Endothelin-1, a member of a novel family of regulatory peptides, is the most potent vasoconstrictor and pressor substance known. Endothelin-1 is a 21-amino-acid endothelium-derived peptide causing uniquely sustained vasoconstriction. In addition, endothelin-1 has pronounced effects on the coronary, renal and cerebral circulations, enhances responses to other vasoconstrictors, and is comitogenic. Recent studies have shown that the endothelins are essential for normal fetal development, and that endothelin-1 plays an important physiological role in the regulation of basal vascular tone and blood pressure in healthy humans.
There is now also a wealth of evidence suggesting that endothelin-1 is a key mediator in a range of cardiovascular diseases associated with sustained vasoconstriction, such as chronic heart failure, and with vasospasm, such as subarachnoid haemorrhage. In addition, endothelin-1 appears to act in opposition to nitric oxide to promote the atherosclerotic process. There are a large number of oral and intravenously active endothelin antagonists entering clinical development and a number of clinical studies, particularly with endothelin receptor antagonists, are now under way. Such studies are beginning to define the role of the endothelins in cardiovascular disease and to confirm the potential of the endothelin system as an important new therapeutic target.
YanagisawaMKuriharaHKimuraS. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature1988; 332: 411–15.
2.
InoueAYanagisawaMKimuraS. The human endothelin family; three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A1989; 86: 2863–67.
3.
KimuraSKasuyaYSawamuraT. Structure-activity relationships of endothelin; importance of the C-terminal moiety. Biochem Biophys Res Commun1988; 156: 1182–86.
4.
RandallM DDouglasS AHileyC R. Vascular activities of endothelin-1 and some alanyl substituted analogues in resistance beds of the rat. Br J Pharmacol1989; 98: 685–99.
5.
MacArthurHWarnerT DWoodE GCorderRVaneJ R. Endothelin-1 release from endothelial cells in culture is elevated both acutely and chronically by short periods of mechanical stretch. Biochem Biophys Res Commun1994; 200: 396–400.
6.
McClellanGWeisbergARoseDWinegradS. Endothelial cell storage and release of endothelin as a cardioregulatory mechanism. Circ Res1994; 75: 85–96.
7.
EmoriTHiratYOhtaK. Cellular mechanisms of endothelin-1 release by angiotensin and vasopressin. Hypertension1991; 18: 165–70.
8.
MarsdenP ADorfmanD MCollinsTBrennerB MOrkinS HBallermannB J. Regulated expression of endothelin-1 in glomerular capillary endothelial cells. Am J Physiol1991; 261: F117–25.
9.
HuR MLevinE RPedramAFrankH J. Insulin stimulates production and secretion of endothelin from bovine endothelial cells. Diabetes1993; 42: 351–58.
10.
YokokawaKKohnoMYasunariKMurakawaKTakedaT. Endothelin-3 regulates endothelin-1 production in cultured human endothelial cells. Hypertension1991; 18: 304–15.
11.
YoshizumiMKuriharaHMontaT. Interleukin-1 increases the production of endothelin-1 by cultured endothelial cells. Biochem Biophys Res Commun1990; 166: 342–29.
12.
KuriharaHYoshizumiMSugiyamaT. Transforming growth factor-beta stimulates the expression of endothelin mRNA by vascular endothelial cells. Biochem Biophys Res Commun1989; 159: 1435–40.
13.
SugiuraMInagamiTKonV. Endotoxin stimulates endothelin release in vivo and in vitro as determined by radioimmunoassay. Biochem Biophys Res Commun1989; 161: 1220–27.
14.
Matin-NizardFHoussainiH SLestavel-DelattreSDuriezPFruehartJ C. Modified low density lipoproteins activate macrophages to secrete ir-ET. FEBS Lett1991; 293: 127–30.
15.
MilnerPBodinPLoeschABurustockG. Rapid release of endothelin and ATP from isolated aortic endothelial cells exposed to increased flow. Biochem Biophys Res Commun1990; 170: 649–56.
16.
KourembanasSMarsdenP AMcQuillanL PFallerD V. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest1991; 88: 1054–57.
17.
GrayG AWebbD J. The molecular biology and pharmacology of the endothelins. Molecular Biology Intelligence Unit Monograph Series. Austin, TX: RG Landes Co., 1995: 173.
18.
InoueAYanagisawaMTakuwaYMitsuiYKobayashiMMasakiT. The preproendothelin-1 gene: Complete nucleotide sequence and regulation of expression. J Biol Chem1989; 264: 14954–59.
19.
BlochK DFriedrichS PLeeM EEddyR LShowsT BQuertermousT. Structural organisation and chromosomal assignment of the gene encoding endothelin. J Biol Chem1989; 264: 10851–57.
20.
XuDEmoloNGiaidA. ECE-1: A membrane-bound metalloprotease that catalyses the proteolytic activation of big endothelin-1. Cell1994; 78: 473–85.
21.
EmotoNYanagisawaM. Endothelin-converting enzyme-2 is a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum. J Biol Chem1995; 270: 15262–68.
22.
WarnerT DElliottJ DOhlsteinE H. California dreamin’ ‘bout endothelin: Emerging new therapeutics. TIPS1996; 17: 177–79.
23.
ShinmiOKimuraSSawamuraT. Endothelin-3 is a novel neuropeptide: Isolation and sequence determination of endothelin-1 and endothelin-3 in porcine brain. Biochem Biophys Res Commun1989; 164: 587–93.
24.
PernowJHemsenALundbergJ M. Tissue specific distribution, clearance and vascular effects of endothelin in the pig. Biochem Biophys Res Commun1989; 161: 647–53.
25.
HowardP GPlumptonCDavenportA P. Anatomical localisation and pharmacological activity of mature endothelins and their precursors in human vascular tissue. J Hypertens1992; 10: 137–86.
26.
FirthJ DRatcliffeP J. Organ distribution of the three rat endothelin messenger RNAs and the effects of ischaemia on renal gene expression. J Clin Invest1992; 90: 1023–31.
27.
YoshimotoSIshizakiYSasakiTMurotaS I. Effect of carbon dioxide and oxygen on endothelial production by cultured porcine cerebral endothelial cells. Stroke1991; 22: 378–83.
28.
NucciGThomasRD'Orleans-JusteP. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A1988; 85: 9797–800.
29.
VijayaraghavanJScicliA GCarreteroO ASlaughterCMoomawCHershL. B.The hydrolysis of endothelins by neutral endopeptidase 24.11. J Biol Chem1990; 265: 14150–55.
30.
HosodaKNakaoKAraiH. Cloning and expression of human endothelin-1 receptor cDNA. FEBS Lett1991; 287: 23–26.
31.
AraiHNakaoKTakayaK. The human endothelin-B receptor gene. Structural organization and chromosomal assignment. J Biol Chem1993; 268: 3463–70.
32.
OgawaYNakaoKAraiH. Molecular cloning of a non-isopeptide-selective human endothelin receptor. Biochem Biophys Res Commun1991; 178: 248–55.
33.
BaxW ASaxenaP R. The current endothelin receptor classification: Time for reconsideration?TIPS1994; 15: 379–86.
34.
DouglasS ABeckG RElliottJ DOhlsteinE H. Pharmacological evidence for the presence of three distinct functional endothelin receptor subtypes in the rabbit lateral saphenous vein. Br J Pharmacol1995; 114: 1529–40.
35.
NambiPPullenMKumarC. Identification of a novel endothelin receptor in Xenopus laevis liver. Neuropeptides1994; 26: 181–85.
36.
HaynesW GStrachanF EWebbD J. Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation1995; 92: 357–63.
37.
DavenportA PMaguireJ J. Is endothelin-induced vasoconstriction mediated only by ETA receptors in humans?TIPS1994; 15: 9–11.
38.
RubanyiG MPolokoffM A. Endothelins: Molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmacological Reviews1994; 46: 328–415.
39.
GriendlingK KTsudaTAlexanderR W. Endothelin stimulates diacylglycerol accumulation and activates protein kinase C in cultured vascular smooth muscle cells. J Biol Chem1989; 264: 8237–40.
40.
SimonsonM SWannSMeneP. Endothelin stimulates phospholipases C, Na+/H+ exchange, c-fos expression and mitogenesis in rat mesangial cells. J Clin Invest1989; 83: 708–12.
41.
WaughC JDockrellM E CHaynesW GOlvermanH JWilliamsB CWebbD J. Inhibition of 125I-endothelin-1 binding to rat cardiac membranes by the potassium channel opener lemakalim. Biochem Biophys Res Commun1992; 185: 630–35.
42.
