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Vasorelaxant effects induced by the antiangiogenic drug linomide in aortic and saphenous vein preparations of the rabbit
Author(s) -
Amerini Sandra,
Filippi Sandra,
Parenti Astrid,
Ledda Fabrizio,
Ziche Marina
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701565
Subject(s) - nitric oxide , vascular smooth muscle , endothelium , medicine , vasodilation , pharmacology , blood vessel , circulatory system , endocrinology , chemistry , smooth muscle
1 Linomide (N‐phenylmethyl‐1,2‐dihydro‐4‐hydroxyl‐1‐methyl‐2‐oxoquinoline‐3‐carboxamide) inhibits vascular proliferation and has been proposed as an antiangiogenic drug. We have investigated the vascular effect of linomide in rabbit aortic and saphenous vein ring preparations and in rat cultured vascular smooth muscle cells (VSMCs). 2 Linomide (25–300 μg ml −1 ) did not alter the basal tone of the preparations. The drug induced a concentration‐dependent relaxant effect in aortic rings with endothelium, preconstricted by noradrenaline (NA), 5‐hydroxytryptamine (5‐HT) and by the thromboxane mimetic U46619. 3 The degree of relaxation induced by linomide was significantly reduced by exposure to the cyclo‐oxygenase inhibitors indomethacin (3 μ m ) and acetylsalicylic acid (500 μ m ), and was not influenced by pretreatment with the nitric oxide synthase inhibitor N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME) (100 μ m ) in aortic rings with endothelium, preconstricted with NA. 4 Endothelium removal significantly reduced the relaxant response to linomide in aortic ring preparations. 5 A concentration‐dependent relaxant response was observed also in rabbit saphenous vein preparations deprived of endothelium and preconstricted either by NA or U46619. The degree of relaxation obtained in a high potassium solution was consistently smaller than that observed in NA‐pretreated venous preparations. 6 The vasorelaxant effect of linomide was consistently blunted by the adenylate cyclase inhibitor SQ 22536 (50 μ m ), both in intact aortic rings and in those deprived of endothelium. 7 In rat cultured vascular smooth muscle cells, linomide (100–200 μg ml −1 ) induced a significant increase in cyclic AMP levels, which was blocked by exposure to 50 μ m SQ 22536. 8 In endothelium‐deprived aortic ring preparations, the linomide‐induced relaxant effect was greatly reduced in high potassium medium (KCl=25 m m ). Pretreatment with the ATP potassium channel inhibitor glibenclamide (3 μ m ) significantly reduced the linomide‐induced relaxation. 9 The results show that linomide possesses a vasorelaxant effect which is attributable to both endothelium‐dependent and ‐independent properties. While the former component of the drug's activity is apparently due to the release of a prostanoid from endothelial cells, the endothelium‐independent mechanism involved in linomide relaxation is linked to cyclic AMP accumulation and to ATP‐sensitive potassium channel activation in VSMCs.