Barton, Matthias

Glodny, Bernhard

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Cardiovascular Research 52 (2001) 161–163www.elsevier.com/ locate /cardioresLetter to the EditorEndothelin receptor blockade and nitric oxide bioactivityq[Cardiovascular Research 2001;49:146–151]*Matthias Barton , Bernhard Glodny¨Medical Policlinic and Clinical Atherosclerosis Research Laboratory, Department of Internal Medicine, University Hospital, Ramistrasse 100,¨CH-8091 Zurich, SwitzerlandReceived 30 May 2001; accepted 18 July 2001Keywords: Acetylcholine; Atherosclerosis; Endothelial function; Endothelins; Nitric oxideIn a recent paper, Verma et al. reported abnormal been shown to improve endothelium-dependent vasomo-endothelium-dependent relaxation to acetylcholine in iso- tion [2,3].lated internal mammary arteries obtained from patients Second, the authors refer to atherosclerosis of thewith coronary artery disease [1]. The authors also observed internal mammary artery (IMA). However, even in patientsa moderate increase of the maximum response but not of with atherosclerosis in the coronary circulation, atheros-the sensitivity of these relaxations after 20 min of incuba- clerotic structural changes rarely occur in the IMA [4,5]tion with micromolar concentrations of either bosentan, a making it the conduit of choice for coronary bypassnon-selective ET receptor antagonist, BQ-123 (an ET surgery. It is known that atherosclerotic changes mayAselective compound) or BQ-788 (an ET selective com- develop after this artery has been grafted as a bypassBpound at low concentrations). The improvement of endo- conduit or in cardiac transplant recipients [6]. Therefore,thelium-dependent relaxation averaged between 10 and the authors’ notion that ‘ET-1 is increased in atheros-17% of complete relaxation compared to control experi- clerotic IMA’ is hard to follow.ments, and was not present in endothelium-denuded ves- Third, endothelium-dependent relaxation in this vesselsels and not evident in response to the endothelium- has been extensively studied, and most studies, includingindependent vasodilator sodium nitroprusside according to our own, have shown that endothelium-dependent relaxa-the authors’ unpublished data. The authors concluded that tion in response to acetylcholine is preserved in the IMAboth ET and ET receptors contribute to ‘endothelial [7–10]. How can the clearly abnormal relaxant response toA Bdysfunction’ and that blocking both the ET and the ET acetylcholine, reaching relaxation of only 40% of pre-A Breceptor may have endothelial protective effects in human contraction, observed in the authors’ experiments beinternal mammary arteries. However, there are several explained? The authors refer to one previous study onissues that must be taken into account when interpreting endothelium-dependent relaxation in human IMA, whichthese data. showed relaxant responses between 0 and 70% despiteFirst, the clinical characteristics and treatments of the comparable ecNOS immunostaining in histologic sectionsstudy patients, a considerable number of which were in the vessels investigated [11]. Not surprisingly, vesselwomen, deserve mentioning. More than half of the patients culture for 24 h with sepiapterin or L-arginine had no effecthad a positive family history for coronary artery disease, on the relaxant response which was abnormal to begin withwere smokers, and/or had hypercholesterolemia. It is [11]. The aforementioned study and the one by Verma et al.surprising to learn that despite the elevated plasma lipids are in strong contrast to several other studies by differentand in view of the beneficial effects of statins in the laboratories demonstrating preserved endothelium-depen-secondary prevention of coronary artery disease, none of dent relaxation in response to acetylcholine in human IMAthe patients was on statin therapy, a treatment that has also [7–9,12,13].As correctly pointed out in the editorial by Hoogerwerf[14], careful intraoperative handling of the arteries is ofqPII of original article: S0008-6363(00)00244-3 paramount importance for the functional integrity of the*Corresponding author. Tel.: 141-1-255-5663, ext. 163105; fax: 141-vessels as bypass conduits and probably contributes to1-255-8747.E-mail address: bartonm@swissonline.ch (M. Barton). long-term graft patency [10,15]. Indeed, our previous0008-6363/01/$ – see front matter Ó 2001 Elsevier Science B.V. All rights reserved.PI I : S0008-6363( 01 )00413-8162 M. Barton, B. Glodny / Cardiovascular Research 52 (2001) 161 –163studies revealed that intraoperative handling of the graft is that blockade of ET receptors improves NO bioactivityAa crucial determinant of endothelium-dependent responses and endothelium-dependent NO-mediated relaxation in thein the IMA and also in other grafts [8,10]. Using acetyl- thoracic aorta of atherosclerotic apolipoprotein-deficient Echoline as a stimulus, it has been demonstrated that