Sarafotoxin S6c

Distinct endothelin-B receptors mediate the effects of sarafotoxin S6c and IRL1620 in the ileum.[Pubmed:9595431]

J Cardiovasc Pharmacol. 1998;31 Suppl 1:S175-8.

In the guinea pig ileum, both Sarafotoxin S6c (S6c) and IRL1620 induced a biphasic effect (relaxation and contraction). S6c induced strong tachyphylaxis of both components of the response, but IRL1620 induced tachyphylaxis mainly of the contractile component. Whereas the tissues rendered tachyphylactic to S6c did not respond to IRL1620, a normal biphasic response to S6c was observed in the tissues rendered tachyphylactic to IRL1620. In the presence of IRL1620, S6c could induce its biphasic effect, whereas in the presence of S6c, IRL1620 was ineffective. BQ-123, a specific ETA antagonist, did not affect the biphasic response induced by either agonist. PD145065, a potent ETA/ETB antagonist, was a competitive and a noncompetitive antagonist, respectively, of the contractile components of IRL1620 and S6c. RES-701-1, a specific ETB1 antagonist, inhibited both components of the response induced by IRL1620. However, it inhibited mainly the relaxant component induced by low doses of S6c. Apamin had different effects on endothelin-1 (ET-1), S6c, and IRL1620. Our results suggest that there are at least two distinct populations of ETB receptors mediating the biphasic response: the ETB1 receptor, sensitive to RES-701-1 and PD145065, and the ETB2 receptor, less sensitive to RES-701-1 and PD145065.

Sarafotoxin 6c (S6c) reduces infarct size and preserves mRNA for the ETB receptor in the ischemic/reperfused myocardium of anesthetized rats.[Pubmed:15243294]

J Cardiovasc Pharmacol. 2004 Aug;44(2):148-54.

The aims of this study were to determine if the ETB receptor agonist, sarafotoxin 6c (S6c) reduces myocardial infarct size following myocardial ischemia and reperfusion and to investigate whether any changes in mRNA for endothelin receptors in the injured myocardium were modified by S6c pretreatment. Hypnorm/Hypnovel anesthetized rats were subjected to occlusion of the left main coronary artery for 30 minutes, followed by 120 minutes reperfusion. Animals were administered a bolus dose of S6c (0.24 nmol kg-1 i.v., n = 10) or saline (n = 15) 5 minutes prior to occlusion. At the end of reperfusion, hearts were stained with Evan's Blue dye to delineate area at risk. A 1.5- to 2.0-mm thick slice was cut transmurally 1 mm below the site of ligation for assessment of infarct size by triphenyltetrazolium chloride. A further transmural slice (2.5-3-mm thick) was cut for assessment of receptor mRNA levels by RTPCR. Administration of S6c caused a transient fall in mean arterial blood pressure (MABP) prior to occlusion and attenuated the fall in MABP induced by coronary occlusion. S6c significantly reduced infarct size (13 +/- 4% of area of slice at risk) compared with control hearts (35 +/- 5%; P < 0.05). In control hearts, there was a marked reduction in mRNA content for both ETA (50% reduction) and ETB (70% reduction) receptors in the ischemic zone, compared with non-ischemic tissue. In hearts pre-treated with S6c there was a reduction in ETA, but not ETB receptor mRNA in the ischemic zone. This study has shown that S6c reduces myocardial infarct size and results in preservation of ETB receptor mRNA in ischemic/reperfused tissue.

Constriction to ETB receptor agonists, BQ-3020 and sarafotoxin s6c, in human resistance and capacitance vessels in vivo.[Pubmed:10886114]

Br J Clin Pharmacol. 2000 Jul;50(1):27-30.

AIMS: The aim of the study was to examine the effects of the ETB receptor selective agonists Sarafotoxin S6c (SFTX6c) and BQ-3020 on the forearm resistance and capacitance vessels in healthy subjects in vivo. METHODS: The local response to intra-arterial or intravenous infusion of SFTX6c (5 pmol min-1) or BQ-3020 (50 pmol min-1) was assessed, on separate occasions, in eight healthy men (aged 20-28 years). Data (mean +/- s.e.mean) were examined by ANOVA. Results are expressed as percentage change from baseline at 90 min. RESULTS: SFTX6c and BQ-3020 reduced forearm blood flow, following local intra-arterial infusion (-25 +/- 7% and -27 +/- 7%, respectively; P < 0.001) and reduced hand vein diameter, following local intravenous infusion (-30 +/- 8% and -16 +/- 7%, respectively; P < 0.001). CONCLUSIONS: We have shown that locally active infusions of the selective ETB receptor agonists SFTX6c and BQ-3020 cause arterial constriction and venoconstriction in healthy human blood vessels in vivo. These results indicate that ETB receptor stimulation may mediate vasoconstriction in humans.

Simultaneous changes in intracellular calcium and tension induced by endothelin-1 and sarafotoxin S6c in guinea pig isolated gallbladder: influence of indomethacin.[Pubmed:12056553]

Can J Physiol Pharmacol. 2002 May;80(5):458-63.

