Endothelium is required in the vascular spasm induced by tetraethylammonium and endothelin-1 in guinea-pig aorta.
1. 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 mM) or elevated (50 mM) glucose concentration. 2. 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 mM) induced a sustained tonic contraction, followed by a phasic spasm, characterized by rhythmic contractions. Elevated glucose, ET-1 (3 nM), or both, reduced the EC50 of TEA-induced tonic contraction, without modifying the maximum contractile effect. 3. 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 ETA antagonist, EMD94246, 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. 4. 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. 5. 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.
Dorigo
P
P
Department of Pharmacology, Padova University, Italy.
Maragno
I
I
Santostasi
G
G
Fraccarollo
D
D
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001018:Aortic Diseases / Q000139:chemically induced* / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D012110:Reserpine / Q000494:pharmacology; D019789:Tetraethylammonium
D018759:Adrenergic Uptake Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D019789:Tetraethylammonium; D012110:Reserpine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester