Effects of AT 1 and AT 2 Angiotensin Receptor Antagonists in Angiotensin II-Infused Rats

Abstract

Angiotensin II (Ang II) appears to exert its contractile and growth-promoting effects through the AT ₁ receptor subtype, whereas the AT ₂ subtype may have growth-inhibitory and proapoptotic properties. Recently, some data have challenged this emerging concept. To clarify the role of AT ₁ and AT ₂ receptors, we treated Wistar rats that were infused with Ang II (120 ng/kg/min subcutaneously by osmotic minipump), with the AT ₁ antagonist losartan (10 mg/kg/d in the drinking water) and the AT ₂ antagonist PD123319 (30 mg/kg/d subcutaneously by osmotic minipump) for 21 days. At the end of the study, tail-cuff systolic blood pressure was 106±2.8 mm Hg in untreated rats and 108±2.0 mm Hg in rats infused with Ang II that received losartan, whereas it rose to 158±4.9 mm Hg in Ang II-infused rats and 158±3.0 mm Hg in rats infused with Ang II rats and PD123319 (the two latter groups P <.01 versus the two other groups). Heart weight, and aorta cross-section/body weight ratio were higher in Ang II-infused rats than in controls and were significantly reduced in Ang II-infused rats that received losartan ( P <.05). Wire-myograph-mounted coronary, renal, mesenteric, and femoral small arteries from Ang II-infused rats and Ang II-infused rats receiving PD123319 had a greater media, media cross-section, and media/lumen ratio than vessels from untreated or Ang II-infused rats treated with losartan. These results support the concept that in Wistar normotensive rats infused for 3 weeks with angiotensin II, growth in the heart, aorta, and coronary, renal, mesenteric, and femoral small arteries is mediated by the AT ₁ receptor; the results show little evidence of a role of AT ₂ receptors in mediating angiotensin II effects in this experimental paradigm.