Induction of nitric oxide synthase by lipoteichoic acid from Staphylococcus aureus in vascular smooth muscle cells.

Inducible vascular nitric oxide synthase accounts for the contractile impairment observed in endotoxemia. We provide evidence that lipoteichoic acid (LTA) from Staphylococcus aureus, a micro-organism without endotoxin, also induces nitric oxide synthase. Our study demonstrates that on endothelium-free rings of rat aorta. LTA-like lipopolysaccharide induces a loss of contractility restored by Methylene blue and NG-nitro-L-arginine-methyl ester (LNAME). Moreover in cultured vascular smooth muscle cells, LTA produces a dose-dependent increase in intracellular cyclic GMP which is antagonized by LNAME and prevented by dexamethasone.

Different alpha1-adrenoceptor subtypes mediate contraction in rabbit aorta and urethra.

The alpha1-adrenoceptor subtypes mediating contraction of rabbit aorta and urethra were pharmacologically characterized using an isolated organ bath technique. Although aorta was as sensitive as urethra to the contractile action of methoxamine, phenylephrine was about 10 times more potent as a contractile agonist on aorta than on urethra. In aorta, the rank order of agonist sensitivity was norepinephrine > phenylephrine > clonidine > methoxamine whereas the rank order in urethra was clonidine > methoxamine > or = phenylephrine > norepinephrine. A lack of significant correlation between the potency of different alpha1-adrenoceptor antagonists tested against the phenylephrine-induced contraction in aorta and in urethra indicated that different alpha1-adrenoceptor subtypes mediated the contractile response in the two preparations. The potency of different alpha1-adrenoceptor antagonists tested in rabbit urethra was significantly correlated with their affinity for the cloned human alpha1c-, but not alpha1a- or alpha1b-, adrenoceptor subtype. Such a clear correlation with the potency of different alpha1-adrenoceptor antagonists tested in rabbit aorta and their affinity for one subtype of cloned human alpha1-adrenoceptor was not found. Chlorethylclonidine, which produced a 10 000-fold rightward shift in the phenylephrine concentration-response curve for rat aorta, had a weak inhibitory effect in rabbit aorta and urethra as well as in other rabbit tissues (spleen, fundus, renal artery, saphenous artery). The results indicate that significant heterogeneity exists among alpha1-adrenoceptor in rabbit aorta and urethra (alpha1c-adrenoceptor). However, chlorethylclonidine does not seem to be a suitable tool for the differentiation of alpha1-adrenoceptor subtypes in the rabbit.

The vasoconstrictor action of big endothelin-1 is phosphoramidon-sensitive in rabbit saphenous artery, but not in saphenous vein.

The effects of big endothelin-1 and endothelin-1 on vascular reactivity were compared in isolated rabbit saphenous artery and vein. The contractile potency of endothelin-1 was three times higher in the vein than in the artery. In contrast, big endothelin-1 was two times more effective in the artery. Phosphoramidon (100 microM), a metalloproteinase inhibitor, antagonised the contractile action of big endothelin-1 in the artery but not in the vein. These data suggest that the biosynthetic pathway leading to the formation of endothelin differs in arterial and venous vessels.

Different regulation of vascular tone by angiotensin II and endothelin-1 in rat aorta.

The effects of moderate cooling and of phenylarsine oxide on the contraction induced by two vasoactive peptides, angiotensin II (AII) and endothelin (ET-1), were investigated on endothelium-free rings of rat aortas. At 37 degrees C, the contraction induced by AII (0.1 microM) was transient. This decline in tension is unlikely to be due to rapid degradation of AII. In contrast, ET-1 (10 nM) induced a slowly developing and sustained contraction similar to the one observed with phorbol 12-13 dibutyrate (PDB, 22 nM). Moderate cooling (25 degrees C) significantly potentiated and prolonged the effect of AII but reduced the velocity of the ET-1 and PDB contraction, although the rate of the phenylephrine (1 microM) response remained unchanged. Phenylarsine oxide (100 microM) reduced the decline in tension in response to AII but inhibited the contraction elicited by ET-1 and PDB. In rings incubated in calcium-free medium (37 degrees C), AII induced a phasic contraction. This was followed by a second phasic contraction after calcium (2.5 mM) had been restored to the bath. The intensity of this second contraction decreased as the time between AII and calcium injection increased. This method, using regression analysis, permitted us to determine the time taken to reduce the contraction by half (4.8 min; r: 0.96), which may reflect the half-time of receptor sequestration. In calcium-free medium, the contractions induced by ET-1 and PDB were slow and sustained. Thus, rapid AII-receptor internalization leads to a short-term regulation of vascular tone whereas activation of protein kinase C by ET-1 may induce a long-term regulation.

