Differential desensitization of Ca2+ mobilization and vasoconstriction by ET(A) receptors in the gerbil spiral modiolar artery

• Published in: The Journal of membrane biology 2001-08, Vol.182 (3), p.183-191
• Main Authors: Scherer, E Q, Wonneberger, K, Wangemann, P
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Arteries - metabolism; Boron Compounds - pharmacology; Calcium - metabolism; Calcium Signaling - physiology; Cochlea - blood supply; Cochlea - drug effects; Cytophotometry - instrumentation; Cytophotometry - methods; Endothelin Receptor Antagonists; Endothelin-1 - pharmacology; Enzyme Inhibitors - pharmacology; Gerbillinae; Microscopy, Video - instrumentation; Microscopy, Video - methods; Oligopeptides - pharmacology; Peptides, Cyclic - pharmacology; Piperidines - pharmacology; Receptor, Endothelin A; Receptors, Endothelin - metabolism; Thapsigargin - pharmacology; Vasoconstriction - physiology; Vasoconstrictor Agents - pharmacology; Viper Venoms - pharmacology
• ISSN: 0022-2631

Endothelins are known to be among the most potent endogenous vasoconstrictors. Vasoconstriction of the spiral modiolar artery, which supplies the cochlea, may be implicated in hearing loss and tinnitus. The purpose of the present study was to determine whether the spiral modiolar artery responds to endothelin, whether a change in the cytosolic Ca2+ concentration ([Ca2+]i) mediates the response and which endothelin receptors are present. The vascular diameter and [Ca2+]i were measured simultaneously by videomicroscopy and microfluorometry in the isolated spiral modiolar artery from the gerbil. ET-1 induced a transient [Ca2+]i increase and a strong and long-lasting vasoconstriction. The transient [Ca2+]i increase underwent rapid desensitization, was independent of extracellular Ca2+ and inhibited by the IP3-receptor blocker (75 microm) 2-aminoethoxydiphenyl borate (2-APB) and by depletion of Ca2+ stores with 10(-6) m thapsigargin. In contrast, the vasoconstriction displayed no comparable desensitization. The initial vasoconstriction was independent of extracellular Ca2+ but maintenance of the constriction depended on the presence of extracellular Ca2+. The half-maximal concentration values (EC50) for the agonists ET-1, ET-3 and sarafotoxin S6c were 0.8 nm, >10 nm and >100 nm, respectively. Affinity constants for the antagonists BQ-123 and BQ-788 were 24 nm and 77 nm, respectively. These observations demonstrate that ET-1 mediates a vasoconstriction of the gerbil spiral modiolar artery via ETA receptors and an IP3 receptor-mediated release of Ca2+ from thapsigargin-sensitive Ca2+ stores. The marked difference in desensitization between Ca2+ mobilization and vasoconstriction suggests that Ca2+ mobilization is not solely responsible for the vasoconstriction and that other signaling mechanisms must be present.