Sarafotoxin S6a

Sarafotoxin S6c is a relatively weak displacer of specifically bound 125I-endothelin.[Pubmed:2543414]

Biochem Biophys Res Commun. 1989 May 30;161(1):89-94.

Sarafotoxin S6a, S6b and S6c are chemically related vasoconstrictor polypeptides obtained from the venom of the snake, Atractaspis engaddensis. Each contains twenty one amino acid residues, two intrachain cysteine linkages and a long hydrophobic tail. Structurally these polypeptides resemble endothelin. Binding studies with 125I-endothelin showed that 125I-endothelin bound to rat ventricular membranes is totally displaceable by sarafotoxin S6b and endothelin, with IC50 values of 0.21 and 0.16 nM, respectively. Sarafotoxin S6c, which differs from sarafotoxin S6b in containing threonine instead of serine at residue 2, arginine instead of lysine at residue 4, and glutamic acid instead of lysine at residue 9, only weakly displaced bound 125I-endothelin (IC50, 854 nM). These results indicate that the ability of the sarafotoxins to interact with the endothelin binding site is not solely dependent on the long hydrophobic tail or the cysteine linkages.

Endothelin-induced nociception in mice: mediation by ETA and ETB receptors.[Pubmed:8632332]

J Pharmacol Exp Ther. 1996 Feb;276(2):647-51.

Endothelins (ET-1, ET-2 or ET-3) or endothelin precursors (big-ET-1[1-38], big-ET-2[1-37] or big-ET-3[1-41]) injected i.p. in mice have previously been shown to elicit a characteristic nociceptive behavioral response. In this study, we investigated the endothelin receptor type (ETA or ETB) that mediates this behavioral response. Mice were injected i.p. with ET-1, ET-2, ET-3, big-ET-1[1-38], big-ET-2[1-37], big-ET-3[1-41], Sarafotoxin S6a, sarafotoxin S6b, sarafotoxin S6c, ET-1 with Ala substitutions for Cys3 and Cys11 or His-Leu-Asp-Ile-Ile-Trp, and quantal dose-response curves were obtained for each of the compounds (except the latter). Co-administration of enzyme inhibitors with the big-endothelins was used to establish the requisite conversion to endothelins and big-ET-1[22-38], big-ET-2[22-37] and ET-3[22-41] amide, and the ETA-selective antagonist cyclo[-D-Asp-Pro-D-Val-Leu-D-Trp-] was used to determine receptor specificity. The ED50 values were 2.9, 3.3 and 23.9 micrograms/kg i.p. for ET-1, ET-2 and ET-3, respectively, 0.6, 0.6 and 13.1 micrograms/kg i.p. for Sarafotoxin S6a, sarafotoxin S6b and sarafotoxin S6c, respectively, and 5.3 micrograms/kg i.p. for ET-1 with Ala substitutions for Cys3 and Cys11. Big-ET-1[22-38], big-ET-2[22-37], big-ET-3[22-41] amide and ET-C produced less than 25% effect up to 2000 micrograms/kg. The big-ET-1-induced effects were blocked by the enzyme inhibitors phosphoramidon and thiorphan (ID50 = 0.9 mg/kg) but not by ubenimex (bestatin), captopril or perindopril. Cyclo[-D-Asp-Pro-D-Val-Leu-D-Trp-] blocked ET-1- and ET-2-induced effects but not ET-3-, ACh- or phenyl-p-quinone-induced effects. These results suggest that endothelin-induced nociceptive behavioral response in mice can be mediated via both ET receptor types, ETA and ETB. Further, the ET-1 carboxy-terminal hexapeptide is insufficient to produce the effect, and the Cys3-Cys11 disulfide bridge of ET-1 is not required.

Differences between endothelin receptors mediating contraction of guinea-pig aorta and pig coronary artery.[Pubmed:8287901]

Eur J Pharmacol. 1993 Nov 9;249(2):199-206.

