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Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor

Research output: Contribution to journalArticle

  • Monica Flores-Munoz
  • Lorraine M Work
  • Kirsten Douglas
  • Laura Denby
  • Anna F Dominiczak
  • Delyth Graham
  • Stuart A Nicklin

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Original languageEnglish
Pages (from-to)300-7
Number of pages8
Issue number2
Publication statusPublished - Feb 2012


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.

    Research areas

  • Angiotensin I, Angiotensin II Type 2 Receptor Blockers, Animals, Blood Pressure, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Echocardiography, Endothelium, Vascular, Fibroblasts, Fibrosis, Heart, Hypertension, Imidazoles, In Vitro Techniques, Male, Myocardium, Peptide Fragments, Pyridines, Rats, Receptor, Angiotensin, Type 2, Renin-Angiotensin System, Stroke

ID: 23493821