Effects of angiotensin I and angiotensin II in blood vessels: greater influence of converting enzyme activity in the rabbit basilar artery.

We investigated the constrictor effects of Angiotensin I (Ang I) and Angiotensin II (Ang II) on rabbit peripheral (aorta, carotid artery, mesenteric artery, saphenous artery) and cerebral (basilar artery) vessels and in rat aorta in functional organ bath studies. The effect of angiotensin converting enzyme (ACE) inhibition by captopril was also assessed in these preparations. Ang II elicited concentration-dependent contractions with comparable potency in rabbit and rat endothelium-free vascular rings (pD2 about 8.5) which indicates a lack of species and regional variation in the contractile responses to Ang II. The responses to Ang II were reduced by the presence of a functional endothelium in rabbit mesenteric artery and in rat aorta. Since ACE determines the plasma and tissue conversion of Ang I to active Ang II, we calculated the ratio R (EC50 Ang I-induced contraction: EC50 Ang II-induced contraction) as an indicator of the tissue ACE effectiveness. In the aorta without endothelium, Ang I was found to be much less potent than Ang II in the rabbit (R = 44) compared with the rat (R = 3.5). This species difference in the aortic conversion of Ang I to Ang II was confirmed by the use of captopril. Captopril (10(-6) M) shifted the Ang I concentration/ response curve by 2- and 14-fold to the right in rabbit and rat respectively. In other rabbit blood vessels, the rank order of potency to Ang I in endothelium denuded rings was basilar artery > > carotid artery > or = aorta > or = saphenous artery. In addition, the R value was the lowest for the basilar artery (R = 2.5). This is in agreement with the highest rightward shift (78-fold) of the Ang I concentration/response curve by captopril for basilar artery in comparison with only 3-, 8- and 3-fold shifts observed in carotid artery, saphenous artery and aorta respectively. In conclusion, our data provide evidence for a greater influence of ACE in rabbit basilar artery than in peripheral vessels.

Comparative effects of endothelin and phorbol 12-13 dibutyrate in rat aorta.

The vasoconstrictive properties of endothelin (ET-1) and the protein kinase C activator, phorbol 12-13 dibutyrate (PDB) were comparatively investigated in isolated rat aorta. ET-1 (0.3-100 nM) and PDB (10 nM-3 microM) induced a slowly developing sustained contraction in endothelium denuded aorta. Maximal contractions induced by ET-1 and PDB were unaffected by diltiazem (10 microM). Substantial contraction to ET-1 (30 nM) and PDB (0.1 microM) remained in calcium-free medium. Contractions of ET-1 and PDB in calcium-free medium were unaffected by intracellular calcium depletion induced by phenylephrine. Following the response to ET-1 and PDB in a calcium-free medium, an additional sustained contraction was observed after calcium (2.5 mM) was added to the bath. The protein kinase C inhibitor, H7 (100 microM) was more potent in inhibiting contractions induced by phenylephrine and KCl than the ones elicited by ET-1 and PDB. The other protein kinase C inhibitors i.e. staurosporine (50 nM) and phloretin (100 microM) inhibited to a similar extent all the agonists tested. These results suggest that protein kinase C may play an important role in mediating the contraction to ET-1 in rat aorta.

Endothelium independent protective effect of NG-monomethyl-L-arginine on endotoxin-induced alterations of vascular reactivity.

The effects of NG-monomethyl-L-arginine (NMMA), a specific inhibitor of nitric oxide (NO) synthesis was tested on the endotoxin-induced alterations of alpha-adrenoceptor function. In isolated aorta, there was no significant difference in the tension induced by phenylephrine (PE, 10 microM) on rings removed from control and endotoxin injected rats (10 mg/kg, ip). However, a lack of tonicity of the contraction was observed in rings of shocked rats (8 +/- 2.9 and 86 +/- 4.6% relaxation at 105 min for sham and shocked rings respectively). The gradual tension decrease to PE was more potent in rings possessing endothelial cells. However, in both preparations, the loss of tonicity was significantly inhibited by NMMA (30 microM). In endothelium-free rings, L-arginine (100 microM) potentiated the loss of tonicity to PE and reversed the inhibitory effect of NMMA. NMMA, like methylene blue, was also able to restore the PE-contraction. The results indicate that the endotoxin-induced alterations of vascular reactivity may be due, in part, to NO formation from L-arginine independent of the endothelium.

