Jin D, Takai S, Shiota N, Miyazaki M
Department of Pharmacology, Osaka Medical College, Takatsuki, Japan.
Eur J Pharmacol. 1998 Nov 20;361(2-3):199-205. doi: 10.1016/s0014-2999(98)00740-7.
N-(3',4'-dimethoxycinnamoyl) anthranilic acid (tranilast), an effective anti-allergic drug, has successfully prevented restenosis in patients who have undergone percutaneous transluminal coronary angioplasty. To elucidate the mechanism of tranilast, we investigated its antagonistic effect to angiotensin II, which plays a pivotal role in the proliferation of vascular smooth muscle cells, using angiotensin II-induced contractions in human gastroepiploic artery and rabbit aorta. The possible antagonistic effects of other anti-allergic agents such as 4-( p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthal azinone hydrochloride (azelastine), 9-methyl-3-( 1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyramidin-4-one potassium salt (pemirolast) and disodium cromoglycate were also compared. Tranilast dose-dependently inhibited the angiotensin II-induced contractions in human and rabbit arteries (IC50 = 3.6x10(-5) M and pD'2 = 3.69, respectively). Pemirolast showed a weak antagonistic effect to angiotensin II, but the effective concentration cannot be administered in clinical dosage. Tranilast and pemirolast had no effect on the concentration-contractile response curves for KCI and norepinephrine. Azelastine inhibited angiotensin II-, KCl- and norepinephrine-induced contractions non-specifically, while disodium cromoglycate did not affect these contractile responses. Tranilast but not azelastine showed synergistic action with 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole-7-carboxylic acid (CV- 11974) in antagonizing angiotensin II-induced contraction and the inhibitory pattern was similar to that of the non-peptide angiotensin II AT1 receptor antagonist CV-11974. These findings indicate that only tranilast possesses the unique ability to antagonize angiotensin II in clinical dosage, which may contribute at least in part to prevention of restenosis after percutaneous transluminal coronary angioplasty.
N-(3',4'-二甲氧基肉桂酰)邻氨基苯甲酸（曲尼司特）是一种有效的抗过敏药物，已成功预防了接受经皮腔内冠状动脉成形术患者的再狭窄。为阐明曲尼司特的作用机制，我们利用人胃网膜动脉和兔主动脉中血管紧张素II诱导的收缩，研究了其对血管紧张素II的拮抗作用，血管紧张素II在血管平滑肌细胞增殖中起关键作用。还比较了其他抗过敏药物如盐酸4-(对氯苄基)-2-(六氢-1-甲基-1H-氮杂卓-4-基)-1(2H)-酞嗪酮（氮卓斯汀）、9-甲基-3-(1H-四氮唑-5-基)-4H-吡啶并[1,2-a]嘧啶-4-酮钾盐（吡嘧司特）和色甘酸二钠的可能拮抗作用。曲尼司特剂量依赖性地抑制人及兔动脉中血管紧张素II诱导的收缩（IC50分别为3.6×10(-5)M和pD'2为3.69）。吡嘧司特对血管紧张素II显示出较弱的拮抗作用，但有效浓度无法以临床剂量给药。曲尼司特和吡嘧司特对氯化钾和去甲肾上腺素的浓度-收缩反应曲线无影响。氮卓斯汀非特异性地抑制血管紧张素II、氯化钾和去甲肾上腺素诱导的收缩，而色甘酸二钠不影响这些收缩反应。曲尼司特而非氮卓斯汀在拮抗血管紧张素II诱导的收缩方面与2-乙氧基-1-[[2'-(1H-四氮唑-5-基)联苯-4-基]甲基]-1H-苯并咪唑-7-羧酸（CV-11974）表现出协同作用，且抑制模式与非肽类血管紧张素II AT1受体拮抗剂CV-11974相似。这些发现表明，只有曲尼司特在临床剂量下具有拮抗血管紧张素II的独特能力，这可能至少部分有助于预防经皮腔内冠状动脉成形术后的再狭窄。
