Evidence that ET-1, but not ET-3 and S6b, ETA-receptor mediated contractions in isolated rat mesenteric arteries are modulated by co-activation of ETB receptors

1 The effects of agonists with endothelin (ET) ETA-receptor activity have been analysed in relation to their interaction with ETB receptors in rat mesenteric arteries. 2 ET-1, sarafotoxin 6b (S6b) and ET-3 induced large, slow-onset and sustained contractions whereas S6c induced weak transient contractions. However, following pre-contraction with U46619 and subsequent relaxation with forskolin, the effect of S6c was amplified, indicating a potential for powerful ETB-receptor mediated contraction. 3 The selective ETA-receptor antagonist, FR139317, produced parallel rightward shifts of ET-1, S6b and ET-3 concentration-effect curves indicating that the contractions were mediated by ETA receptors. However, the corresponding FR139317 pK(B) values were significantly different between the agonists. As expected FR139317 had no effect on S6c responses. 4 Pre-treatment with S6c to desensitize ETB receptors, increased ET-1 potency and the pK(B) value for FR139317. In contrast, neither the potency of S6b and ET-3 nor the pK(B) values for FR139317 estimated using these agonists were affected by ETB-receptor desensitization. 5 Segments pre-contracted with submaximal concentrations of S6b and ET-3, but not ET-1, rapidly relaxed following wash-out or FR139317 administration. 6 The results indicate that the small contractile response to selective ETB receptor activation, barely detectable under standard bioassay conditions, is greatly amplified when adenylate cyclase activity is elevated. Moreover, the response to ETA receptor activation by ET-1, but not ET-3 and S6b, is significantly modified by co-activation of ETB receptors. This interaction has a significant effect on the apparent affinity of ETA-receptor selective antagonists when ET-1 is used as agonist and decreases the potency of ET-I.