Role of endothelium on phenylephrine-triggered contractile events in aorta of spontaneously hypertensive rats.

The ability of basal release of endothelium derived relaxing factor (EDRF) to alter contractile events in phenylephrine (PE)-triggered contraction was tested on ring segments of the thoracic aorta removed from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). In normal medium, PE (1 microM) elicited similar whole contractions in endothelium denuded arteries of SHR and WKY. The presence of endothelium only reduced the WKY response. On aorta incubated in a Ca2+ free-medium, PE (1 microM) induced an initial phasic contraction due to intracellular Ca2+ release. This was followed by a tonic contraction after Ca2+ (2.5 mM) was restored to the bath. This sustained contraction was dependent on extracellular calcium influx. Identical phasic and tonic contractions were observed in endothelium denuded rings of SHR and WKY. However, the presence of endothelium only reduced the sustained contraction of WKY arteries. When experiments were carried out in medium containing D600 (1 microM), the presence of endothelium diminished the whole contraction of both SHR and WKY rings whereas the sustained but not the phasic contractions of WKY was also inhibited. This inhibitory effect of endothelium on WKY sustained contraction was significantly higher in the presence of D600. The calcium antagonist reduced both the whole and the tonic contractions of all preparations but was ineffective on the phasic one. The D600 inhibitory action on the sustained contraction was more pronounced in denuded SHR rings than in the corresponding WKY arteries. Thus it is concluded that there is a basal influence of endothelium in both SHR and WKY. Under our conditions, the endothelial function inhibited the extracellular Ca2+ influx and especially the part of Ca2+ influx insensitive to D600. This part of Ca2+ influx is diminished in SHR and thus the efficacy of endothelium products (e.g. EDRF) is reduced in this strain.

Increased influence of endothelium in obese Zucker rat aorta.

The ability of endothelium to alter contractile events in phenylephrine (PE)-triggered contraction has been tested on ring segments of the thoracic aorta removed from obese Zucker rats (plasma cholesterol 3.63 mM; n = 8) and from age matched lean rats (plasma cholesterol 2.38 mM; n = 8). In normal medium, PE (1 microM) elicited similar contractions in endothelium-denuded arteries of both strains. However, the presence of endothelium reduced these contractile events and the endothelium-dependent relaxation induced by carbachol (10 microM) was higher in obese rats. In rings incubated in Ca2+ free medium containing EGTA (1 mM), PE (1 microM) induced a phasic contraction and a sustained contraction following addition of Ca2+ (2.5 mM) to the medium. The phasic contraction was due to intracellular Ca2+ release, whereas the sustained response was dependent on extracellular Ca2+ influx. In endothelium-free preparations, the size of both the phasic and sustained contraction was similar for the two strains. The Ca2+ antagonist gallopamil (1 microM) reduced the sustained contraction of lean (24%) and obese (34%) rats without affecting the phasic contraction. In preparations possessing endothelium, the sustained, but not the phasic contraction, of both strains was inhibited. This inhibitory effect of endothelium on the sustained contraction was significantly higher in obese than in lean rats. Thus, it can be concluded that phenylephrine elicited quantitatively and qualitatively similar contractions in obese and lean rats. In both strains, the endothelium diminished the contraction induced by PE, however, this effect was more pronounced in obese rats than in lean ones. These results may explain, in part, the described absence of atherosclerotic lesions in the obese strain.

In vivo and in vitro effects of cicletanine in spontaneously hypertensive rats.

