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Hypertension ; 59(2): 300-7, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22184331

ABSTRACT

The renin-angiotensin system regulates cardiovascular physiology via angiotensin II engaging the angiotensin type 1 or type 2 receptors. Classic actions are type 1 receptor mediated, whereas the type 2 receptor may counteract type 1 receptor activity. Angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7) and angiotensin I to angiotensin-(1-9). Angiotensin-(1-7) antagonizes angiotensin II actions via the receptor Mas. Angiotensin-(1-9) was shown recently to block cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Here, we investigated in vivo effects of angiotensin-(1-9) via the angiotensin type 2 receptor. Angiotensin-(1-9) (100 ng/kg per minute) with or without the angiotensin type 2 receptor antagonist PD123 319 (100 ng/kg per minute) or PD123 319 alone was infused via osmotic minipump for 4 weeks into stroke-prone spontaneously hypertensive rats. We measured blood pressure by radiotelemetry and cardiac structure and function by echocardiography. Angiotensin-(1-9) did not affect blood pressure or left ventricular mass index but reduced cardiac fibrosis by 50% (P<0.01) through modulating collagen I expression, reversed by PD123 319 coinfusion. In addition, angiotensin-(1-9) inhibited fibroblast proliferation in vitro in a PD123 319-sensitive manner. Aortic myography revealed that angiotensin-(1-9) significantly increased contraction to phenylephrine compared with controls after N-nitro-l-arginine methyl ester treatment, an effect abolished by PD123 319 coinfusion (area under the curve: angiotensin-(1-9) N-nitro-l-arginine methyl ester=98.9±11.8%; control+N-nitro-l-arginine methyl ester=74.0±10.4%; P<0.01), suggesting that angiotensin-(1-9) improved basal NO bioavailability in an angiotensin type 2 receptor-sensitive manner. In summary, angiotensin-(1-9) reduced cardiac fibrosis and altered aortic contraction via the angiotensin type 2 receptor supporting a direct role for angiotensin-(1-9) in the renin-angiotensin system.


Subject(s)
Angiotensin I/pharmacology , Heart/drug effects , Hypertension/complications , Hypertension/physiopathology , Myocardium/pathology , Peptide Fragments/pharmacology , Receptor, Angiotensin, Type 2/physiology , Stroke/prevention & control , Angiotensin II Type 2 Receptor Blockers/pharmacology , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Cell Proliferation/drug effects , Cells, Cultured , Disease Models, Animal , Echocardiography , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Fibroblasts/cytology , Fibroblasts/drug effects , Fibrosis , Heart/physiology , Imidazoles/pharmacology , In Vitro Techniques , Male , Pyridines/pharmacology , Rats , Receptor, Angiotensin, Type 2/drug effects , Renin-Angiotensin System/physiology
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