HaynesW GWebbD J. Venoconstriction to endothelin-1 in humans: The role of calcium and potassium channels. Am J Physiol1993; 265: H1676–81.
43.
ClozelMLöfflerB MBreuVHilfigerLMarieJ PButschaB. Downregulation of endothelin receptors by autocrine production of endothelin-1. Am J Physiol1993; 265: 188–92.
44.
RoubertPGillardVPlasPGuillonJ MChabrierP EBraquetP. Angiotensin II and phorbolesters potently downregulate endothelin binding sites in vascular smooth muscle cells. Biochem Biophys Res Commun1989; 164: 809–15.
45.
LiuJChenRCasleyD JNaylerW N. Ischaemia and reperfusion increase 125-I labelled endothelin-1 binding in rat cardiac membranes. Am J Physiol1990; 258: H828–35.
46.
NambiPPullenMContinoL CBrooksD P. Upregulation of renal endothelin receptors in rats with cyclosporin-A induced nephrotoxicity. Eur J Pharmacol1990; 187: 113–16.
47.
NewmanPKakkarV VKanseS M. Modulation of endothelin receptor expression in human vascular smooth muscle cells by interleukin-1 beta. FEBS Lett1995; 363: 161–64.
48.
KuriharaYKuriharaHSuzukiHKodamaTMacmuraKNagaiR. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature1994; 368: 703–10.
49.
KuriharaYKuriharaHOdaH. Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1. J Clin Invest1995; 96: 293–300.
50.
HosodaKHammerR ERichardsonJ A. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell1994; 79: 1267–76.
51.
PuffenbergerE GHosodaKWashingtonS S. A missense mutation of the endothelin-B receptor gene in multigenic Hirsch-sprung's disease. Cell1994; 79: 1257–66.
52.
AttiéTPeletAEderyP. Mutation of the endothelin-receptor B gene in the Waardenburg-Hirschsprung disease. Hum Mol Genet1995; 4: 2407–409.
53.
OngA C M. Surprising new roles for endothelins. BMJ1996; 312: 195–96.
54.
ClarkeJ GBenjaminNLarkinS W. Endothelin is a potent long-lasting vasoconstrictor in men. Am J Physiol1989; 257: H2033–35.
55.
HaynesW GWebbD J. Endothelium dependent modulation of responses to endothelin-1 in human hand veins. Clin Sci1993; 84: 427–33.
56.
HaynesW GWebbD J. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet1994; 344: 852–54.
57.
HaynesW GFerroC JO'KaneK P JSomervilleDLomaxC CWebbD J. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in man. Circulation1996; 93: 1860–70.
58.
ClavellA LMattinglyM MNirAAarhusL LHeubleinD MBurnettJ C. Angiotensin converting enzyme inhibition modulates circulating and tissue endothelin activity in experimental heart failure. Circulation1994; 90: 1–452.
59.
YangZRichardVVon SegesserL. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries: A new mechanism for vasospasm?Circulation1990; 82: 188–95.
60.
NishimuraMTakahashiHMatsusawaM. Chronic intra cerebroventricular infusions of endothelin elevate arterial pressure in rats. J Hypertens1991; 9: 71–76.
61.
RakugiHTabuchiYNakamuraM. Endothelin activates the vascular renin-angiotensin system in rat mesenteric arteries. Biochem Int1990; 21: 867–72.
62.
YamamotoTKimuraTOtaK. Central effects of endothelin-1 on vasopressin and atrial natriuretic peptide release and cardiovascular and renal function in conscious rats. J Cardiovasc Pharmacol1991; S316–18.
63.
DubinDPrattR EDzauV J. Endothelin, a potent vasoconstrictor, is a vascular smooth muscle mitogen. J Vasc Med Biol1989; 1: 150–54.
64.
BattistiniBChailerPD'Orleans-JustePBriereNSiroisP. Growth regulatory properties of endothelins. Peptides1993; 14: 385–99.
65.
TamamoriMItoHAdachiSAkimotoHMarumoFHiroeM. Endothelin-3 induces hypertrophy of cardiac myocytes by the endogenous endothelin-1 mediated method. J Clin Invest1996; 97: 366–72.
66.
IshikawaTYanagisawaMKimuraSGotoKMasakiT. Positive chronotropic effects of endothelin, a novel endothelium derived vasoconstrictor peptide. Pflugers Arch1988; 413: 108–10.
67.
FirthJ DRobertsA FRaineA E. Effect of endothelin on the function of the isolated perfused working rat heart. Clin Sci1990; 79: 221–26.
68.
DominiczakA FBohrD F. Nitric oxide and its putative role in hypertension. Hypertension1995; 25: 1202–11.
LariviereRThibaultGSchiffrinE L. Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate salt hypertensive but not spontaneously hypertensive rats. Hypertension1993; 21: 294–300.
71.
SchiffrinE LLariviereRLiJ SSventekPTouyzR M. Endothelin-1 gene expression and vascular hypertrophy in doca salt hypertension compared to spontaneously hypertensive rats. Clin Exp Pharmacol Physiol1995; 22: S188–90.
72.
SventekPTurgeonAGarciaRSchiffrinE L. Vascular and cardiac overexpression of endothelin-1 gene in one-kidney, one clip Goldblatt hypertensive rats but only in the late phase of two-kidney one clip Goldblatt hypertension. J Hypertension1996; 14: 57–64.
73.
SventekPLiJ SGroveKDeschepperC FSchiffrinE L. Vascular structure and expression of endothelin-1 gene in L-NAME treated spontaneously hypertensive rats. Hypertension1996; 27: 49–55.
74.
ClozelM. Endothelin sensitivity and receptor binding in the aorta of spontaneously hypertensive rats. J Hypertens1989; 7: 913–17.
75.
BolgerG TLiardFJodoinAJaramilloJ. Vascular reactivity, tissue levels and binding sites for endothelin: A comparison in the spontaneously hypertensive and Wistar-Kyoto rats. Can J Physiol Pharmacol1991; 69: 406–13.
76.
DohiYCriscioneLLuscherT F. Renovascular hypertension impairs formation of endothelium derived relaxing factors and sensitivity to endothelin-1 in resistance arteries. Br J Pharmacol1991; 104: 349–54.
77.
NguyenP VParentADengL YFluckigerJ PThibaultGSchiffrinE L. Endothelin vascular receptors and responses in DOCA salt hypertensive rats. Hypertension1992; 19(suppl II): II-98–104.
78.
OhnoANaruseMKatoS. Endothelin specific antibodies decrease blood pressure and increase glomerular filtration rate and renal plasma flow in spontaneously hypertensive rats. J Hypertens1992; 10: 781–85.
79.
McMahonE GPalomoM ABrownM ABertenshawS TCarterJ S. Effect of phosphoramidon (endothelin converting enzyme inhibitor) and BQ-123 (endothelin receptor subtype A antagonist) on blood pressure in hypertensive rats. Am J Hypertens1993; 6: 667–73.
80.
LanviereRSventekPThibaultGSchiffrinE L. Endothelin-1 expression in blood vessels of DOCA-salt hypertensive rats treated with the combined ETA/B endothelin receptor antagonist bosentan. Can J Physiol Pharmacol1995; 73: 390–98.
81.
HaynesW GHandM FJohnstoneH APadfieldP LWebbD J. Direct and sympathetically mediated venoconstriction in essential hypertension: Enhanced response to endothelin. J Clin Invest1994; 94: 1359–64.
82.
SchiffrinE LThibaultG. Blunted effects of endothelin upon small subcutaneous arteries of mild essential hypertensive patients. J Hypertens1992; 10: 437–44.
83.
FerroC JHaynesW GHandM FWebbD J. Are the vascular endothelin and nitric oxide systems involved in the pathophysiology of essential hypertension?Eur J Clin Invest1996; 26(suppl 1): A51.
84.
SchmittRBelzG GFellD. Effects of the novel endothelin receptor antagonist bosentan in hypertensive patients. 7th European hypertension meeting, Milan, June 1995.
85.
RossR. The pathogenesis of atherosclerosis. Nature1993; 362: 801–809.
86.
BoulangerC MTannerF CBeaM LHahnA W AWernerALuscherT F. Oxidised low density lipoprotein induces mRNA expression and release of endothelin from human and porcine endothelium. Circ Res1992; 70: 1191–97.
87.
LermanAEdwardsB SHallettJ WHeubleinD MSandbergS MBurnettJ C. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med1991; 325: 997–1001.
88.
DagassanP HBreuVClozelM. Upregulation of endothelin-B receptors in atherosclerotic human coronary arteries. J Cardiovasc Pharmacol1996; 27: 147–53.
89.