Oral treatment for 2 weeks with cicletanine [1,3-dihydro-6-methyl-7-hydroxy-3-(4-chloro-phenyl)furo(3,4-c)pyridine] at 30 mg/kg/day delayed the onset of hypertension in spontaneously hypertensive rats (SHR) (15.7 mmHg, p less than 0.001). This antihypertensive effect was increased when the animals were maintained on a high-salt diet (40.8 mmHg, p less than 0.001). The ability of cicletanine to alter calcium movements in phenylephrine (PE)- and angiotensin II (ANGIO)-triggered contraction was tested on isolated SHR aorta. PE (1 microM) and ANGIO (0.1 microM) induced a phasic contraction in calcium-free medium due to intracellular calcium release. Upon addition of calcium (2.5 mM) a second sustained (PE) or biphasis (ANGIO) contraction was observed. This second contraction was dependent on extracellular calcium influx. Cicletanine (0.1-0.3 mM) both reduced the phasic (77%, p less than 0.001 for PE; 68%, p less than 0.05 for ANGIO with cicletanine 0.3 mM) and the second contraction elicited by the two agonists (27%, p less than 0.001 for PE; 84%, p less than 0.001 for ANGIO with cicletanine 0.3 mM). These results suggest that in addition to its stimulatory effect on prostaglandin, a direct vascular action of cicletanine could also be involved in the antihypertensive properties of the drug.

In vitro cardiovascular antihistamine properties of cicletanine in comparison with diphenhydramine.

Cicletanine (CIC) (pA2: 7.0) was found to be as potent as diphenhydramine (DIPH) (pA2: 7.2) in competitively inhibiting histamine-induced contraction of isolated rabbit aorta. Both CIC (pA2: 7.3) and DIPH (pA2: 7.5) similarly shifted histamine-induced endothelium-dependent relaxation of isolated rat aorta to the right. The similarity of results (in terms of pA2 values) indicates that in spite of their opposite responses on vascular tone, the H1 receptors on rabbit and rat aortae may be similar. DIPH was found to be as potent as cocaine in potentiating the chronotropic action of noradrenaline on isolated right atria, whereas CIC was without effect. The ability of DIPH to inhibit the noradrenaline uptake at the neuronal membrane seems to be independent of its H1-receptor antagonism potency. Finally, the furopyridine framework of CIC does not elicit the cocaine-like activity of the oxyethylamine residue of DIPH.

[Interaction of atrial natriuretic factor and cicletanine in relation to contractions induced by endothelin and phenylephrine on the isolated rat aorta]. / Interaction entre le facteur natriurétique atrial et le ciclétanine vis-à-vis de la contraction induite par l'endothéline et la phényléphrine sur l'aorte isolée de rat.

The interaction between cicletanine (CIC) and atrial natriuretic factor (ANF) on vessels was studied using the isolated rat aorta as model. Contractions induced by endothelin (ET1), a vasoconstrictor peptide from vascular endothelial cells, and by phenylephrine (PE), an alpha 1-adrenoceptor agonist, were recorded isometrically on aortic rings the endothelium of which had deliberately been damaged. Both agonists produced a concentration-dependent contraction (ET1:EC50 1.8 nM, Emax 2.2 g; PE:EC50 30 nM, Emax 2.4 g) which was antagonized by a 30 min pretreatment with either CIC (100 microM) or ANF (1 nM). However, PE was more sensitive than ET1 to the inhibitory action of CIC or ANF. Moreover, during inhibition by ANF spasmodic contractions were observed with PE but not with ET1; this was not observed when the antagonist was CIC. The inhibitory effect produced by the combination of CIC and ANF was additive with ET1 whereas a potentiation was observed with PE. Thus, on the isolated rat aorta model the contraction induced by PE was more sensitive to the action of ANF than that induced by ET1, which indicates that the two antagonists have a different mechanism of action. A direct action of CIC on the alpha-adrenoceptor might account for the potentiation observed between ANF and CIC against PE.

[Vasoconstricting effect of endothelin. Interaction with atrial natriuretic factor, sodium nitroprusside, cicletanine and nifedipine]. / Effet vasoconstricteur de l'endothéline. Interaction avec le facteur natriurétique atrial, le nitroprussiate de sodium, le ciclétanine et la nifédipine.

