Journal
HYPERTENSION
Volume 59, Issue 2, Pages 300-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.111.177485
Keywords
renin-angiotensin system; angiotensin-(1-9); cardiac fibrosis; angiotensin type 2 receptor; stroke-prone spontaneously hypertensive rat
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Funding
- University of Glasgow
- CONACYT (Consejo Nacional de Ciencia y Technologia)
- BHF (British Heart Foundation) Chair [CH98001]
- BHF [RG1071005]
- BBSRC (Biotechnology and Biological Sciences Research Council)
- BPS (British Pharmacological Society)
- KTN (Knowledge Transfer Network)
- MRC (Medical Research Council)
- SFC (Scottish Funding Council)
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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. (Hypertension. 2012; 59: 300-307.). Online Data Supplement
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