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Characterization of endothelin receptors mediating the effects of the endothelin/sarafotoxin peptides on autonomic neurotransmission in the rat vas deferens and guinea‐pig ileum
Author(s) -
Warner Timothy D.,
Allcock Graham H.,
Mickley Emma J.,
Vane John R.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13880.x
Subject(s) - endothelin receptor , vas deferens , medicine , endocrinology , receptor , stimulation , endothelins , endothelin 3 , endothelin 1 , agonist , guinea pig , neurotransmission , chemistry , biology
1 To characterize the receptors mediating the effects of the endothelin/sarafotoxin family of peptides on the responses to electrical stimulation of the rat vas deferens (RVD) and guinea‐pig ileum (GPI) we have used endothelin‐1 (ET‐1), ET‐3, sarafotoxin 6b (SX6b) and SX6c as agonists and the endothelin‐receptor antagonists BQ‐123 (ET A receptor selective) and PD 142893 (non‐selective). 2 In the RVD, ET‐1 and SX6b increased the twitches induced by field stimulation starting at a threshold concentration of 10 −10 m while the threshold concentration for ET‐3 was 3 × 10 −9 m . SX6c (up to 3 × 10 −8 m ) did not potentiate the twitches. SX6b produced significantly ( P < 0.05) greater potentiations than ET‐1 at concentrations of 3 × 10 −9 m and higher, and 10 −7 m ET‐3 also produced a significantly greater effect than ET‐1 at the same concentration. Thus, at threshold the rank order of peptides was ET‐1 = SX6b > ET‐3 >> SX6c, and at concentrations of 3 × 10 −8 m and higher, SX6b > ET‐3 > ET‐1 >>> SX6c. 3 In the presence of BQ‐123 or PD 142893 (10 −5 m ) the threshold concentrations for ET‐1 to augment the twitches were increased 30 fold. In the same conditions neither SX6b nor ET‐3 potentiated the responses. The relative activities of the endothelin/sarafotoxin peptides and the effectiveness of the endothelin receptor antagonists are consistent with postjunctional ET A receptors mediating these effects. 4 In the transmurally stimulated GPI the endothelin/sarafotoxin peptides produced two effects; an increase in the basal tension of the tissues and an inhibition of the twitch responses. To increase the basal tension the peptides had the order of potency ET‐1 > SX6b >> ET‐3 = SX6c. These direct effects of ET‐1 or SX6b were strongly antagonized (100 fold) by either BQ‐123 (10 −5 m ) or PD 142893 (10 −5 m ). Thus, ET A receptors mediate contractions of the GPI induced by these peptides. 5 The endothelin/sarafotoxin peptides were approximately equipotent at depressing twitches of the GPI in response to transmural stimulation (EC50S, 4 × 10 −11 to 1.5 × 10 −10 m ). The depressions induced by ET‐1 were unaffected by either BQ‐123 (10 −5 m ) or PD 142893 (10 −5 m ). BQ‐123 produced a small (three fold) antagonism of the inhibitory effects of ET‐3 or SX6c. These results indicate that a receptor of the ET B type mediates the inhibitory effects of the endothelin/sarafotoxin peptides on neurotransmission in the GPI. 6 Thus, both ET A receptors and ET B receptors mediate the effects of the endothelin/sarafotoxin peptides on neurotransmission.