Abstract-We administered angiotensin II (Ang II) receptor type 1 (AT 1 ) blockade (losartan, 40 mg ⅐ kg Ϫ1 ⅐ d
Ϫ1), type II receptor (AT 2 ) blockade (PD123319, 100 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ), or angiotensin-converting enzyme (ACE) inhibitor (enalapril, 30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age. Control SHR and Wister-Kyoto rats (WKY) received a placebo for the same period. At the end of treatment, losartan and enalapril were both found to have significantly reduced the arterial systolic blood pressure and the collagen concentration to the level of WKY, whereas PD123319 had no effect. Enalapril and PD123319 significantly reduced the media cross-sectional area of the aorta in comparison to that of untreated SHR, which was still larger than that of the WKY; however, losartan did not change it. Using reverse transcription-polymerase chain reaction, we next examined the mRNA expressions for ACE, AT 1 receptor, and AT 2 receptor in experimental animals. We observed significantly enhanced mRNA expression for AT 1 and AT 2 receptors and ACE in untreated SHR compared with WKY. The AT 1 mRNA level was also significantly decreased in the SHR treated with either losartan or enalapril, whereas the AT 2 mRNA level was significantly decreased in the SHR treated with either PD123319 or enalapril in comparison to untreated SHR. The level of ACE mRNA was significantly decreased only in the SHR treated with enalapril. These results indicate that AT 1 receptor, but not AT 2 receptor, plays a crucial role in the remodeling of matrix tissue, while AT 2 receptor may play a role in the development of hypertrophy of smooth muscle in aorta in SHR, and that the reduction of hypertrophy of smooth muscle does not fully account for the suppression of hypertension. (Hypertension. 1998;32:467-472.) Key Words: angiotensin II Ⅲ receptors, angiotensin Ⅲ hypertrophy, vascular Ⅲ collagen Ⅲ rats, inbred SHR L ong-term hypertension is reported to be associated with cardiovascular remodeling, which consists of cardiovascular hypertrophy and an increase in the extracellular matrix (especially collagen).1,2 In spontaneously hypertensive rats (SHR), both left ventricular hypertrophy and the properties of characteristic vascular resistance are already present early in life, based on the results of a comparison with normotensive Wister-Kyoto rats (WKY).3,4 Angiotensin-converting enzyme (ACE) inhibitors can lower the blood pressure in SHR mainly by reducing the production of angiotensin II (Ang II).5 Ang II is considered to act as a growth-promoting factor in aortic smooth muscle cells, 6,7 while it also increases collagen synthesis in smooth muscle cells.8 ACE inhibitors suppress such vascular remodeling in experimental models, possibly through blood pressure-independent mechanisms. 9,10 Recently, a selective Ang II receptor antagonist has been developed that inhibits the renin-angiotensin system (RAS) more specifically than ACE inhibitors. Two main Ang II receptor subtypes, AT 1 and AT 2 , have been identified, a...