limitation of cardiac remodeling.
Abstract:
Angiotensin-converting enzyme (ACE) inhibitors have been shown to prolong life expectancy in patients with congestive heart failure. In order to determine the relative contributions of the different factors involved in this beneficial effect, we investigated in an experimental model of postinfarction cardiac insufficiency in the rat over a 9-12-month period (1) the kinetics of the development of the hemodynamic, biologic, and morphologic alterations that accompany heart failure, and (2) the kinetics of the effects of a new, long-acting ACE inhibitor, trandolapril. Following induction of infarction, systolic blood pressure, left ventricular dP/dt, and end-diastolic pressure were immediately decreased, decreased, and increased, respectively, and these modifications persisted throughout the study. Cardiac index, on the other hand, was only initially and transiently decreased. Cardiac remodeling (left ventricular dilation, myocardial hypertrophy, and fibrosis) occurred as early as 7 days after infarction and worsened throughout the study. Plasma atrial natriuretic factor (ANF) and urinary cyclic guanosine monophosphate (cGMP) were also increased. In this model, a 1-year oral treatment with trandolapril resulted in early hemodynamic and biologic beneficial effects (reductions in pre- and afterload, increase in cardiac index, and decrease in plasma ANF), and in a delayed reversal of the infarction-induced cardiac morphologic alterations. Hence, the trandolapril-induced increase in survival rate is due initially to the drug's hemodynamic effects and over the long-term to both its hemodynamic and cardiac morphologic (limitation of remodeling) effects.