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
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.