ET-1-associated vasomotion and vasospasm in lymphatic vessels of the guinea-pig mesentery.
In vitro experiments were performed to investigate the actions of endothelin-1 (ET-1) on vasomotion and vasospasm in guinea-pig mesenteric lymphatics. ET-1 modulated lymphatic vasomotion independent of the endothelium, with lower concentrations (<or=10 nm) increasing lymphatic vasomotion and higher concentrations (>or=100 nm) causing vasospasm. ET-1-induced increases in vasomotion were accompanied by an increase in tonic [Ca2+]i. These actions were inhibited by the ETA receptor antagonist BQ-123 (1 microm), the phospholipase C (PLC) inhibitor U73122 (5 microm), removal of extracellular Ca2+, chelation of intracellular Ca2+ with BAPTA/AM (10 microm), the store Ca2+-ATPase inhibitor thapsigargin (1 microm), caffeine (10 mm) and the inositol 1,4,5-trisphosphate (IP3) receptor blocker heparin and 2-APB (30 microm). In contrast, the ETB receptor antagonist BQ-788 (1 microm), ryanodine (1 & 20 microm), pertussis toxin (PTx) or Cs+ had no significant actions on vasomotion or the magnitude of increase in tonic [Ca2+]i. ET-1-induced vasospasm was accompanied by a transient increase in smooth muscle [Ca2+]i followed by a sustained plateau, an action that was abolished by removal of extracellular Ca2+, but only marginally inhibited by nifedipine (1 microm). Caffeine (10 mm), SKF 96165 (30 microm) or U73122 (5 microm) together with nifedipine (1 microm) abolished ET-1-induced vasospasm and increase in [Ca2+]i. These results indicate that ET-1 increases lymphatic vasomotion by acting on smooth muscle ETA receptors and activation of G-protein-PLC-IP3 cascade, which is known to cause pacemaker Ca2+ release and resultant pacemaker potentials. High concentrations of ET-1 cause a failure in Ca2+ homeostasis causing vasospasm, triggered by excessive Ca2+ influx primarily through store-operated channels (SOCs) with l-Ca2+ voltage-operated channels (VOCs) also contributing, but to a much lesser extent.
Zhao
Jun
J
The Neuroscience Group, Discipline of Human Physiology, The School of Biomedical Sciences, Faculty of Medicine and Health Sciences, The University of Newcastle, Room MS 405, Callaghan, NSW 2308, Australia.
van Helden
Dirk F
DF
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D004729:Endothelium, Lymphatic / Q000502:physiology; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D042601:Lymphatic Vessels / Q000187:drug effects* / Q000502:physiology; D008643:Mesentery / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D044022:Receptor, Endothelin A / Q000502:physiology; D015398:Signal Transduction
D002121:Calcium Channel Blockers; D019332:Endothelin-1; D007093:Imidazoles; D007295:Inositol Phosphates; D044022:Receptor, Endothelin A; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium