(Hypertension. 1995;25:739-743.)
© 1995 American Heart Association, Inc.
Articles |
Endothelin Receptor Subtypes in Small Arteries
Studies With FR139317 and Bosentan
From the Department of Cardiology, Cardiovascular Research, University Hospital/Inselspital, Bern, Switzerland.
Correspondence to Thomas F. Lüscher, Cardiology, Cardiovascular Research, University Hospital/Inselspital, CH-3010 Bern, Switzerland.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract We studied the effects of the selective endothelin A receptor antagonist FR139317 and the combined endothelin A/endothelin B receptor antagonist bosentan in rat mesenteric arteries by using a video dimension analyzer. In endothelium-denuded arteries, increasing concentrations of endothelin-1 evoked a biphasic vasoconstriction. The first phase was observed at low concentrations (10-16 to 10-11 mol/L) of endothelin-1 and was relatively weak. However, the contractions characterizing the second phase, which occurred at higher concentrations (10-10 to 3x10-8 mol/L) of endothelin-1, were much stronger. FR139317 concentration-dependently shifted the second phase of the endothelin-1–induced contraction curve to the right without affecting the first phase. In contrast, bosentan inhibited both the first and the second phase. Even after the blockade of endothelin A receptor, increasing concentrations of the endothelin B receptor agonists endothelin-3 and sarafotoxin S6c still induced small contractions. Maximal contractions induced by single-bolus extraluminal application of endothelin-3 (10-9 mol/L) or sarafotoxin S6c (3x10-8 mol/L) were markedly more pronounced than responses induced by cumulative concentrations, suggesting endothelin B receptor downregulation upon repeated and sustained activation. The response induced by a single bolus of endothelin-3 (10-9 mol/L) was antagonized by bosentan but not by FR139317, confirming that endothelin B receptors were involved. In endothelium-intact arteries half-maximally precontracted with norepinephrine, bosentan but not FR139317 inhibited the relaxations induced by intraluminally applied endothelin-3. Thus, selective endothelin A receptor antagonist preserves relaxations to endothelins, and combined endothelin A/endothelin B receptor antagonist is more efficacious in inhibiting contractions in resistance arteries.
Key Words: endothelins • receptors, endothelin • vascular resistance
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Endothelin-1 (ET-1), which is a member of the 21-amino acid endothelin family (ET-1, ET-2, ET-3, and sarafotoxins), is a potent vasoactive peptide produced by the endothelium.1 2 These peptides play important roles in the regulation of vascular smooth muscle tone by inducing either vasoconstriction or vasodilation by means of two distinct endothelin receptors that have been cloned. The endothelin A (ETA) receptor, which has a high specificity for ET-1, is present on vascular smooth muscle cells and mediates vasoconstriction.3 The endothelin B (ETB) receptor has an equal affinity for all isoforms of endothelins and was originally detected in vascular endothelial cells.4 Stimulation of endothelial ETB receptors produces nitric oxide,5 prostacyclin,6 7 or both to evoke vasodilation. However, recent studies have demonstrated that ETB receptors not only exist on endothelial cells but also on vascular smooth muscle cells of certain vessels of dogs,8 humans,9 pigs,9 10 11 rabbits,12 13 14 15 and rats,16 where they mediate vasoconstriction.
In endothelium-denuded mesenteric arteries of young but not of old rats, ET-1 evokes biphasic concentration-dependent vasoconstriction.17 If ETB receptors contribute to endothelin-induced vasoconstriction, combined ETA/ETB receptor antagonists may be advantageous. On the other hand, combined ETA/ETB receptor antagonists might interfere with the endothelial effects of endothelins. This study was designed to pharmacologically characterize the endothelin receptor subtypes involved in contraction as well as in endothelium-dependent relaxation induced by endothelin. Two endothelin receptor antagonists were used: FR139317, a novel potent and selective nonpeptide ETA receptor antagonist,18 19 20 and bosentan, a nonpeptide combined ETA/ETB receptor antagonist.9 21 All experiments were performed in isolated, perfused mesenteric resistance arteries of Wistar-Kyoto rats.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Experimental Animals
Male Wistar-Kyoto rats 8 to 9 weeks of age were obtained from Charles-River Wiga GmbH. The rats were anesthetized with thiopentalum natricum (50 mg/kg IP) and exsanguinated by decapitation. The mesentery was removed and immersed in a cold Krebs' solution of the following composition (in mmol/L): NaCl 118.6, KCl 4.7, CaCl2 2.5, KH2PO4 1.2, MgSO4 1.2, NaHCO3 25.1, edetate calcium disodium 0.026, and glucose 10.1.
Experimental Setup
A segment about 2 mm in length of the second or third
branch of the mesenteric artery of each rat was isolated under a
dissection microscope (intraluminal diameter, 200 to 250 µm). After
the fatty tissue was removed, the artery was transferred to an
arteriograph chamber filled with warmed (37±0.5°C) and oxygenated
(95% O2 and 5% CO2) Krebs' solution
circulating from a 250-mL oxygenated reservoir at a flow rate of 50
mL/min.6 17 The chamber contained two glass microcannulas.
The proximal end of the artery was mounted on an afferent cannula and
secured with a surgical nylon suture, and the distal end of the vessel
was positioned inside an efferent cannula. The artery was then perfused
intraluminally with Krebs' solution containing 1.0% bovine serum
albumin and equilibrated under a constant optimal perfusion pressure of
30 mm Hg for 45 minutes before the experiments. The arteriograph was
placed on the stage of a microscope equipped with a video camera. The
signal derived from the video image of the vessel was processed by a
video dimension analyzer (Living Systems Instrumentation) for
continuous measurement and recording of intraluminal diameter. The
intraluminal application of drugs was done through the afferent cannula
with an infusion pump (Harvard Apparatus) at a rate that was one tenth
the intraluminal perfusion rate.
To remove the endothelium, 0.3 mL of a Krebs' solution containing 0.5% CHAPS was infused intraluminally for 30 to 60 seconds.6 17 The presence or absence of the endothelium was confirmed by acetylcholine (10-5 mol/L) in preparations half-maximally precontracted with norepinephrine (1x10-6 to 3x10-6 mol/L). The integrity of the vascular smooth muscle function was further assessed by a relaxation to sodium nitroprusside (10-6 mol/L).
Protocols
Concentration-response curves to ET-1 (10-16 to
3x10-8 mol/L) were obtained by cumulative extraluminal
application of the peptide on endothelium-denuded
arteries. Control experiments were performed without any other
pharmacological agents. To inhibit the ETA receptors, some
arteries were preincubated with the ETA receptor antagonist
FR139317 (10-7, 10-6, and
10-5 mol/L) 30 minutes before application of ET-1. In
another set of experiments, both ETA and ETB
receptors were blocked by the addition of the nonselective endothelin
receptor antagonist bosentan (10-7,
10-6, and 10-5 mol/L) 30 minutes
before ET-1 application. To confirm the existence of ETB
receptors on the arteries, extraluminal concentration-response curves
were constructed for the ETB receptor agonists ET-3
(10-16 to 10-7 mol/L)22 and
sarafotoxin S6c (10-11 to 3x10-8
mol/L)23 in the presence of FR139317 (10-5
mol/L). To determine whether the small contractions of
concentration-response curves observed during prolonged ETB
receptor stimulation were due to downregulation of the receptor, single
concentrations of ET-3 (10-9 mol/L) and sarafotoxin S6c
(3x10-8 mol/L) were applied extraluminally. Additionally,
a single concentration of ET-3 was administered in the presence of
either FR139317 (10-5 mol/L) or bosentan
(10-5 mol/L) to confirm the nature of the receptors
involved. Finally, ET-3 (10-12 to 10-9 mol/L)
was infused intraluminally, in the absence or the presence of the
endothelin receptor antagonists FR139317 (10-5 mol/L) or
bosentan (10-5 mol/L), in
endothelium-intact arteries half-maximally
precontracted with norepinephrine (1x10-6 to
3x10-6 mol/L) to study the relaxant effect of the
endothelial ETB receptor stimulation.
Drugs
The following drugs were used: acetylcholine chloride, CHAPS,
(-)-norepinephrine bitartrate, sodium nitroprusside (all from Sigma
Chemical Co), ET-1, ET-3 (both from Calbiochem-Novabiochem AG),
bosentan (F. Hoffmann–La Roche Ltd), FR139317 (Fujisawa Pharmaceutical
Co Ltd), and sarafotoxin S6c (Bachem Feinchemikalien AG). All drugs
were dissolved in distilled water and diluted with Krebs' solution
except for ET-1, ET-3, and sarafotoxin S6c, which were dissolved in
distilled water containing 0.1% bovine serum albumin and diluted with
Krebs' solution containing 0.05% bovine serum albumin, and FR139317,
which was dissolved with 20% ethanol and diluted with distilled water
before the experiments. The final concentration of ethanol in the
chamber was less than 0.02%, which by itself did not cause any
significant effect (data not shown).
Calculations and Statistical Analysis
The contractions were expressed as percentage of the
decrease in intraluminal vascular diameter. The diameter at the resting
period was taken as 100%. The relaxations to intraluminal ET-3 were
expressed as percentage of the increase in intraluminal vascular
diameter obtained during the contraction evoked by norepinephrine. Data
are expressed as mean±SEM. The concentrations of the agonists causing
half-maximal response were calculated for the second phase of
ET-1–induced contraction by use of a nonlinear regression
analysis. These data are expressed as the negative logarithm of the
molar concentration (pD2 value). To evaluate the response
to endothelin occurring at low concentrations (ie, in the first phase
of the concentration-response curve), the C11 value (the
percentage of contraction obtained at 10-11 mol/L ET-1)
was calculated. An ANOVA followed by Bonferroni's correction for
multiple comparisons24 was used to compare the results of
each group of experiments. A probability value less than .05 was
considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Effects of FR139317 and Bosentan on ET-1–Induced Contraction
Cumulative concentrations of ET-1 evoked biphasic contractions of endothelium-denuded mesenteric resistance arteries of 8- to 9-week-old Wistar-Kyoto rats (Fig 1). Low concentrations (10-16 to 10-11 mol/L) of ET-1 elicited small contractions (first phase), and higher concentrations (10-10 to 3x10-8 mol/L) induced more potent concentration-dependent contractions (second phase). The ETA receptor antagonist FR139317 concentration-dependently shifted the second phase of the concentration-response curves to the right in a parallel fashion (Fig 1). The pD2 values of those experiments are reported in the Table. However, FR139317 did not affect the first phase of ET-1–induced contraction (Fig 1 and Table). In contrast, bosentan not only shifted the second phase of the curves in a concentration-dependent manner to the right, but also completely inhibited the first phase of the curve (Fig 2 and Table). The C11 values for 10-6 and 10-5 mol/L bosentan were significantly lower compared with the control responses (Table). The maximal responses obtained in the control experiments were not modified significantly by the antagonists.
|
|
|
Responses to Extraluminal ET-3 and Sarafotoxin S6c
The cumulative extraluminal application of both ET-3
(10-16 to 10-7 mol/L) and sarafotoxin S6c
(10-11 to 3x10-8 mol/L) evoked small
contractions (maximal responses, 16±5% at 10-9 mol/L
ET-3 and 7±2% at 10-8 mol/L sarafotoxin S6c) in vessels
pretreated with FR139317 (10-5 mol/L for 30 minutes) (Fig 3). Under the same conditions of ETA
receptor blockade, the maximal contraction of the first phase of
ET-1–induced biphasic contraction was 15±6% at 10-9
mol/L ET-1 (Fig 3).
|
In contrast, single-bolus extraluminal application of ET-3 (10-9 mol/L) or sarafotoxin S6c (3x10-8 mol/L) produced much more potent contractions (39±5% and 38±9%, respectively) than the cumulatively induced maximal contractions (Fig 4a). This response produced by a single concentration of ET-3 (10-9 mol/L) was significantly blocked by bosentan (10-5 mol/L) but not FR139317 (10-5 mol/L) (Fig 4b).
|
P<.001
versus control (ANOVA). These responses were obtained in perfused and
pressurized mesenteric resistance arteries after removal of the
endothelium. Values are mean±SEM (SEM shown by vertical bars) for six
rats per group.
Responses to Intraluminal ET-3
The cumulative intraluminal application of ET-3
(10-12 to 10-9 mol/L) induced
concentration-dependent relaxations (56±8% at 10-9 mol/L
ET-3) in endothelium-intact arteries half-maximally
precontracted with norepinephrine (1x10-6 to
3x10-6 mol/L). Bosentan (10-5 mol/L)
significantly inhibited ET-3–induced relaxation, but FR139317
(10–5 mol/L) had no significant effect on this response
(10±2% and 52±12% at 10-9 mol/L ET-3, respectively)
(Fig 5).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In this study, two novel endothelin receptor antagonists, FR139317 (selective ETA receptor antagonist) and bosentan (combined ETA/ETB receptor antagonist), were used to characterize the endothelin receptors involved in the vascular responses of mesenteric resistance arteries of Wistar-Kyoto rats. Our results suggest that both ETA and ETB receptors exist on vascular smooth muscle cells and mediate ET-1–induced contraction with different affinities and efficacies as well as different propensities to tachyphylaxis. The results also confirm that ETB receptors are responsible for endothelium-dependent relaxation induced by endothelin. Accordingly, bosentan was more efficacious in inhibiting contraction, and FR139317 but not bosentan preserved endothelium-dependent relaxations to endothelin.
Previous experiments with young rats have shown a biphasic contraction to ET-1 in mesenteric resistance artery without endothelium,6 suggesting that two distinct endothelin receptors are involved. Indeed, in endothelium-denuded mesenteric resistance arteries, both FR139317 and bosentan inhibited the low-affinity and high-efficacy contraction (second phase) to ET-1, and bosentan but not FR139317 prevented the high-affinity and low-efficacy contraction (first phase) to ET-1. These results indicate an involvement of ETA receptors in the second phase and of ETB receptors in the first phase. Indeed, the fact that cumulative administration or a single concentration of ET-322 or sarafotoxin S6c,23 both ETB receptor agonists, evoked contractions after blockade of ETA receptor with FR139317 confirms the existence of ETB receptors in this tissue, as has been reported in other vascular beds and species.8 9 10 11 12 13 14 15 16 The existence of two subtypes of endothelin receptors on vascular smooth muscle cells therefore seems to be a common phenomenon. However, the relative contribution of vascular ETB receptors to endothelin-induced contraction may vary depending on the vascular bed or species.9 Aging also seems to influence ETB receptor–mediated contraction in rats, as suggested by the disappearance of the high-affinity contraction to ET-1 in older rats.17 Moreover, the relative importance of ETB receptor–mediated contraction in different vascular beds, or even in the same vascular bed of different animals, may depend on local regulation of ETB receptor expression. In this respect, our results demonstrate that ETB receptors can undergo downregulation. Indeed, prolonged exposure to ET-3 or sarafotoxin S6c, such as during a cumulative concentration-response curve, resulted in markedly smaller contraction than with a single-bolus application of the agonists. In addition, the contraction obtained with these agonists was not sustained, and the vessels regained initial vascular diameter prior to the addition of the drugs after 40 to 60 minutes (data not shown).13 25 Both ETA and ETB receptors have been reported to be downregulated.26 27 However, the present study suggests marked ETB receptor downregulation, but the ETA receptor–mediated contraction induced by ET-1 was not downregulated in the same way. Indeed, our experiments showed that maximal contractions could be obtained despite prolonged exposure to ET-1. Similarly, indirect evidence from in vivo experiments also indicates that downregulation of ETB receptors mediating vasodilation is more obvious than that of the vasoconstrictor ETA receptors.28 Our results are therefore consistent with the suggestion that ETB receptors are downregulated much more easily and more rapidly than ETA receptors.27
Because ETB receptors occur in endothelium and smooth muscle cells, the existence of two ETB subtypes has been suggested.8 11 29 Other results, however, suggest that the same ETB receptor subtype mediates both vasoconstriction and vasodilation. Indeed, the ETB receptor agonist ET-3 induces relaxation followed by contraction in porcine ophthalmic microcirculation.30 In the present study, the ETB receptor agonists ET-3 and sarafotoxin S6c produced relaxations in endothelium-intact precontracted arteries and contractions in endothelium-denuded arteries. However, the ET-3–induced but not the sarafotoxin S6c–induced contraction was similar to the first phase of ET-1–induced contraction after preincubation with FR139317. Hence, the two selective ETB receptor agonists may have different affinities to the same ETB receptor, or subtypes of ETB receptors (ETB1 and ETB2) or even an ETC receptor31 32 33 may exist on vascular smooth muscle and endothelium. More likely, however, sarafotoxin S6c causes more profound tachyphylaxis than ET-3, because the contractions to a single-bolus application of either ET-3 or sarafotoxin S6c were identical.
The contribution of different endothelin receptors to the response to endothelins will have important consequences for the use of endothelin receptor antagonists. Circulating endothelin levels are increased in certain forms of hypertension,1 coronary spasm,34 myocardial infarction,35 heart failure,36 and other vascular diseases.37 Because both ETA and ETB receptors are expressed and contribute to contractions, combined ETA/ETB receptor antagonists may be required to interfere with the effects of endothelin. However, combined ETA/ETB receptor antagonists inhibit endothelium-dependent relaxations as well as contractions to endothelin. On the contrary, because the selective ETA receptor antagonist leaves endothelium-dependent relaxation to ET-3 unaffected, this effect may be therapeutically beneficial. Therefore, if endothelin antagonists are to be used therapeutically, it will be important to know more about the relative importance of ETB receptor–mediated contraction and relaxation.
In conclusion, both ETA and ETB receptors are present on the smooth muscle of rat mesenteric resistance arteries and mediate vasoconstriction. ETB receptors, which are more easily downregulated by prolonged activation than ETA receptors, mediate responses to endothelin with high affinity but low efficacy, and responses involving ETA receptors occur at higher concentrations of endothelin and are more efficacious. The development of new pharmacological tools, such as FR139317 and bosentan, is helpful to the better understanding of the physiological role of the endothelin family of peptides as well as to the determination of their contribution to hypertension and other cardiovascular diseases.
|
Acknowledgments |
|---|
This study was supported by the Swiss National Research Foundation (No. 32-32541.91), the Swiss National Science Foundation (No. 3100-039695.93-1), the Karl Meyer Foundation, Vaduz, Liechtenstein, the Patria Insurance Company, and an educational grant from F. Hoffmann–La Roche AG, Basel, Switzerland.
|
Footnotes |
|---|
Read before the 48th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research of the American Heart Association, Chicago, Ill, September 27-30, 1994 (Hypertension. 1994;24:403. Abstract).
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lüscher TF, Boulanger CM, Dohi Y, Yang Z. Endothelin-derived contracting factors. Hypertension. 1992;19:117-130.
2. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415. [Medline] [Order article via Infotrieve]
3. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990;348:730-732. [Medline] [Order article via Infotrieve]
4. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of endothelin receptor. Nature. 1990;348:732-735. [Medline] [Order article via Infotrieve]
5. Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K, Marumo F. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest. 1993;91:1367-1373.
6.
Dohi Y, Lüscher TF. Endothelin in hypertensive
resistance arteries: intraluminal and extraluminal dysfunction.
Hypertension. 1991;18:543-549.
7. Filep J, Battistini B, Coté YP, Beaudoin AR, Sirois P. Endothelin-1 induced prostacyclin release from bovine aortic endothelial cells. Biochem Biophys Res Commun. 1991;177:171-176. [Medline] [Order article via Infotrieve]
8. Teerlink JR, Breu V, Sprecher U, Clozel M, Clozel J-P. Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries. Circulation. 1993;88(suppl I):I-568. Abstract.
9.
Seo B, Oemar BS, Siebenmann R, von Ludwig S, Lüscher
TF. Both ETA and ETB receptors mediate
contraction to endothelin-1 in human blood vessels.
Circulation. 1994;89:1203-1208.
10. Ihara M, Saeki T, Funabashi K, Nakamichi K, Yano M, Fukuroda T, Miyaji M, Ikemoto M. Two endothelin receptor subtypes in porcine arteries. J Cardiovasc Pharmacol. 1991;17(suppl 7):S119-S121.
11. Baribeau J, Perreault T. Heterogeneous endothelin (ET) receptors in the piglet pulmonary vasculature. Circulation. 1993;88(suppl I):I-478. Abstract.
12. Panek RL, Major TC, Hingorani GP, Doherty AM, Taylor DG, Rapundalo ST. Endothelin and structurally related analogs distinguish between endothelin receptor subtypes. Biochem Biophys Res Commun. 1992;183:566-571. [Medline] [Order article via Infotrieve]
13. La Douceur DM, Flynn MA, Keiser JA, Reynolds E, Haleen SJ. ETA and ETB receptors coexist on rabbit pulmonary artery vascular smooth muscle mediating contraction. Biochem Biophys Res Commun. 1993;196:209-215. [Medline] [Order article via Infotrieve]
14. Sumner MJ, Cannon TR, Mundin JM, White DG, Watts IS. Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. Br J Pharmacol. 1992;107:858-860. [Medline] [Order article via Infotrieve]
15. Moreland S, McMullen DM, Delaney CL, Lee VG, Hunt JT. Venous smooth muscle contains vasoconstrictor ETB-like receptor. Biochem Biophys Res Commun. 1992;184:100-106. [Medline] [Order article via Infotrieve]
16.
Batra VK, McNeill JR, Xu Y, Wilson TW, Gopalakrishnan V.
ETB receptors on aortic smooth muscle cells of
spontaneously hypertensive rats. Am J Physiol. 1993;264:C479-C484.
17. Dohi Y, Lüscher TF. Aging differentially affects direct and indirect actions of endothelin-1 in perfused mesenteric arteries of the rat. Br J Pharmacol. 1990;100:889-893. [Medline] [Order article via Infotrieve]
18. Sun XY, Hedner T, Feng Q, Edvinsson L. Inhibition of endothelin (ET-1) induced pressor responses by the endothelin (ETA) receptor antagonist FR139317. Blood Press. 1992;1:108-112. [Medline] [Order article via Infotrieve]
19.
Sogabe K, Nirei H, Shoubo M, Nomoto A, Ao S, Notsu Y,
Ono T. Pharmacological profile of FR139317, a novel, potent endothelin
ETA receptor antagonist. J Pharmacol Exp
Ther. 1993;264:1040-1046.
20. Cardell LO, Uddman R, Edvinsson L. A novel ETA-receptor antagonist, FR139317, inhibits endothelin-induced contractions of guinea-pig pulmonary arteries, but not trachea. Br J Pharmacol. 1993;108:448-452. [Medline] [Order article via Infotrieve]
21.
Clozel M, Breu V, Gray GA, Kalina B, Löffler B-M, Burri
K, Cassal J-M, Hirth G, Müller M, Neidhart W, Ramuz H.
Pharmacological characterization of bosentan, a new potent orally
active non-peptide endothelin receptor antagonist. J Pharmacol
Exp Ther. 1994;270:228-235.
22. Saeki T, Ihara M, Fukuroda T, Yamagiwa M, Yano M. [Ala1,3,11,15]Endothelin-1 analogs with ETB agonistic activity. Biochem Biophys Res Commun. 1991;179:286-292. [Medline] [Order article via Infotrieve]
23. Williams DLJ, Jones KL, Pettibone DJ, Lis EV, Clinschmidt BV. Sarafotoxin S6c: an agonist which distinguishes between endothelin receptor subtypes. Biochem Biophys Res Commun. 1991;175:556-561. [Medline] [Order article via Infotrieve]
24.
Wallenstein S, Zucker CL, Fleiss J. Some statistical methods
useful in circulation research. Circ Res. 1980;47:1-9.
25.
Häfliger IO, Flammer J, Lüscher TF. Nitric oxide
and endothelin-1 are important regulators of human ophthalmic artery.
Invest Ophthalmol Vis Sci. 1992;33:2340-2343.
26. Hirata Y, Yoshimi H, Takaichi S, Yanagisawa M, Masaki T. Binding and receptor down-regulation of a novel vasoconstrictor endothelin in cultured rat vascular smooth muscle cells. FEBS Lett. 1988;239:13-17. [Medline] [Order article via Infotrieve]
27. Masaki T. Overview: reduced sensitivity of vascular response to endothelin. Circulation. 1993;87(suppl V):V-33-V-35.
28.
