Endothelium-dependent noradrenergic hyperresponsiveness induced by thapsigargin in human saphenous veins: role of thromboxane and calcium.
To further investigate the mechanisms which regulate sympathetic vascular tone, we studied the effects of the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, thapsigargin, on the vasoconstriction induced by transmural nerve stimulation and noradrenaline in superfused human saphenous vein rings. The contractions induced by both transmural nerve stimulation and noradrenaline were potentiated by thapsigargin in endothelium-intact, but not in endothelium-denuded vessels. This potentiation was unaffected by the non-selective endothelin ET(A/B) receptor antagonist, Ro 47-0203 (4-tert-Butyyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4yl]benzene sulfonamide), or by the nitric oxide (NO) synthase inhibitor, L-NNA (N(omega)-nitro-L-arginine), but was inhibited by the thromboxane A(2) receptor antagonist, Bay u3405 (3(R)-[[(4-flurophenyl) sulphonyl]amino-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid]) or by the thromboxane A(2) synthase inhibitor, UK 38485 (3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid). Moreover, the thapsigargin-induced noradrenergic hyperresponsiveness, as well as that produced by subthreshold concentrations of the thromboxane A(2) mimetic, U 46619, were blocked by the Ca(2+) channel antagonist, verapamil. In conclusion, our results indicate that thapsigargin enhances the contractions produced by sympathetic nerve stimulation in human saphenous vein rings through the endothelial release of thromboxane A(2) that potentiates the vasoconstriction induced by the noradrenergic mediator with a verapamil-sensitive mechanism.
Fabi
Fulvia
F
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Di Maio
Giuseppe
G
Musumeci
Francesco
F
del Basso
Paola
P
D000704:Analysis of Variance; D002118:Calcium / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D009638:Norepinephrine / Q000494:pharmacology; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D013928:Thromboxane A2; D019284:Thapsigargin; D002118:Calcium; D009638:Norepinephrine