TonnessenTGiaidASalehDNaessP AYanagisawaMChristensenG. Increased in vivo expression of endothelin-1 by porcine cardiomyocytes subject to ischaemia. Circ Res1995; 76: 767–72.
90.
RayS GMcMurrayJ JMortonJ JDargieH J. Circulating endothelin in acute ischaemic syndromes. Br Heart J1992; 67: 383–86.
91.
WieczorekIHaynesW GWebbD JLudlamC AFoxK A. Raised plasma endothelin in unstable angina and non-Q wave myocardial infarct ion: Relation to cardiovascular outcome. Br Heart J1994; 72: 436–41.
92.
LechleitnerPGenserNMairJ. Endothelin-1 in patients with complicated and uncomplicated myocardial infarction. Clin Invest1992; 70: 1070–72.
93.
OmlandTLieR TAakvaagA. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation1994; 89: 1573–79.
94.
McMurdoLSessaW CThiemermannCVaneJ R. Ischaemia and reperfusion injury potentiates the vasoconstrictor effects of endothelin-1 in the isolated perfused heart of the rat. Br J Pharmacol1991; 104: 343P.
95.
ZeiherA MIhlingCPistoriusKSchachingerVSchaeferH-E. Increased tissue endothelin immunoreactivity in atherosclerotic lesions associated with acute coronary syndromes. Lancet1994; 344: 1405–406.
96.
GroverG JDzwonczykSParhomC S. The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion. Cardiovasc Res1993; 27: 1613–18.
97.
McMurdoLThiermannCVaneJ R. The effects of the endothelin ETA receptor antagonist, FR 139317 on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion. Br J Pharmacol1994; 112: 75–80.
98.
DagassanP HBreuVClozelMClozelJ-P. Role of endothelin during reperfusion after ischaemia in isolated perfused rat heart. J Cardiovasc Pharmacol1994; 24: 867–74.
99.
LiX SWangW-DPernowJ. The nonpeptide endothelin receptor antagonist bosentan enhances myocardial recovery and endothelial function during reperfusion of the ischaemic rat heart. J Cardiovasc Pharmacol1995; 26: S445–47.
WangXDouglasS ALoudenCVickery-ClarkL MFeuersteinG ZOhlsteinE H. Expression of endothelin-1, endothelin-3, endothelin-converting enzyme-1 and endothelin-A and endothelin-B receptor mRNA after angioplasty-induced neointimal formation in the rat. Circ Res1996; 78: 322–28.
102.
TrachtenbergJ DSunSChoiE TCallowA DRyanU S. Effect of endothelin-1 infusion on the development of intimai hyperplasia after balloon catheter injury. J Cardiovasc Pharmacol1993; 22(suppl 8): S355–59.
103.
DouglasS ALoudenCVickery-ClarkL M. Arole for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty: Protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670. Circ Res1994; 75: 190–97.
SwedbergKEnerothPKjekshusJ. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation1990; 82: 1730–36.
106.
CodyR JHaasG JBinkleyP FCapersQKelleyR. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation1992; 85: 504–509.
107.
KrumHGoldsmithRWilshire-ClementMMillerMPackerM. Importance of endothelin in the exercise intolerance of heart failure in humans. Mayo Clin Proc1992; 67: 719–24.
108.
Galatius-JensenSWroblewskiHEmmeleuthCBiePHaunsoSKastrupJ. Plasma endothelin-1 in chronic heart failure: A predictor of cardiac death?Circulation1994; 90: 379.
109.
PacherRBergler-KleinJGlobitsS. Plasma big endothelin-1 concentrations in congestive heart failure patients with or without systemic hypertension. Am J Cardiol1993; 71: 1293–99.
110.
YoshidaHNakamuraM. Inhibition by angiotensin converting enzyme inhibitors of endothelin secretion from cultured human endothelial cells. Life Sci1992; 50(22): 195–200.
111.
AbernethyD RLaurieNAndrawisN S. Local angiotensin-converting enzyme inhibition blunts endothelin-1 induced increase in forearm vascular resistance. Clin Pharmacol Ther1995; 58: 328–34.
112.
TownendJDoranJJonesSDaviesM. Effect of angiotensin converting enzyme inhibition on plasma endothelin in congestive heart failure. Int J Cardiol1994; 43: 299–304.
113.
