VASORELAXANT EFFECTS INDUCED BY THE ANTIANGIOGENIC DRUG LINOMIDE IN AORTIC AND SAPHENOUS-VEIN PREPARATIONS OF THE RABBIT

Citation
S. Amerini et al., VASORELAXANT EFFECTS INDUCED BY THE ANTIANGIOGENIC DRUG LINOMIDE IN AORTIC AND SAPHENOUS-VEIN PREPARATIONS OF THE RABBIT, British Journal of Pharmacology, 122(8), 1997, pp. 1739-1745
Citations number
24
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00071188
Volume
122
Issue
8
Year of publication
1997
Pages
1739 - 1745
Database
ISI
SICI code
0007-1188(1997)122:8<1739:VEIBTA>2.0.ZU;2-X
Abstract
1 Linomide -4-hydroxyl-1-methyl-2-oxoquinoline-3-carboxamide) inhibits vascular proliferation and has been proposed as an antiangiogenic dru g. We have investigated the vascular effect of linomide in rabbit aort ic and saphenous vein ring preparations and in rat cultured vascular s mooth muscle cells (VSMCs). 2 Linomide (25-300 mu g ml-(1)) did not al ter the basal tone of the preparations. The drug induced a concentrati on-dependent relaxant effect in aortic rings with endothelium, precons tricted by noradrenaline (NA), 5-hydroxytryptamine (5-HT) and by the t hromboxane mimetic U46619. 3 The degree of relaxation induced by linom ide was significantly reduced by exposure to the cyclooxygenase inhibi tors indomethacin (3 mu M) and acetylsalicylic acid (500 mu M), and wa s not influenced by pretreatment with the nitric oxide synthase inhibi tor N-G-nitro-L-arginine methyl ester (L-NAME) (100 mu M) in aortic ri ngs with endothelium, preconstricted with NA. 4 Endothelium removal si gnificantly reduced the relaxant response to linomide in aortic ring p reparations. 5 A concentration-dependent relaxant response was observe d also in rabbit saphenous vein preparations deprived of endothelium a nd preconstricted either by NA or U46619. The degree of relaxation obt ained in a high potassium solution was consistently smaller than that observed in NA-pretreated venous preparations. 6 The vasorelaxant effe ct of linomide was consistently blunted by the adenylate cyclase inhib itor SQ 22536 (50 mu M), both in intact aortic rings and in those depr ived of endothelium. 7 In rat cultured vascular smooth muscle cells, l inomide (100-200 mu g ml(-1)) induced a significant increase in cyclic AMP levels, which was blocked by exposure to 50 mu M SQ 22536. 8 In e ndothelium-deprived aortic ring preparations, the linomide-induced rel axant effect was greatly reduced in high potassium medium (KCl=25 mM). Pretreatment with the ATP potassium channel inhibitor glibenclamide ( 3 mu M) significantly reduced the linomide-induced relaxation. 9 The r esults show that linomide possesses a vasorelaxant effect which is att ributable to both endothelium-dependent and -independent properties. W hile the former component of the drug's activity is apparently due to the release of a prostanoid from endothelial cells, the endothelium-in dependent mechanism involved in linomide relaxation is linked to cycli c AMP accumulation and to ATP-sensitive potassium channel activation i n VSMCs.