Endothelin receptors mediating contraction were characterized and compared in rings from guinea-pig thoracic aorta and pig left circumflex coronary artery. In guinea-pig aorta, the following rank order of agonist potencies was found (mean EC50 value, nM): endothelin-1 (5.0) = endothelin-2 (5.5) > vasoactive intestinal contractor (VIC; 11.0) > sarafotoxin S6b (39.8) > [Ala3,11]endothelin-1 (121) > Sarafotoxin S6a (> 150) > endothelin-3 (> 500). [Ala1,3,11,15] Endothelin-1, endothelin-(16-21), sarafotoxin S6c and sarafotoxin S6d were neither agonists nor antagonists at concentrations up to 1, 10, 3 and 1 microM, respectively. Cyclo-(D-Trp-D-Asp-Pro-D-Val-Leu) (BQ-123; 0.1-1 microM) behaved as a competitive antagonist of endothelin-1 (pA2 7.4 +/- 0.1, slope factor 0.91 +/- 0.17, n = 4). In pig coronary artery, all endothelins and sarafotoxins were agonists, except for endothelin-(16-21). Sarafotoxin S6c, [Lys4]sarafotoxin S6c, [Nle6]sarafotoxin S6c and [Ala1,3,11,15]endothelin-1 acted as partial agonists (Emax about 40% of that of endothelin-1). The rank order of agonist potencies was: sarafotoxin S6c (1.5) = [Lys4]sarafotoxin S6c (1.5) > [Nle6]sarafotoxin S6c (6.7) > or = Sarafotoxin S6a (7.5) > or = endothelin-1 (12.6) > or = sarafotoxin S6b (14.8) > or = VIC (18.3) = endothelin-2 (19.3) > or = [Ala1,3,11,15]endothelin-1 (41.7) > or = [Ala3,11]endothelin-1 (55.2) > endothelin-3 (96.8) > sarafotoxin S6d (> 200). Endothelin-(16-21) was neither agonist nor antagonist at 10 microM. The concentration-response curves of endothelin-3 and Sarafotoxin S6a were biphasic, consisting of a higher sensitivity (40-45% of the total effect) and a lower sensitivity component. BQ-123 (0.1-1 microM) did not alter the concentration-response curve of endothelin-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of responses to sarafotoxins 6a and 6c in pulmonary and systemic vascular beds.[Pubmed:1348398]

Am J Physiol. 1992 Mar;262(3 Pt 2):H852-61.

Cardiovascular and pulmonary responses to sarafotoxin (S) 6a and S6c were investigated in the anesthetized cat. Intravenous injections of the peptides in doses of 0.1-1.0 nmol/kg caused decreases or biphasic changes in arterial pressure (AP) and increases in central venous pressure, pulmonary arterial pressure (PAP), and cardiac output (CO). Secondary decreases in CO were observed in response to higher doses, and biphasic changes in systemic (SVR) and pulmonary (PVR) vascular resistances were observed. Under constant-flow conditions, the peptides only increased pulmonary lobar arterial perfusion pressure and lobar vascular resistance. AP responses to S6a, S6c, endothelin (ET)-1, ET-2, vasoactive intestinal contractor (VIC), and Lys7-ET-1 were similar, whereas AP responses to S6b and ET-3 were similar. S6a, S6b, S6c, ET-1, ET-2, ET-3, VIC, Lys7-ET-1, and big ET-1 increased PAP. S6a and S6c increased distal aortic and superior mesenteric arterial (SMA) blood flow and caused biphasic changes at the highest doses. Under constant-flow conditions, S6a and S6c produced dose-dependent biphasic changes in hindquarters perfusion pressure. Changes in SVR and PVR in response to the peptide were not affected by hexamethonium, glyburide, or meclofenamate, indicating that responses are independent of autonomic reflexes, activation of ATP-regulated K+ channels, or release of cyclooxygenase products. In contrast, N-nitro-L-arginine methyl ester decreased hindquarters vasodilator response to S6a and S6c. The present data show that S6a and S6c produce both vasodilation and vasoconstriction in the systemic vascular bed and increase lobar vascular resistance and that hindquarters vasodilator responses are mediated, in part, by the release of endothelium-derived relaxing factor.