Article date: October 1993
By: Timothy D. Warner, Graham H. Allcock, Emma J. Mickley, John R. Vane, in Volume 110, Issue 2, pages 783-789
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 (ETA receptor selective) and PD 142893 (non‐selective).
In the RVD, ET‐1 and SX6b increased the twitches induced by field stimulation starting at a threshold concentration of 10−10m while the threshold concentration for ET‐3 was 3 × 10−9m. SX6c (up to 3 × 10−8m) did not potentiate the twitches. SX6b produced significantly (P < 0.05) greater potentiations than ET‐1 at concentrations of 3 × 10−9m and higher, and 10−7m 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 × 10−8m and higher, SX6b > ET‐3 > ET‐1 >>> SX6c.
In the presence of BQ‐123 or PD 142893 (10−5m) 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 ETA receptors mediating these effects.
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 (10−5m) or PD 142893 (10−5m). Thus, ETA receptors mediate contractions of the GPI induced by these peptides.
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 × 10−10m). The depressions induced by ET‐1 were unaffected by either BQ‐123 (10−5m) or PD 142893 (10−5m). 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 ETB type mediates the inhibitory effects of the endothelin/sarafotoxin peptides on neurotransmission in the GPI.
Thus, both ETA receptors and ETB receptors mediate the effects of the endothelin/sarafotoxin peptides on neurotransmission.
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 (ETA receptor selective) and PD 142893 (non‐selective).
In the RVD, ET‐1 and SX6b increased the twitches induced by field stimulation starting at a threshold concentration of 10−10m while the threshold concentration for ET‐3 was 3 × 10−9m. SX6c (up to 3 × 10−8m) did not potentiate the twitches. SX6b produced significantly (P < 0.05) greater potentiations than ET‐1 at concentrations of 3 × 10−9m and higher, and 10−7m 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 × 10−8m and higher, SX6b > ET‐3 > ET‐1 >>> SX6c.
In the presence of BQ‐123 or PD 142893 (10−5m) 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 ETA receptors mediating these effects.
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 (10−5m) or PD 142893 (10−5m). Thus, ETA receptors mediate contractions of the GPI induced by these peptides.
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 × 10−10m). The depressions induced by ET‐1 were unaffected by either BQ‐123 (10−5m) or PD 142893 (10−5m). 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 ETB type mediates the inhibitory effects of the endothelin/sarafotoxin peptides on neurotransmission in the GPI.
Thus, both ETA receptors and ETB receptors mediate the effects of the endothelin/sarafotoxin peptides on neurotransmission.
DOI: 10.1111/j.1476-5381.1993.tb13880.x
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