Combined selective angiotensin II AT1-receptor blockade and angiotensin I-converting enzyme inhibition on coronary flow reserve in postischemic heart failure in rats.
We investigated whether angiotensin I-converting enzyme inhibition (ACEI) and angiotensin II AT1-receptor blockade (AT1-) would exert beneficial additive effects on coronary hemodynamics and on cardiac remodeling in post-myocardial infarction (MI) heart failure in rats. Wistar rats with MI were treated daily for 6 weeks with either trandolapril (0.1 mg/kg), losartan (3 mg/kg), or their combination, after which coronary hemodynamics (basal and at maximal vasodilation, fluospheres), systemic hemodynamics, and cardiac remodeling were investigated. Neither trandolapril nor losartan (both in nonantihypertensive doses) nor their combination (which significantly decreased blood pressure) proved to be effective at improving MI-induced impairments of basal coronary hemodynamics and of coronary flow reserve, and at preventing cardiac fibrosis development. In contrast, both trandolapril and losartan significantly improved the hemodynamic status [e.g., left ventricular end diastolic pressure: -27% and -39%, urinary cyclic guanosine monophosphate (GMP): -37%, and -26%, respectively] and slightly limited cardiac hypertrophy (-5% and -3%, respectively), and, in their combination, tended to exert additive effects on these three parameters (-49, -42, and -10%, respectively). Thus whereas the ACEI/AT1- combination tended to exert additive effects on systemic hemodynamics and cardiac hypertrophy in post-MI heart failure rats, no such effect was found for coronary hemodynamics, probably in relation to the lack of prevention of cardiac fibrosis. We conclude that an early (6 weeks) drug-induced improvement in coronary hemodynamics does not contribute to the long-term survival prolongation observed in this experimental model after either ACEI or AT1-.
Richer
C
C
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Gervais
M
M
Fornes
P
P
Giudicelli
J F
JF
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D006332:Cardiomegaly / Q000503:physiopathology; D003326:Coronary Circulation / Q000187:drug effects*; D006152:Cyclic GMP / Q000652:urine; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000627:therapeutic use; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000150:complications* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012084:Renin-Angiotensin System / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007211:Indoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C052035:trandolapril; D006152:Cyclic GMP; D019808:Losartan