Tissue expression of components of the renin-angiotensin system in experimental post-infarction heart failure in rats: effects of heart failure and angiotensin-converting enzyme inhibitor treatment.
1. It has been suggested that local tissue renin-angiotensin systems may be activated in heart failure and that effects on such systems may, at least partially, explain the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in this syndrome. To investigate these hypotheses, we examined expression of renin-angiotensin system components in several tissues in a rodent model of post-myocardial infarction (MI) heart failure, and analysed whether such expression is modified by ACE inhibitor treatment. 2. Four groups of rats (n = 8 - 12 per group) were studied 30 days after surgery: (A) sham-operated rats with no treatment, (B) rats with post-MI heart failure induced by ligation of the left coronary artery, (C) sham-operated rats treated with the ACE inhibitor perindopril (1.5 mg day-1 kg-1), and (D) rats as per B, but treated with perindopril. Expression of renin, angiotensinogen, ACE and angiotensin subtype 1 receptor was assessed by quantification of their respective mRNAs by Northern blotting. 3. Renal renin mRNA increased 2-fold in animals with MI (group B) compared with controls (group A) (P < 0.05) and between 50 and 100-fold after ACE inhibitor treatment (P < 0.001). No change in renin gene expression was found in any extra-renal site either following MI or after ACE inhibitor treatment. Hepatic angiotensinogen mRNA level was similar in all groups, but kidney angiotensinogen mRNA level was increased 1.6-fold (P < 0.01) in the groups receiving perindopril. ACE mRNA level in the lung was not affected by ACE inhibitor treatment but decreased by 50% following MI (groups B and D, P < 0.01). This was associated with a similar (50%, P < 0.01) fall in lung ACE activity and was correlated with the severity of heart failure. Angiotensin subtype 1 receptor mRNA level was not affected in any tissue by either MI or ACE inhibitor treatment. 4. We did not find a systematic activation of tissue renin-angiotensin systems, as assessed by steady-state mRNA levels of key components of the system in experimental post-MI heart failure, or a major effect of ACE inhibitor treatment on expression of these components. However, we observed tissue-specific changes in expression of selected components of the renin-angiotensin system in the kidney and the lung in post-MI heart failure and after ACE inhibitor treatment, which may be of relevance to the pathophysiology of the syndrome and the effects of ACE inhibition.
Kelly
M P
MP
Department of Cardiology, University of Leicester, U.K.
Kahr
O
O
Aalkjaer
C
C
Cumin
F
F
Samani
N J
NJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D007211:Indoles / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000201:enzymology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D020913:Perindopril; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D020913:Perindopril