The relationships between changes in intracellular Ca2+ and smooth muscle tension triggered by endothelin-1 and the selective endothelin ETB receptor agonist Sarafotoxin S6c, as well as their susceptibility to modification by the nonselective cyclooxygenase blocker indomethacin, were assessed in guinea pig isolated gallbladder strips. Cumulative additions of either agonist (1, 10, and 100 nM) induced simultaneous graded, strongly correlated, slowly developing, and sustained changes in tension and intracellular Ca+2 (Fura-2 technique). Sarafotoxin S6c was more effective than endothelin-1 in raising intracellular Ca2+ at 1 or 10 nM, but their abilities to cause contractions were similar at all concentrations. Indomethacin (5.6 microM) markedly inhibited the changes in both intracellular Ca2+ and tension caused by all concentrations of Sarafotoxin S6c (in response to 100 nM, increases in Ca2+ fluorescence intensity and tension were inhib ited from 7.7 +/- 0.7 to 4.0 +/- 0.4% and from 460 +/- 100 to 160 +/- 40 mg, respectively) but only reduced the contraction triggered by 100 nM endothelin-1 (from 560 +/- 100 to 230 +/- 70 mg). Endothelin-1 caused greater prostacyclin release from gallbladder than Sarafotoxin S6c (at 100 nM, 6-keto-PGF1alpha levels in the medium rose 4.8- and 2.8-fold, respectively; P < 0.05) and slightly increased thromboxane A2 release (1.6-fold; P < 0.05). Thus, gallbladder contractions triggered by combined ETA/ETB or selective ETB receptor stimulation (with endothelin-1 or Sarafotoxin S6c, respectively) are strongly correlated with increases in intracellular Ca2+ but differentially affected by indomethacin. It remains to be assessed if this difference is because endothelin-1 triggers greater prostacyclin release than Sarafotoxin S6c and (or) is due to the coupling of ETA and ETB receptors to distinct patterns of generation of cyclooxygenase-derived eicosanoids.

Effects of sarafotoxin S6c on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.[Pubmed:9023305]

J Pharmacol Exp Ther. 1997 Feb;280(2):905-10.

We previously reported that endothelin (ET) may function as an inhibitory modulator of renal noradrenergic neurotransmission (Suzuki et al., J. Cardiovasc. Pharmacol. 19: 905-910, 1992). In our study, we examined the effect of Sarafotoxin S6c (S6c), a selective ET(B) receptor agonist, on changes in renal function and norepinephrine overflow induced by renal nerve stimulation (RNS) in anesthetized dogs. RNS at a low frequency (0.5-2.0 Hz) caused significant decreases in urine flow, urinary excretion of sodium and fractional excretion of sodium and increased norepinephrine secretion rate, without affecting systemic and renal hemodynamics. RNS at a high frequency (2.5-5.0 Hz), which diminishes renal hemodynamics, produced more potent decreases in urine formation and increase in norepinephrine secretion rate than seen with low frequency RNS. When S6c (1 ng/kg/min) was infused intrarenally, there was a slight and transient increase in renal blood flow, and then this response was followed by a gradual reduction. S6c administration produced increase in the basal level of urine flow with no apparent effects on urinary excretion of sodium and fractional excretion of sodium. During S6c infusion, low frequency RNS-induced antidiuretic action and increase in norepinephrine secretion rate were markedly attenuated. Qualitatively, similar results were observed in the case of high frequency RNS. In addition, high frequency RNS-induced decreases in glomerular filtration rate and filtration fraction were significantly suppressed by S6c infusion. Taken together with our previous findings, it seems likely that ET plays an important role as an inhibitory modulator of renal noradrenergic neurotransmission, through ET(B) receptor mechanisms.

Characterization of cloned human endothelin receptors.[Pubmed:8336519]

Life Sci. 1993;53(5):407-14.

Two subtypes of human endothelin receptors, ETA and ETB, have been cloned and stably expressed in Chinese Hamster Ovary cells. These receptors have been characterized by [125I]-endothelin-1 binding and phosphatidyl inositol hydrolysis using the potent peptidyl ETA antagonists BQ-123 and BQ-153, as well as the potent ETB agonist, Sarafotoxin S6c. In binding studies, Ki values for BQ-123 and BQ-153 are 17 nM and 13 nM for ETA compared to 11,100 nM and 7200 nM for ETB. Conversely, Ki values for Sarafotoxin S6c are 2800 nM for ETA and 0.29 nM for ETB. Endothelin-1 stimulates phosphatidyl inositol hydrolysis in cells expressing either ETA or ETB with EC50 values of 0.2-0.3 nM, while Sarafotoxin S6c stimulates phosphatidyl inositol hydrolysis only in ETB expressing cells with an EC50 value of 0.2 nM, consistent with the binding data. Comparison of binding data for the cloned and expressed human receptors with binding data for receptors obtained from human tissues indicates the cloned and expressed receptors are essentially indistinguishable from the naturally occurring receptors.

Sarafotoxin S6c: an agonist which distinguishes between endothelin receptor subtypes.[Pubmed:1850245]

Biochem Biophys Res Commun. 1991 Mar 15;175(2):556-61.

In contrast to endothelin-1 (ET-1) and several of its analogues, Sarafotoxin S6c (S6c) was a much more potent inhibitor of [125I]-ET-1 binding in rat hippocampus and cerebellum (Ki approximately 20 pM) than in rat atria and aorta (Ki approximately 4500 nM), suggesting the existence of ET-1 receptor subtypes (aorta/atria, ETA; hippocampus/cerebellum, ETB). S6c was a potent activator of PI turnover in hippocampus (EC50 approximately 10 nM) but not atria (EC50 greater than 1 microM), unlike ET-1 which was active in both tissues. S6c, therefore, is a highly selective ETB agonist. Furthermore, S6c was a potent pressor agent in the pithed rat (ED25 mm Hg approximately 0.1 nmoles/kg, i.v.), suggesting that the ETB receptor subtype may be important in cardiovascular function.