Differential regulation of cardiac adrenomedullin and natriuretic peptide gene expression by AT1 receptor antagonism and ACE inhibition in normotensive and hypertensive rats.
OBJECTIVE
To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression.


METHODS
Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared.


RESULTS
Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments.


CONCLUSIONS
Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.
Magga
J
J
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Kalliovalkama
J
J
Romppanen
H
H
Vuolteenaho
O
O
Pörsti
I
I
Kähönen
M
M
Tolvanen
J P
JP
Ruskoaho
H
H
D053607:Adrenomedullin; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000473:pathology; D004656:Enalapril / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D020097:Natriuretic Peptide, Brain; D010455:Peptides / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012016:Reference Values
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D020097:Natriuretic Peptide, Brain; D053607:Adrenomedullin; D004656:Enalapril; D009320:Atrial Natriuretic Factor; D019808:Losartan