Pharmacological characterization of endothelin‐induced contraction in the guinea‐pig oesophageal muscularis mucosae

1 In the oesophageal muscularis mucosae, we examined the effects of endothelin‐1 (ET‐1), endothelin‐2 (ET‐2), endothelin‐3 (ET‐3) and sarafotoxin S6c (SX6c) as agonists, and FR139317, BQ‐123 and RES‐701‐1 as endothelin receptor antagonists. 2 All of the endothelins produced tonic contractions which were frequently superimposed on rhythmic motility in a concentration‐dependent manner. The order of potency (−log EC 50 ) was ET‐1 (8.61)=SX6c (8.65)>ET‐2 (8.40)>ET‐3 (8.18). 3 FR139317 (1–3 μ M ) and BQ‐123 (1 μ M ) caused parallel rightward shifts of the concentration‐response curve to ET‐1, but at higher concentrations caused no further shift. RES‐701‐1 (3 μ M ) caused a rightward shift of the concentration‐response curve to ET‐1, while RES‐701‐1 (10 μ M ) had no additional effect. RES‐701‐1 (0.1–1 μ M ) concentration‐dependently caused a rightward shift of the concentration‐response curve to SX6c. The contraction to ET‐1 (10 n M ) in preparations desensitized to the actions of SX6c was greatly inhibited by pretreatment with FR139317 (10 μ M ). 4 Modulation of the Ca 2+ concentration in the Krebs solution caused the concentration‐response curve to ET‐1 or SX6c to shift to the right and downward as external Ca 2+ concentrations decreased. Verapamil (30 μ M ) abolished rhythmic motility induced by ET‐1 or SX6c. Ni 2+ (0.1 m M ) weakly inhibited ET‐1‐ or SX6c‐induced tonic contraction. SK&F 96365 (60 μ M ) completely inhibited ET‐1‐induced contractions. 5 We conclude that there are two types of ET‐receptors, excitatory ET A ‐ and ET B ‐receptors in the oesophageal muscularis mucosae. These receptors mediate tonic contractions predominantly by opening receptor‐operated Ca 2+ channels (ROCs) and partly by opening T‐type Ca 2+ channels, and mediate rhythmic motility by opening L‐type Ca 2+ channels.British Journal of Pharmacology (1998) 125 , 849–857; doi: 10.1038/sj.bjp.0702140