Angiotensin-(1-9) regulates cardiac hypertrophy in vivo and in vitro.
BACKGROUND
Angiotensin-(1-9) is present in human and rat plasma and its circulating levels increased early after myocardial infarction or in animals treated with angiotensin-converting enzyme inhibitor. However, the cardiovascular effects of this peptide are unknown.


OBJECTIVE
To determine whether angiotensin-(1-9) is a novel anti-cardiac hypertrophy factor in vitro and in vivo and whether this peptide is involved in the pharmacological effects of cardiovascular drugs acting on the renin-angiotensin system.


RESULTS
The administration of angiotensin-(1-9) to myocardial infarcted rats by osmotic minipumps (450 ng/kg per min, n = 6) vs. vehicle (n = 8) for 2 weeks decreased plasma angiotensin II levels, inhibited angiotensin-converting enzyme activity and also prevented cardiac myocyte hypertrophy. However, cardiac myocyte hypertrophy attenuation triggered by angiotensin-(1-9) was not modified with the simultaneous administration of the angiotensin-(1-7) receptor antagonist A779 (100 ng/kg per min, n = 6). In experiments in vitro with cultured cardiac myocytes incubated with norepinephrine (10 micromol/l) or with insulin-like growth factor-1 (10 nmol/l), angiotensin-(1-9) also prevented hypertrophy. In other experimental setting, myocardial infarcted rats (n = 37) were randomized to receive either vehicle (n = 12), enalapril (10 mg/kg per day, n = 12) or angiotensin II receptor blocker candesartan (10 mg/kg per day, n = 13) for 8 weeks. Both drugs prevented left ventricle hypertrophy and increased plasma angiotensin-(1-9) levels by several folds. Angiotensin-(1-9) levels correlated negatively with different left ventricular hypertrophy markers even after adjustment for blood pressure reduction.


CONCLUSIONS
Angiotensin-(1-9) is an effective and a novel anti-cardiac hypertrophy agent not acting via the Mas receptor.
Ocaranza
Maria Paz
MP
Departamento de Enfermedades Cardiovasculares, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. mocaran@med.puc.cl
Lavandero
Sergio
S
Jalil
Jorge E
JE
Moya
Jaqueline
J
Pinto
Melissa
M
Novoa
Ulises
U
Apablaza
Felipe
F
Gonzalez
Leticia
L
Hernandez
Carol
C
Varas
Manuel
M
Lopez
Rene
R
Godoy
Ivan
I
Verdejo
Hugo
H
Chiong
Mario
M
D000803:Angiotensin I / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001920:Bradykinin / Q000097:blood; D006332:Cardiomegaly / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D049108:Cell Enlargement / Q000187:drug effects; D002478:Cells, Cultured; D004656:Enalapril / Q000494:pharmacology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
C092006:7-Ala-angiotensin (1-7); D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D010446:Peptide Fragments; D013777:Tetrazoles; C506331:angiotensin I (1-9); D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D004656:Enalapril; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C081643:candesartan; D001920:Bradykinin; D009638:Norepinephrine