P. Dorigo et al., Endothelium is required in the vascular spasm induced by tetraethylammonium and endothelin-1 in guinea-pig aorta, BR J PHARM, 127(2), 1999, pp. 505-513
1 To investigate the role of endothelium in vascular spasm, we studied the
influence of endothelial (ET-1) on the contracting and spasmogenic effect o
f the K+-channel blocker, tetraethylammonium (TEA), in aorta rings of reser
pine-treated guinea-pigs, perfused with either control (5.5 mM) or elevated
(50 mM) glucose concentration.
2 Endothelium-dependent relaxation induced by acetylcholine was lost in rin
gs contracted by noradrenaline in the presence of elevated glucose. In cont
rol medium, TEA (1-20 mM) induced a sustained tonic contraction, followed b
y a phasic spasm, characterized by rhythmic contractions. Elevated glucose,
ET-1 (3 nM), or both, reduced the EC50 of TEA-induced tonic contraction, w
ithout modifying the maximum contractile effect.
3 In control medium, ET-1 reduced the time before TEA-induced spasm and inc
reased the rate of rhythmic contractions. TEA-induced spasm was abolished b
y elevated glucose, and restored by ET-1. The spasm induced by TEA and ET-I
was amplified by the ETA antagonist, EMD94246, and suppressed by the ETA-E
TB antagonist, bosentan. In endothelium-denuded vessels incubated with high
glucose and ET-I, TEA evoked only a tonic contraction.
4 In control medium, L-NAME (N-G-nitro-L-arginine methyl ester) abolished T
EA-induced rhythmic contractions. L-arginine, but not D-arginine, prevented
the effect of L-NAME. In the presence of elevated glucose and ET-1, TEA-in
duced spasm was not affected by L-NAME, whereas verapamil, indomethacin, me
tyrapone, glybenclamide or apamin abolished the phasic spasm, unmasking the
tonic contracture.
5 In conclusion, endothelium plays a regulatory role in the genesis and mai
ntenance of TEA-induced rhythmic contractions, through the release endothel
ium derived relaxing factor and vasodilating eicosanoids.