Abstract

We investigated the effects of the angiotensin II (Ang II) type 1 receptor (AT₁) antagonist KRH-594 on levels of the mRNAs for AT_1A, AT_1B, platelet-derived growth factor-receptor β (PDGF-Rβ), and extracellular matrix (ECM)-related genes using the competitive reverse transcription-polymerase chain reaction (RT-PCR) method and on neointimal formation in the balloon-injured rat carotid artery. The mRNA levels for AT_1A and PDGF-Rβ, but not for AT_1B, increased from day 3 after injury to day 14. KRH-594 administered orally at 3 and 10 mg/kg/day significantly suppressed these increases. KRH-594 (10 mg/kg/day) also suppressed the injury-induced gene expressions for transforming growth factor-β₁ and fibronectin and reduced collagen α1(I) and α1(III) mRNA levels for the first 7 days after injury. KRH-594 (10 and 30 mg/kg/day) significantly and dose-dependently reduced the neointimal area in cross sections of the artery 14 days after injury. Another AT₁ antagonist, TCV-116 (candesartan cilexetil; 1 and 3 mg/kg/day p.o.), had similar effects on the morphological change and AT_1A mRNA level, whereas a smooth muscle relaxant, hydralazine (10 mg/kg/day p.o.), did not. These results indicate that up-regulation of AT_1A, PDGF-Rβ, and ECM-related genes in the balloon-injured carotid artery is in part an AT₁-mediated phenomenon and that prevention of receptor up-regulation may contribute to the attenuating effects of AT₁ antagonists on neointimal formation after injury.