Endothelin receptors in lower esophageal sphincter circular smooth muscle.
To characterize endothelin (ET) receptors in the lower esophageal sphincter, we measured contraction of transverse strips from the guinea-pig lower esophageal sphincter induced by ET-related peptides and binding of 125I-ET-1 to cell membranes prepared from the lower esophageal sphincter circular muscle. Visualization of 125I-ET-1 binding sites in tissue was performed by autoradiography. ET-1 or ET-2 alone did not cause contraction or relaxation in resting strips. However, in carbachol precontracted lower esophageal sphincter strips, ET-1 and ET-2 caused marked, tetrodotoxin-insensitive relaxation. The ET-1-induced relaxation was abolished by BQ-123, an ETA receptor selective antagonist, but not inhibited by BQ-788, an ETB receptor selective antagonist. ET-3 and sarafotoxin S6c, a selective ETB receptor agonist, did not cause relaxation in the carbachol precontracted muscle strips. These clearly indicate that ETA receptors mediate relaxation. On the other hand, ET-3 and sarafotoxin S6c caused tetrodotoxin and atropine-insensitive contraction in the resting strips. The sarafotoxin S6c-induced contraction was inhibited by BQ-788, but not by BQ-123. Furthermore, ET-1 and ET-2 caused contraction of the resting muscle strips after pretreatment with BQ-123. This ET-1-induced contraction was also inhibited by BQ-788. Taken together, these indicate that ETB receptors mediate contraction. Autoradiography localized 125I-ET-1 binding to the lower esophageal sphincter circular muscle as well as longitudinal muscle of the esophagus. Binding of 125I-ET-1 to cell membranes prepared from the circular smooth muscle was saturable and specific. Analysis of dose-inhibition curves indicated the presence of two classes of receptors, ETA and ETB receptors. These results demonstrate that the guinea-pig lower esophageal sphincter possesses ETA receptors mediating relaxation and ETB receptors mediating contraction.
Huang
Shih-Che
SC
Department of Internal Medicine, Tzu Chi General Hospital and Tzu Chi University, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan. shihchehuang@hotmail.com
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D019333:Endothelin-2 / Q000378:metabolism; D019334:Endothelin-3 / Q000378:metabolism; D049630:Esophageal Sphincter, Lower / Q000033:anatomy & histology* / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D009126:Muscle Relaxation / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D011869:Radioligand Assay; D017466:Receptors, Endothelin / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D000959:Antihypertensive Agents; D018679:Cholinergic Agonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D007457:Iodine Radioisotopes; D020033:Protein Isoforms; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D002217:Carbachol