COMPARISON OF THE CONTRACTILE EFFECTS OF ENDOTHELIN-1 AND SARAFOTOXIN S6B IN GOAT ISOLATED CEREBRAL-ARTERIES

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-1 and sarafotoxin S6b contracted cerebral arteries in a concentration-dependent manner. The potency of endothelin-1 (EC50 = 4.9 (3.9-6.2) x 10(-10) M) 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-1 could be reproduced. Endothelin-I and sarafotoxin S6b induced further contraction in arteries precontracted with prostaglandin F2-alpha (10(-5) M). 3 Mechanical removal of the endothelium or incubation with indomethacin (10(-5) M) displaced the concentration-response curves to endothelin-1 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-1 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-1 and sarafotoxin S6b. 5 Bay K 8644 (10(-10) M, 10(-8) M) enhanced and nicardipine (10(-10) M, 10(-8) M) inhibited in a concentration-dependent manner vasoconstrictor response to endothelin-1. Response to sarafotoxin S6b was only affected by 10(-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-1 and sarafotoxin S6b depend on extracellular Ca2+ and on intracellular, caffeine-sensitive Ca2+ stores to develop vasoconstriction. However, endothelin-1 depends to a larger extent than sarafotoxin S6b on free extracellular Ca2+.