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-1 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' Ca(2+)-free medium attenuated the vasoconstrictor response to endothelin-1 but not to sarafotoxin S6b, which was inhibited after incubation in Ca(2+)-free medium to which EGTA (10(-4) M) had been added. Pretreatment with caffeine (2 x 10(-2) M) in Ca(2+)-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-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+.
Salom
J B
JB
Centro de Investigación, Hospital La Fe, Valencia, Spain.
Torregrosa
G
G
Miranda
F J
FJ
Alabadí
J A
JA
Alborch
E
E
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006041:Goats; D007213:Indomethacin / Q000494:pharmacology; D009529:Nicardipine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014757:Viper Venoms / Q000494:pharmacology*
D016232:Endothelins; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009529:Nicardipine; D007213:Indomethacin