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

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.

• Authors: Monica Flores-Munoz, Lorraine M Work, Kirsten Douglas, Laura Denby, Anna F Dominiczak, Delyth Graham, Stuart A Nicklin
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 59 Issue 2 Pg. 300-7 (Feb 2012) ISSN: 1524-4563 [Electronic] United States
• PMID: 22184331 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 2 Receptor Blockers
• Imidazoles
• Peptide Fragments
• Pyridines
• Receptor, Angiotensin, Type 2
• angiotensin I (1-9)
• PD 123319
• Angiotensin I

Topics

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