Comparison of the contractile effects of endothelin‐1 and sarafotoxin S6b in goat isolated cerebral arteries

Abstract

1 The effects of endothelium-derived endothelin-1 and snake venom-derived sarafotoxin S6b, peptides with striking structural and functional similarities, were examined and compared in isolated middle cerebral arteries of goats. 2 Endothelin-l and sarafotoxin S6b contracted cerebral arteries in a concentration-dependent manner.The potency of endothelin-l (EC50 = 4.9 (3.9-6.2) x 10-IOM) was about ten times higher than that of sarafotoxin S6b (EC50 = 5.5 (4.4-6.9) x 10-9 M). The tension returned to basal values after repeated washings and contraction with endothelin-l could be reproduced. Endothelin-l and sarafotoxin S6b induced further contraction in arteries precontracted with prostaglandin F2., (10-5 M).3 Mechanical removal of the endothelium or incubation with indomethacin (10-5 M) displaced the concentration-response curves to endothelin-l and, more pronouncedly, to sarafotoxin S6b to the left. The maximum response to sarafotoxin S6b was also increased by either of these two treatments.4 Incubation in 'nominally' Ca2"-free medium attenuated the vasoconstrictor response to endothelin-l but not to sarafotoxin S6b, which was inhibited after incubation in Ca2'-free medium to which EGTA (10-4 M) had been added. Pretreatment with caffeine (2 x 10-2 M) in Ca2'-free medium abolished responses to endothelin-l and sarafotoxin S6b. 5 Bay K 8644 (1O -M, 10-8 M) enhanced and nicardipine (10-1°M, 10-8 M) inhibited in a concentration-dependent manner vasoconstrictor response to endothelin-1. Response to sarafotoxin S6b was only affected by l0-8 M Bay K 8644 or nicardipine. 6 It is concluded that endothelin-1 and sarafotoxin S6b are potent vasoconstrictors of goat cerebral arteries, having direct effects on smooth muscle which are counteracted by the endothelium through the release of a vasodilatator substance, probably prostacyclin. Both endothelin-l and sarafotoxin S6b depend on extracellular Ca2+ and on intracellular, caffeine-sensitive Ca2+ stores to develop vasoconstriction. However, endothelin-l depends to a larger extent than sarafotoxin S6b on free extracellular Ca2+.

Endothelin receptors mediating contraction in goat cerebral arteries

“…A similar differentiation of ETA receptor subtypes has been proposed for endothelin-land endothelin-3-induced contractions in rat thoracic aorta (Sumner et al, 1992). In a previous report (Salom et al, 1992) we have shown that the nature of the extracellular Ca2+ source mobilized by endothelin-1 and sarafotoxin S6b in goat cerebral arteries is also different since endothelin-1 depends on free extracellular Ca2+ and sarafotoxin S6b depends on externally membrane-bound Ca2 . The Ca2+ source could be related to the receptor subtype involved in the response to each of the peptides.…”

“…We have previously reported the vasoconstrictor effects of endothelin-1 on the cerebrovascular bed of the goat (Salom et al, 1991) and compared them with those of sarafotoxin S6b (Salom et al, 1992). In the present study we have examined the agonist potency of endothelin isopeptides (endothelin-1, endothelin-2 and endothelin-3) and used the selective ETA-receptor antagonist, to …”

“…in cerebral vasospasm following subarachnoid hemorrhage is being investigated (Masaki et al, 1992). We have previously reported the vasoconstrictor effects of endothelin-1 on the cerebrovascular bed of the goat (Salom et al, 1991) and compared them with those of sarafotoxin S6b (Salom et al, 1992). In the present study we have examined the agonist potency of endothelin isopeptides (endothelin-1, endothelin-2 and endothelin-3) and used the selective ETA-receptor antagonist, BQ-123, to identify the receptors mediating endothelin-1-and sarafotoxin S6b-induced contraction in goat isolated middle cerebral artery.…”