Le Monnier de Gouville A, Lippton H, Cohen G, Cavero I,
Hyman A. Vasodilator activity of endothelin-1 and endothelin-3: rapid
development of cross-tachyphylaxis and dependence on the rate of
endothelin administration. J Pharmacol Exp Ther. 1990;254:1024-1028.
29.
Sokolovsky M, Ambar I, Garlon R. A novel subtype of endothelin
receptors. J Biol Chem. 1992;267:20551-20554.
30.
Meyer P, Flammer J, Lüscher TF. Endothelin-dependent
regulation of the ophthalmic microcirculation in the perfused porcine
eyes: role of nitric oxide and endothelins. Invest Ophthalmol Vis
Sci. 1993;34:3614-3621.
31. Samson WK, Skala KD, Alexander BD, Huang FS. Pituitary site of action of endothelin: selective inhibition of prolactin release in vitro. Biochem Biophys Res Commun. 1990;169:737-743. [Medline] [Order article via Infotrieve]
32.
Karne S, Jayawickreme CK, Lerner MR. Cloning and
characterization of an endothelin-3 specific receptor (ETC receptor)
from Xenopus levis dermal melanophores. J Biol
Chem. 1993;268:19126-19133.
33. Emori T, Hirata Y, Marumo F. Specific receptors for endothelin-3 in cultured bovine endothelial cells and its cellular mechanism of action. FEBS Lett. 1990;263:261-264. [Medline] [Order article via Infotrieve]
34.
Toyo-oka T, Aizawa T, Suzuki N, Hirata Y, Miyauchi T, Shin WS,
Yanagisawa M, Masaki T, Sugimoto T. Increased plasma level of
endothelin-1 and coronary spasm induction in patients with vasospastic
angina. Circulation. 1991;83:476-483.
35. Stewart DJ, Kubac G, Costello KB, Cernacek P. Increased plasma endothelin-1 in the early hours of acute myocardial infarction. J Am Coll Cardiol. 1991;18:38-43. [Abstract]
36. Rodeheffer R, Lerman A, Heublein DH, Burnnett JCJ. Plasma endothelin concentrations are increased in humans with congestive heart failure. Mayo Clin Proc. 1992;67:719-724. [Medline] [Order article via Infotrieve]
37. Lüscher TF. Do we need endothelin antagonists? Cardiovasc Res. 1993;27:2089-2093.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  T. Quaschning, F. Voss, K. Relle, P. Kalk, N. Vignon-Zellweger, T. Pfab, C. Bauer, F. Theilig, S. Bachmann, A. Kraemer-Guth, et al. Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension: Lessons from Endothelin-1 Transgenic/Endothelial Nitric Oxide Synthase Knockout Mice J. Am. Soc. Nephrol., March 1, 2007; 18(3): 730 - 740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wendel, W. Kummer, L. Knels, J. Schmeck, and T. Koch Muscular ETB Receptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature J. Histochem. Cytochem., February 1, 2005; 53(2): 187 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kjekshus, O. A. Smiseth, R. Klinge, E. Oie, M. E. Hystad, and H. Attramadal Regulation of ET: pulmonary release of ET contributes to increased plasma ET levels and vasoconstriction in CHF Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1299 - H1310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hasdai, V. Mathew, R. S. Schwartz, L. A. Smith, D. R. Holmes Jr, Z. S. Katusic, and A. Lerman Enhanced Endothelin-B-Receptor–Mediated Vasoconstriction of Small Porcine Coronary Arteries in Diet-Induced Hypercholesterolemia Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 2737 - 2743. [Abstract] [Full Text]
|
|
|
|
 |
|
 L. V. d'Uscio, M. Barton, S. Shaw, P. Moreau, and T. F. Luscher Structure and Function of Small Arteries in Salt-Induced Hypertension : Effects of Chronic Endothelin-Subtype-A–Receptor Blockade Hypertension, October 1, 1997; 30(4): 905 - 911. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||