Tranilast, an anti-allergic drug, possesses antagonistic potency to angiotensin II.
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.
Jin
D
D
Department of Pharmacology, Osaka Medical College, Takatsuki, Japan.
Takai
S
S
Shiota
N
N
Miyazaki
M
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D001011:Aorta; D001158:Arteries; D004205:Cromolyn Sodium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D057911:Angiotensin Receptor Antagonists; D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D006633:Histamine Antagonists; D011725:Pyridines; D011744:Pyrimidinones; D062367:ortho-Aminobenzoates; D000804:Angiotensin II; C055139:pemirolast; D011189:Potassium Chloride; C012293:tranilast; D004205:Cromolyn Sodium; D009638:Norepinephrine