Abstract
We investigated the effects of the angiotensin II (Ang II) type 1 receptor (AT1) antagonist KRH-594 on levels of the mRNAs for AT1A, AT1B, 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 AT1A and PDGF-Rβ, but not for AT1B, 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 AT1A mRNA level, whereas a smooth muscle relaxant, hydralazine (10 mg/kg/day p.o.), did not. These results indicate that up-regulation of AT1A, 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.
Footnotes
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Send reprint requests to: Tokio Nakane, M.D., Department of Pharmacology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
- Abbreviations:
- ACE
- angiotensin-converting enzyme
- Ang II
- angiotensin II
- AT1
- angiotensin II type 1 receptor
- AT1A
- angiotensin II type 1A receptor
- AT1B
- angiotensin II type 1B receptor
- AT2
- angiotensin II type 2 receptor
- ECM
- extracellular matrix
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- PCR
- polymerase chain reaction
- PDGF-Rβ
- platelet-derived growth factor-receptor β
- RAS
- renin-angiotensin system
- RT
- reverse transcription
- TGF-β1
- transforming growth factor-β1
- VSMC
- vascular smooth muscle cell
- Received May 13, 1998.
- Accepted September 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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