DavidsonN CCoutieW JWebbD JStruthersA D. Hormonal and renal differences between low dose and high dose angiotensin converting enzyme inhibitor treatment in patients with chronic heart failure. Heart1996; 75: 576–81.
114.
KrumHGuAClementWilshire MBernsteinSackner JGoldsmithR. Changes in plasma endothelin-1 levels reflect clinical response to beta blockade in chronic heart failure. Am Heart J1996; 131: 337–41.
115.
KiowskiWSutschGHunzikerP. Evidence for endothelin-1 mediated vasoconstriction in severe chronic heart failure. Lancet1995; 346: 732–36.
116.
LoveM PHaynesW GGrayG AWebbD JMcMurrayJ J V. Vasodilator effect of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation1996; 94: 2131–37.
117.
CannanC RBurnettJ CJrLermanA. Enhanced coronary vasoconstriction to endothelin-B-receptor activation in experimental congestive heart failure. Circulation1996; 93: 646–51.
118.
MillerDWatersD DWamicaWSzlachacJKreeftJTherouxP. Is variant angina the coronary manifestation of a generalised vasospastic disorder?N Engl J Med1981; 304: 763–66.
119.
MatsuyamaKYashueHOkumuraK. Increased plasma levels of endothelin-1-like immunoreactivity during coronary vasospasm in patients with coronary spastic angina. Am J Cardiol1991; 68: 991–95.
120.
QuyyumiA ACannonR OIIIPanzaJ ADiodatiJ GEpsteinS E. Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation1989; 86: 1864–71.
121.
ZamoraM RO'BrienR FRutherfordR B. Serum endothelin-1 concentrations and cold provocation in primary Raynaud's phenomenon. Lancet1990; 336: 1144–47.
122.
PalmerK TMasonH. Serum endothelin concentrations in workers exposed to vibration. Occ Env Med1996; 53: 118–24.
123.
FyhrquistFSaijonmaaOMertarinneKTikkanenIRosenlofKTikkanenT. Raised plasma endothelin-1 concentration following cold pressor test. Biochem Biophys Res Commun1990; 169: 217–21.
124.
SinghSDe TraffordJ CBaskervilleP AMartinJ F. Response of digital arteries to endothelium dependent and independent vasodilators in patients with Raynaud's phenomenon. Eur J Clin Invest1995; 25: 182–85.
125.
SmithP J W. An investigation into the pathogenesis of Raynaud's disease: The role of the vascular endothelium [PhD thesis], Edinburgh, 1995.
126.
BedaridaG VKimDBlashkeT F. Venodilatation in Raynaud's disease. Lancet1993; 342: 1451–54.
127.
GallaiVSarchielliPFirenzeC. Endothelin-1 in migraine and tension-type headache. Acta Neurol Scand1994; 89: 47–55.
128.
MillerW LRedfieldM MBurnettJ CJr. Integrated cardiac, renal and endocrine actions of endothelin-1. J Clin Invest1989; 83: 317–20.
129.
KaasjagerK A HKoomansH ARabelinkT J. Effectiveness of enalapril versus nifedipine to antagonize blood pressure and the renal response to endothelin in humans. Hypertension1995; 25: 620–25.
130.
KaretF EDavenportA P. Endothelin and the human kidney: A potential target for new drugs. Nephrol Dial Transplant1994; 9: 465–68.
131.
ShiboutaYSuzukiNShinoAMatsumotoHTerashitaZKondoK. Pathophysiological role of endothelin in acute renal failure. Life Sci1990; 46: 1611–18.
132.
TornitaKUjheKNakanishiT. Plasma endothelin levels in patients with acute renal failure. N Engl J Med1989; 321: 1127.
133.
GellaiMJugusMFletcherTDe WolfRNambiP. Reversal of post ischaemic renal failure with a selective endothelin A receptor antagonist in the rat. J Clin Invest1994; 93: 900–906.
134.
ChanLChittinandanaAShapiroJ IShanleyP FSchrierR W. Effect of an endothelin receptor antagonist on ischaemic acute renal failure. Am J Physiol1994; 266: F135–38.
135.
BrooksD PDePalmaP DGellaiM. Nonpeptide endothelin receptor antagonists. III. Effect of SB 209670 and BQ123 on acute renal failure in anaesthetised dogs. J Pharmacol Exp Therap1994; 271: 769–75.
136.
