Endothelium is required in the vascular spasm induced by tetraethylammonium and endothelin‐1 in guinea‐pig aorta

To investigate the role of endothelium in vascular spasm, we studied the influence of endothelin‐1 (ET‐1) on the contracting and spasmogenic effect of the K + ‐channel blocker, tetraethylammonium (TEA), in aorta rings of reserpine‐treated guinea‐pigs, perfused with either control (5.5 m M ) or elevated (50 m M ) glucose concentration. Endothelium‐dependent relaxation induced by acetylcholine was lost in rings contracted by noradrenaline in the presence of elevated glucose. In control medium, TEA (1–20 m M ) induced a sustained tonic contraction, followed by a phasic spasm, characterized by rhythmic contractions. Elevated glucose, ET‐1 (3 n M ), or both, reduced the EC 50 of TEA‐induced tonic contraction, without modifying the maximum contractile effect. In control medium, ET‐1 reduced the time before TEA‐induced spasm and increased the rate of rhythmic contractions. TEA‐induced spasm was abolished by elevated glucose, and restored by ET‐1. The spasm induced by TEA and ET‐1 was amplified by the ET A antagonist, EMD 94246 , and suppressed by the ET A ‐ET B antagonist, bosentan. In endothelium‐denuded vessels incubated with high glucose and ET‐1, TEA evoked only a tonic contraction. In control medium, L ‐NAME (N G ‐nitro‐ L ‐arginine methyl ester) abolished TEA‐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‐induced spasm was not affected by L ‐NAME, whereas verapamil, indomethacin, metyrapone, glybenclamide or apamin abolished the phasic spasm, unmasking the tonic contracture. In conclusion, endothelium plays a regulatory role in the genesis and maintenance of TEA‐induced rhythmic contractions, through the release endothelium derived relaxing factor and vasodilating eicosanoids.British Journal of Pharmacology (1999) 127 , 505–513; doi: 10.1038/sj.bjp.0702557