Jpn. J. Pharmacol. 77 (2), 117-128 (1998)

NK-104, a Newly Developed HMG-CoA Reductase Inhibitor, Suppresses Neointimal Thickening by Inhibiting Smooth Muscle Cell Growth and Fibronectin Production in Balloon-Injured Rabbit Carotid Artery

Masaki Kitahara (1), Tatsuro Kanaki (1), Kyomi Toyoda (1), Chie Miyakoshi (1), Sakuya Tanaka (1), Taro Tamaki (2) and Yasushi Saito (3)

(1) Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Shiraoka-Machi, Minamisaitama, Saitama 349-0294, Japan
(2) Tokyo Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43 Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
(3) The Second Department of Internal Medicine, School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba 260-0856, Japan

Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress smooth muscle cell growth and arterial neointimal thickening. In this study, to elucidate the potency and mechanisms of NK-104 ((+)-monocalcium bis{(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}, CAS 147526-32-7) in neointimal thickening, the effect of NK-104 on the neointimal thickening, Br-dU-labeled cell number and extracellular matrix immunohistochemistry were examined in balloon-injured rabbit carotid artery. NK-104 suppressed the neointimal thickening dose-dependently, and the suppression was 69.5% at 1.0 mg/kg. NK-104 suppressed the intimal total and Br-dU-labeled cell number. Fibronectin and type I collagen were observed in 81% and 38% of the total intimal area in the control arteries, respectively, and the areas occupied by fibronectin and type I collagen were significantly decreased by 1.0 mg/kg NK-104 to 39% and 22%, respectively. The decrease in fibronectin per cell was more potently demonstrated. Aortic total and activated TGF-beta contents that were markedly increased in the injured artery were increased further by NK-104. NK-104 concentration-dependently suppressed fibronectin content of the basement lesion in rabbit primary cultured smooth muscle cells. These findings suggest that NK-104 suppresses balloon-injury-induced neointimal thickening through inhibition of intimal smooth muscle cell growth and extracellular matrix accumulation.

Keywords: NK-104, Atherosclerosis, Smooth muscle cell, Growth, Extracellular matrix

Copyrightę The Japanese Pharmacological Society 1998

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