The contractile properties of endothelin (ENDO) and its interactions with some putative antagonists were investigated in endothelium free ring of rat aorta. ENDO induced a slowly developing contraction which is only partially affected by sodium nitroprusside (10(-8) M - 10(-5) M) and to a lesser extend by the calcium antagonist nifedipine (10(-8) M - 10(-5) M). Atrial natriuretic factor (ANF) (10(-9) M - 10(-8) M), cicletanine (3.10(-5) M - 3.10(-4) M) and quercetin (10(-5) M - 10(-4) M) induced a dose dependent relaxation in ENDO precontracted preparations. ANF was less effective in inhibiting ENDO- than phenylephrine precontracted aorta. In addition, the ANF vasodilating effect upon ENDO contraction is potentiated by cicletanine (10(-4) M). The protein kinase C inhibitor phloretin, induced a dose-dependent relaxation (10(-5) M - 3.10(-4) M) in both ENDO and phorbol 12, 13-dibutyrate precontracted aorta. Whereas H7 (10(-5) M - 3.10(-4) M) an other protein kinase C inhibitor was only effective in ENDO-induced contraction. These data indicate that in isolated rat aorta, the contraction induced by ENDO does not mainly occur through membrane potential-dependent calcium channels. The vasoconstrictor mechanism of ENDO, which is different from the one triggered by phenylephrine could involve activation of protein kinase C.

[Loss of contractile stability induced by phenylephrine and endothelin in the aorta of rats treated with endotoxin]. / Perte de stabilité de la contraction provoquée par la phényléphrine et l'endothéline sur l'aorte de rats traités par l'endotoxine.

The alterations of vascular reactivity in endotoxemia were investigated using the aorta from intraperitoneally endotoxin-injected rats (E. Coli 0111: B4; 10 mg/kg). After 3 hours, rings were removed and isometric contractions recorded. Using single maximal agonist concentration, similar contractions were observed in sham and shocked preparations for phenylephrine (PE), endothelin (ET-1) and phorbol 12, 13 dibutyrate (PDB) but not for KCl. Nevertheless, contraction elicited by PE lost tonicity (105 min observation). This fact was not due to endothelium, prostaglandins (since indomethacin and aspirin were ineffective) PE degradation (since medium contained, propranolol, hydrocortisone acetate, cocaine and EDTA) or excitation-contraction coupling fading (since contraction was restored by other agonists) but may involve synthesis of protein (since cycloheximide significantly antagonized this phenomenon). This loss of tonicity was also observed with ET-1 but was less pronounced with KCl and PDB. In conclusion, endotoxin induced impairment of vascular reactivity may occur through different pathways: contractile events (e.g. calcium influx as exemplified by KCl) and receptor events (loss of tonicity and/or desensitization as exemplified by PE and ET-1) from the different agonists tested, PDB, which activates the protein kinase C, was the less affected by endotoxin.

[Pharmacological bases of the vascular impact of Ginkgo biloba extract]. / Bases pharmacologiques de l'impact vasculaire de l'extrait de Ginkgo biloba.

The preferential tissue irrigatory effect of Ginkgo biloba extract in ischaemic areas is largely explained by the direct impact of this product on both arteries and veins. The adrenergic vasoregulatory system and the vascular endothelium are the preferential targets for arterial impact. Ginkgo biloba extract reinforces the physiological vasoregulation of the sympathetic nervous system directly, by acting on neuromediator release, and indirectly, by inhibiting their extraneuronal degradation by catechol-orthomethyltransferase (C.O.M.T.) In the arterial endothelium Ginkgo biloba extract stimulates the release of endogenous relaxing factors, such as endothelium-derived relaxing factor, (EDRF) and prostacyclin. The action of Ginkgo biloba extract on the venous system has been shown to have a venoconstrictor component that maintains the degree of parietal tonus essential to the dynamic clearing of toxic metabolites accumulated during tissue ischaemia. The originality of the vascular impact mechanisms of Ginkgo biloba extract is due to the fact that the product can at the same time combat the phenomena resulting from vascular spasm and with the same efficiency restore circulation in areas subject to vasomotor paralysis.

Discrimination between phenylephrine-triggered contractile events by atrial natriuretic factor in rat aorta.

The effects of atrial natriuretic factor (ANF) on contractile events triggered by phenylephrine (PE) were investigated in rat aorta. Isometric contraction of endothelium-free rat aorta rings was recorded in Ca2+-free medium containing 1 mM EGTA. PE (1 microM) induced a phasic contraction and a sustained contraction following addition of Ca2+ (2.5 mM) to the medium. The phasic contraction was due to intracellular Ca2+ release whereas the sustained one was dependent on extracellular Ca2+ influx. ANF (1-3 nM) and prazosin (3-10 nM) both reduced the two types of contraction. However, during the sustained contraction, a rhythmic activity was observed when ANF, but not prazosin, was used as an inhibitory agent. The calcium antagonist diltiazem (0.1-1 microM) abolished this rhythmic activity, which was attributed to a Ca2+ influx through potential-dependent channels. The results indicate that ANF, unlike prazosin, may discriminate between PE-triggered contractile events in the rat aorta.