mice [24]. Similarly, indices of increased NO bioactivityendothelium-dependent relaxations average between 75 have been found after ET blockade in coronary effluents ofand more than 95% of precontraction in arteries obtained perfused rat hearts, and similar effects were seen with ETAfrom CAD patients with multiple risk factors [7–9,12,13]. selective and non-selective ET /ET receptor antagonists.A BThis notion is also supported by a study demonstrating that Interestingly, no effect was observed with selective ETBmechanical manipulation such as distension does indeed receptor blockade alone [25]. In humans ET blockadeAimpair endothelial-dependent responses to acetylcholine improves NO-mediated vascular function in the brachial[16]. artery in vivo which can be blocked by ET receptorBIn their article, the authors repeatedly refer to ‘endotheli- blockade [26], and in a recent clinical study, improvedal dysfunction’ as simply the ‘net balance of endothelium- acetylcholine-mediated vasomotion in coronary arteries ofderived vasoconstriction and vasodilation’. Although at- patients with coronary atherosclerosis after treatment withtractive, this view does not take into account the complexi- the ET receptor antagonist BQ-123 has been demon-Aty of the abnormalities occurring in the injured endo- strated [27]. Taken together, the results from these studiesthelium [17] determining the endothelial phenotype. Thus, strongly are consistent with the concept that ET and notAimpairment of NO-mediated endothelium-dependent relax- ET receptors are responsible for increases in NO bioac-Bation represents only one aspect of the spectrum of tivity after acute or chronic ET receptor blockade.‘endothelial dysfunction’ which comprises the dysregula- As endothelin receptor antagonists are reaching thetion of all endothelial cell functions, including cytokine clinical arena, the therapeutic potential of this new class ofrelease, lipid metabolism, morphological cellular changes, drugs must be carefully assessed [28]. Combined ETdisturbances of coagulation, etc. [17,18]. Abnormal endo- receptor antagonists, including bosentan, have unques-thelium-dependent vasomotion as part of ‘endothelial tionably provided a great step in the therapy of patientsdysfunction’ not only occurs in atherosclerosis, but also in with advanced congestive heart failure. The majority ofconditions such as heart failure and pulmonary hyperten- studies, experimental ones as well as clinical ones, inves-sion. Several previous studies have shown that ET receptor tigating physiopathologies such as heart failure, endo-blockade can improve or even reverse this abnormality thelium-dependent vasomotion, and hypertension, have(reviewed in Ref. [19]). shown beneficial effects through blockade of the ETAFinally, the authors claim an ‘equal contribution of both receptor, in most cases irrespective whether the ETBET and ET receptors towards endothelial function in receptor was blocked or not. The data presented by VermaA Bhuman IMA’ based on their observations of responses to et al. essentially support this notion, demonstrating com-acetylcholine in absence or presence of receptor specific parable effects between the ET selective antagonist BQ-AET antagonists. Moreover, demonstrating a 13% increase 123 and bosentan on endothelium-dependent vasomotion.in endothelium-mediated relaxation after acute ET re-Bceptor blockade with BQ-788 at a concentration of 1mmol / l, the authors interpret this finding as: (a) ETB Referencesreceptors contributing to impairment of ‘NO-mediated’relaxation in human arteries; and (b) that both ET andA [1] Verma S, Lovren F, Dumont AS et al. Endothelin receptor blockadeET receptors equally impair this relaxation. The first improves endothelial function in human internal mammary arteries.BCardiovasc Res 2001;49:146–151.assumption cannot be the case since NO synthase inhibi-[2] Stroes ES, Koomans HA, de Bruin TW, Rabelink TJ. Vasculartion only in part blocks the relaxant response to acetyl-function in the forearm of hypercholesterolaemic patients off and oncholine in the human IMA [12,20] and acetylcholine alsolipid-lowering medication. Lancet 1995;346:467–471.causes endothelium-dependent hyperpolarization in this [3] Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P.vessel [21]. Moreover, it is likely that at the concentration The effect of cholesterol-lowering and antioxidant therapy onused in vitro, BQ-788 loses its selectivity over the ET endothelium-dependent coronary vasomotion. N Engl J MedB1995;332:488–493.receptor. Furthermore, Verma et al. postulate that ETB [4] Singh RN. Atherosclerosis and the internal mammary arteries.receptors in the IMA do not mediate relaxation and are notCardiovasc Intervent Radiol 1983;6:72–77.linked to NO bioactivity, referring to a previous publi- [5] Nikkari ST. Phenotype of smooth muscle cells in internal mammarycation [22] but without performing the appropriate