ETA receptors in the gerbil spiral modiolar artery

A reduction of blood flow in the spiral modiolar artery (SMA), which supplies the cochlea, is implicated in hearing loss and tinnitus. Endothelins are known to be the most potent endogenous vasoconstrictors. The purpose of the present study was to determine whether the SMA responds to endothelin, which receptor type is present and which signal transduction pathway is involved. The SMA was isolated from the gerbil cochlea by microdissection and superfused in a bath chamber on the stage of an inverted microscope. The vascular diameter was measured by video microscopy, and the cytosolic Ca2+ concentration was monitored simultaneously by fluo-4 fluorescence microscopy. ET-1 and ET-3 caused a dose-dependent vasoconstriction with ET-1 being the more potent agonist. The agonist sarafotoxin S6c had no significant effect. The preferential ET(A) receptor antagonist BQ123 had a higher affinity inhibiting the ET-1-induced vasoconstriction than the preferential ET(B) receptor antagonist BQ788. The ET-1-induced vasoconstriction was prevented by inhibition of phospholipase C with U73122. Blockade of the inositol 1,4,5-trisphosphate (IP3) receptor on the sarcoplasmic reticulum Ca2+ stores with 2-aminoethoxydiphenyl borate and depletion of Ca2+ stores by inhibition of the sarcoplasmic Ca2+-ATPase with thapsigargin prevented ET-1-induced cytosolic Ca2+ increase and reduced the ET-1-induced vasoconstriction. These results demonstrate that endothelin causes a vasoconstriction of the SMA, which is mediated via ET(A) receptors. The data suggest that the signal transduction pathway of the ET(A) receptor involves phospholipase C, IP3 receptors and release of Ca2+ from thapsigargin-sensitive Ca2+ stores.