Verapamil as an apparent competitive antagonist of the serotonin receptor of rabbit isolated aorta.

The actions of four Ca2+-antagonists (verapamil, diltiazem, nifedipine and flunarizine) were tested on serotonin- (5-HT-) induced contraction of rabbit isolated aorta. Verapamil produced a dose-dependent, parallel shift to the right of the concentration-response curve for 5-HT (pA2 approximately equal to 7.13; Schild slope approximately equal to 1.01), indicative of competitive antagonism. The effects of diltiazem, nifedipine and flunarizine were much less pronounced and best characterized as non-competitive interactions. The effect of verapamil, which likely involves its antagonism of smooth muscle 5-HT2-receptors, might be useful in explaining its therapeutic actions and/or its side-effects.

Pharmacological evidence that different alpha 1 adrenoceptor subtypes mediate contraction in rabbit prostate and hypogastric artery.

The alpha 1 adrenoceptor subtypes mediating contraction of rabbit prostate and hypogastric artery were pharmacologically characterized using an isolated organ bath technique. The prostate had the same sensitivity to the contractile action of methoxamine and phenylephrine, whereas the hypogastric artery was five times less sensitive to the action of methoxamine in comparison with phenylephrine. Clonidine elicited contraction in the hypogastric artery but not in the prostate. BMY7378 was about 70-fold more potent to antagonize the phenylephrine-induced contraction in the hypogastric artery (pA2 8.14) than in the prostate (pA2 6.28), and 5-methyl-urapidil was about three-fold more potent on prostrate than on hypogastric artery. The potency of different alpha 1-adrenoceptor antagonists tested in the rabbit prostate was significantly correlated with their binding affinity for the expressed recombinant alpha 1A-, but not alpha 1B- or alpha 1D-, adrenoceptor subtype, whereas, the potency of the alpha 1-adrenoceptor antagonists tested in the rabbit hypogastric artery was better correlated with the defined alpha 1D-adrenoceptor. Chloroethylclonidine produced a 10-fold rightward shift in the phenylephrine concentration-response curve in the hypogastric artery but only had a weak effect in the prostate. The results indicate that significant heterogeneity exists among alpha1-adrenoceptor in the rabbit hypogastric artery (alpha 1D-adrenoceptor) and the prostate (alpha 1A-adrenoceptor).

Characterization of endothelin receptors mediating contraction and relaxation in rabbit saphenous artery and vein.

The endothelin receptors in rabbit isolated rings of saphenous artery and saphenous vein have been characterized using endothelin-1, endothelin-2, endothelin-3, sarafotoxin S6c, and BQ123. Although artery rings were more sensitive than those from vein to the contractile action of phenylephrine, endothelin-1 was about three times more potent as a contractile agonist on vein than on artery. In rings precontracted with phenylephrine, carbachol was 10 times more potent in vein than in artery rings to induce endothelium-dependent relaxation. However, in rings precontracted to a similar tone by endothelin-1, the relaxation elicited by carbachol was reduced in the vein but remained unchanged in the artery. In endothelium-denuded saphenous artery, endothelin-1 and endothelin-2 elicited contraction with equal potency, whereas endothelin-3 and sarafotoxin S6c were weak agonists. In saphenous vein, the rank order of sensitivity was sarafotoxin S6c > endothelin-2 > or = endothelin-1 = endothelin-3, whereas sarafotoxin S6c and, to a lesser extent, endothelin-3 act as partial agonists. The ETA receptor antagonist BQ123 shifted, to the right, the concentration-response curves of endothelin-1 on endothelium-denuded saphenous artery (pA2 = 7.25). In the endothelium-denuded saphenous vein, 10 microM BQ123 shifted to the right only the response to high concentrations of endothelin-1. In vein but not in artery, endothelin-1 and sarafotoxin S6c induced an endothelium-dependent relaxation, which was increased, in the case of endothelin-1, in the presence of BQ123.2+.