experi- arteries. Artery 1989;16:346–352.ments with an NO-synthase inhibitor. In fact, it has been [6] Berkenboom G, Crasset V, Giot C, Unger P, Vachiery JL, LeClercJL. Endothelial dysfunction of internal mammary artery in patientspreviously shown that ET receptor stimulation may causeBwith coronary artery disease and in cardiac transplant recipients. Amrelaxation in human IMA [23].Heart J 1998;135:488–494.It was suggested in the editorial by Hoogerwerf that¨[7] Luscher TF, Diederich D, Siebenmann R et al. Difference betweenmore animal studies should be done to implement these endothelium-dependent relaxation in arterial and in venous coronaryfinding into clinical use [14]. It has been previously shown bypass grafts. N Engl J Med 1988;319:462–467.M. Barton, B. Glodny / Cardiovascular Research 52 (2001) 161 –163 163¨[8] Mugge A, Barton M, Cremer J, Frombach R, Lichtlen PR. Different [19] Barton M. Endothelial dysfunction and atherosclerosis: endothelinvascular reactivity of human internal mammary and inferior epi- receptor antagonists as novel therapeutics. Curr Hypertens Repgastric arteries in vitro. Ann Thorac Surg 1993;56:1085–1089. 2000;2:84–91.[9] Pompilio G, Polvani GL, Antona C et al. Retention of endothelium- [20] Qi X, Chen D, Nottin R, Mace L, Herve P, Weiss M. Evidence ofdependent properties in human mammary arteries after cryo- L-arginine /nitric oxide pathway in endothelium and smooth musclepreservation. Ann Thorac Surg 1996;61:667–673. of human internal mammary artery. Biochem Biophys Res Commun[10] Cremer J, Mugge A, Schulze M et al. The inferior epigastric artery 1993;195:90–96.for coronary bypass grafting. Functional assessment and clinical [21] Liu ZG, Ge ZD, He GW. Difference in endothelium-derivedresults. Eur J Cardiothorac Surg 1993;7:423–427. hyperpolarizing factor-mediated hyperpolarization and nitric oxide[11] Huraux C, Makita T, Kurz S et al. Superoxide production, risk release between human internal mammary artery and saphenousfactors, and endothelium-dependent relaxations in human internal vein. Circulation 2000;102:III296–III301.mammary arteries. Circulation 1999;99:53–59. [22] Seo B, Oemar BS, Siebenmann R, von Segesser L, Luscher TF.[12] Yang ZH, von Segesser L, Bauer E, Stulz P, Turina M, Luscher TF. Both ET and ET receptors mediate contraction to endothelin-1 inA BDifferent activation of the endothelial L-arginine and cyclo- human blood vessels. Circulation 1994;89:1203–1208.oxygenase pathway in the human internal mammary artery and [23] Liu JJ, Chen JR, Buxton BF. Unique response of human arteries tosaphenous vein. Circ Res 1991;68:52–60. endothelin B receptor agonist and antagonist. Clin Sci (Colch)[13] Yang Z, Siebenmann R, Studer M, Egloff L, Luscher TF. Similar 1996;90:91–96.endothelium-dependent relaxation, but enhanced contractility, of the [24] Barton M, Haudenschild CC, d’Uscio LV, Shaw S, Munter K,right gastroepiploic artery as compared with the internal mammary Luscher TF. Endothelin ET receptor blockade restores NO-me-Aartery. J Thorac Cardiovasc Surg 1992;104:459–464. diated endothelial function and inhibits atherosclerosis in apolipo-[14] Hoogerwerf N. A role for endothelin receptor blockade in improving protein E-deficient mice. Proc Natl Acad Sci USA 1998;95:14367–the endothelial function of coronary artery grafts? Cardiovasc Res 14372.2001;49:15–16. [25] Goodwin AT, Amrani M, Gray CC, Jayakumar J, Yacoub MH. Role[15] Cremer J, Liesmann T, Wimmer-Greinecker G, Abraham C, Mugge of endogenous endothelin in the regulation of basal coronary tone inA, Haverich A. In vivo comparison of free coronary grafts using the the rat. J Physiol (Lond) 1998;511:549–557.inferior epigastric (IEA), the gastroepiploic (GEA) and the internal [26] Verhaar MC, Strachan FE, Newby DE et al. Endothelin-A receptorthoracic artery (ITA). Eur J Cardiothorac Surg 1994;8:240–245. antagonist-mediated vasodilatation is attenuated by inhibition of[16] Cooper GJ, Locke TJ. Distension reduces the vasoreactivity of the nitric oxide synthesis and by endothelin-B receptor blockade.internal mammary artery. Eur J Cardiothorac Surg 1996;10:26–31. Circulation 1998;97:752–756.[17] Ross R. The pathogenesis of atherosclerosis. In: Braunwald E, [27] Halcox JPJ, Sharma A, Zalos G et al. Coronary vasodilation andeditor, Heart disease, 2nd ed., Philadelphia: Saunders, 1992, pp. improved endothelial dysfunction with endothelin ET receptorA1106–1124. blockade. Circulation 2000;102(suppl. II):1, (abstract).¨[18] Barton M, Haudenschild CC. Endothelium and atherosclerosis: [28] Luscher TF, Barton M. Endothelins and endothelin receptor antago-endothelial therapy revisited. J Cardiovasc Pharmacol 2001 (in nists. Therapeutic considerations for a novel class of cardiovascularpress). drugs. Circulation 2000;102:2434–2440.

Endothelin receptor blockade and nitric oxide bioactivity: [Cardiovascular Research 2001;49:146-151]

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