ClavellA LStinogoA JMarguliesK BBrandtR RBurnettJ C. Role of endothelin receptor subtypes in the in vivo regulation of renal function. Am J Physiol1995; 268: F445–60.
137.
MooreKWendonJFrazerMKaraniJWilliamsRBadrK. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. N Engl J Med1992; 327: 1774–78.
138.
TakahashiKGhateiM AJonesP M. Endothelin in human brain and pituitary gland: Comparison with rat. J Cardiovasc Pharmacol1991; 17: S101–103.
139.
LeeM EDe la MonteS MNgS CBlochK DQuertermousT. Expression of the potent vasoconstrictor endothelin in the human central nervous system. J Clin Invest1990; 86: 141–47.
140.
AlafaciCJansenIArbabM AShiokawaYSvendgaardN AEdvinssonL. Enhanced vasoconstrictor effect of endothelin in cerebral arteries from rats with subarachnoid haemorrhage. Acta Physiol Scand1990; 138: 317–19.
141.
IdeKYamakawaKNakagomiT. The role of endothelin in the pathogenesis of vasospasm following subarachnoid haemorrhage. Neurol Res1989; 11: 101–104.
142.
ClozelMWatanabeH. BQ-123, a peptidic endothelin ETA receptor antagonist, prevents the early cerebral vasospasm following subarachnoid haemorrhage after intracisternal but not intravenous injection. Life Sci1993; 52: 825–34.
143.
ZuccarelloMSoattinG BLewisA IBreuVHallakHRapoportR M. Prevention of subarachnoid haemorrhage induced cerebral vasospasm by oral administration of endothelin antagonists. J Neurosurg1996; 84: 503–507.
144.
SuzukiRMasaokaHHiratYMarumoFIsotaniEHirakawaK. The role of endothelin-1 in the origin of cerebral vasospasm in patients with aneurysmal subarachnoid haemorrhage. J Neurosurg1992; 77: 96–100.
FeuersteinGGuJ LOhlsteinE H. Peptidic endothelin-1 receptor antagonist, BQ-123, and neuroprotection. Peptides1994; 15: 467–69.
147.
OhlsteinE HNambiPDouglasS A. SB209670, a rationally designed potent nonpeptide endothelin receptor antagonist. Proc Nat Acad Sci U S A1994; 91: 8052–56.
148.
StelznerT JO'BrienR FYanagisawaM. Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension. Am J Physiol1992; 262: 1614–20.
149.
ZamoraM RStelznerT JWebbSPanosR JRuffL JDempseyE C. Overexpression of endothelin-1 and enhanced growth of pulmonary artery smooth muscle cells from fawn-hooded rats. Am J Physiol1996; 270: L101–109.
150.
HayD W PLuttmannM AHubbardW C. Endothelin receptor subtypes in human and guinea-pig pulmonary tissues. Br J Pharmacol1993; 110: 1175–83.
151.
ZamoraM ADempseyE CWalchakS JStelznerT J. BQ123, an ETA receptor antagonist, inhibits endothelin-1 mediated proliferation of human pulmonary artery smooth muscle cells. Am J Cell Mol Biol1993; 9: 429–33.
152.
GiaidAYanagisawaMLanglebenD. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med1993; 328: 1732–39.
153.
StewartD JLevyR DCernacekPLanglebenD. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease?Ann Intern Med1991; 114: 464–69.
154.
TookeJ E. Microvascular function in human diabetes. Diabetes1995; 44: 721–26.
155.
CameronN ECotterM A. Impaired contraction and relaxation in aorta from streptozotocin-diabetic rats: Role of polyol pathway. Diabetologia1992; 35: 1011–19.
McNallyP GWattP ARimmerTBurdenA CHearnshawJ RThurstonH. Impaired contraction and endothelium dependent relaxation in isolated resistance vessels from patients with insulin dependent diabetes mellitus. Clin Sci1994; 87: 31–36.
158.
McVeighG EBrennanG MJohnstonG D. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin dependent) diabetes mellitus. Diabetologia1992; 35: 771–76.
159.
MorrisS JShoreA CTookeJ E. Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM. Diabetologia1995; 38: 1337–44.
160.
TakahashiKGhateiM ALamH-CO'HalloranD JBloomS R. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia1990; 33: 306–10.
161.
NugentA GMcGurkCHayesJ RJohnstonG D. Impaired vasoconstriction to endothelin-1 in patients with NIDDM. Diabetes1996; 45: 105–107.
