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Enhanced vasoconstrictor effect of big endothelin-1 in patients with atherosclerosis: relation to conversion to endothelin-1

      Abstract

      The enhanced production of endothelin-1 (ET-1) in atherosclerotic arteries may be related to increased activity of the endothelin converting enzyme (ECE) which converts big ET-1 to ET-1. The purpose of the present study was to investigate whether the vasoconstrictor activity of big ET-1 is altered as a result of increased conversion to ET-1 in patients with atherosclerosis. Big ET-1 was infused into the brachial artery of nine patients with atherosclerosis and nine healthy controls. Forearm blood flow (FBF) was measured with venous occlusion plethysmography. Big ET-1 (15 and 50 pmol/min) evoked more pronounced reduction in FBF in the patients than in the controls (P<0.01). The low dose big ET-1 elevated local venous plasma ET-1 (from 2.8±0.3 to 9.0±1.6 pmol/l; P<0.01) and the net formation of ET-1 (from −6.6±8.6 to 50.5±16.0 fmol/min; P<0.01) in the patients but not in the controls. Furthermore, histological examination revealed ECE immunoreactivity in the fibrous cap of atherosclerotic plaques in addition to the endothelium and smooth muscle cells of radial arteries. In conclusion, administration of big ET-1 results in enhanced vasoconstriction and increased formation of ET-1 in patients with atherosclerosis as compared to healthy controls which may be due to increased activity of ECE.

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      References

        • Yanagisawa M.
        • Kurihara H.
        • Kimura S.
        • et al.
        A novel potent vasoconstrictor peptide produced by vascular endothelial cells.
        Nature. 1988; 332: 411-415
        • Xu D.
        • Emoto N.
        • Giaid A.
        • Slaughter C.
        • Kaw S.
        • deWit D.
        • et al.
        ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1.
        Cell. 1994; 78: 473-485
        • Emoto N.
        • Yanagisawa M.
        Endothelin-convering enzyme-2 is a membrane bound phosphoramidon-sensitive metalloprotease with acid pH optimum.
        J. Biol. Chem. 1995; 270: 15262-15268
        • Arai S.
        • Hori S.
        • Aramori I.
        • Ohkubo H.
        • Nakanishi S.
        Cloning and expression of a cDNA encoding an endothelin receptor.
        Nature. 1990; 348: 730-732
        • Sakurai T.
        • Yanagisawa M.
        • Takuwat Y.
        • Miyazaki H.
        • Kimura S.
        • Goto K.
        • et al.
        Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor.
        Nature. 1990; 348: 732-735
        • Pernow J.
        • Kaijser L.
        • Lundberg J.M.
        • Ahlborg G.
        Comparable potent coronary vasoconstrictor effects of endothelin-1 and big endothelin-1 in humans.
        Circulation. 1996; 94: 2077-2082
        • Weitzberg E.
        • Ahlborg G.
        • Lundberg J.M.
        Long-lasting vasoconstriction and efficient regional extraction of endothelin-1 in human splanchnic and renal tissues.
        Biochem. Biophys. Res. Commun. 1991; 180: 1298-1303
        • Pernow J.
        • Hemsén A.
        • Lundberg J.M.
        • Nowak J.
        • Kaijser L.
        Potent vasoconstrictor effects and clearance of endothelin in the human forearm.
        Acta Physiol. Scand. 1991; 141: 319-324
        • Haynes W.G.
        • Webb D.J.
        Contribution of endogenous generation of endothelin-1 to basal vascular tone.
        Lancet. 1994; 344: 852-854
        • Love M.
        • Haynes W.
        • Gray G.
        • Webb D.
        • McMurray J.
        Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors.
        Circulation. 1996; 94: 2131-2137
        • Miyauchi T.
        • Masaki T.
        Pathophysiology of endothelin in the cardiovascular system.
        Annu. Rev. Physiol. 1999; 61: 391-415
        • Kowala M.C.
        The role of endothelin in the pathogenesis of atherosclerosis.
        Adv. Pharmacol. 1997; 37: 299-318
        • Hirata Y.
        • Takagi Y.
        • Fukuda Y.
        • Marumo F.
        Endothelin is a potent mitogen for rat vascular smooth muscle cells.
        Atherosclerosis. 1989; 78: 225-228
        • Helset E.
        • Sildnes T.
        • Konopski Z.
        Endothelin-1 stimulates monocytes in vitro to release chemotactic activity identified as interleukin-8 and monocyte chemotactic protein-1.
        Med. Inflamm. 1994; 3: 155-160
        • Joris I.
        • Zand T.
        • Nunnari J.J.
        • Krolikowski F.J.
        • Majno G.
        Studies on the pathogenesis of atherosclerosis: I: Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats.
        Am. J. Pathol. 1983; 113: 341-358
        • Zeiher A.M.
        • Goebel H.
        • Schächinger V.
        • Ihling C.
        Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque.
        Circulation. 1995; 91: 941-947
        • Barton M.
        • Haudenschild C.
        • D'Uscio L.
        • Shaw S.
        • Münter K.
        • Lüscher T.
        Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice.
        Proc. Natl. Acad. Sci. USA. 1998; 95: 14367-14372
        • Minamino T.
        • Kurihara H.
        • Takahashi M.
        • et al.
        Endothelin-converting enzyme expression in the rat vascular injury model and human coronary atherosclerosis.
        Circulation. 1997; 95: 221-230
        • Grantham J.
        • Schirger J.
        • Wennberg P.
        • Sandberg S.
        • Heublein D.
        • Subkowski T.
        • et al.
        Modulation of functionally active endothelin-converting enzyme by chronic neutral endopeptidase inhibition in experimental atherosclerosis.
        Circulation. 2000; 101: 1976-1981
        • Maguire J.J.
        • Davenport A.P.
        Increased response to big endothelin-1 in atherosclerotic human coronary artery: functional evidence for up-regulation of endothelin-converting enzyme activity in disease.
        Br. J. Pharmacol. 1998; 125: 238-240
        • Plumpton C.
        • Haynes W.G.
        • Webb D.J.
        • Davenport A.P.
        Phosphoramidon inhibition of the in vivo conversion of big endothelin-1 to endothelin-1 in the human forearm.
        Br. J. Pharmacol. 1995; 116: 1821-1828
        • Hemsen A.
        Biochemical and functional characterization of endothelin peptides with special reference to vascular effects.
        Acta. Physiol. Scand. Suppl. 1991; 602: 1-61
        • Subkowski T.
        • Hillen H.
        • Kröger B.
        • Schmidt M.
        Monoclonal antibodies against human endothelin-converting enzyme-1.
        J. Immunoassay. 1998; 19: 75-93
        • Grantham J.
        • Schirger J.
        • Williamson E.
        • et al.
        Enhanced endothelin-converting enzyme immunoreactivity in early atherosclerosis.
        J. Cardiovasc. Pharmacol. 1998; 31: S22-26
        • Fukuroda T.
        • Noguchi K.
        • Tsuchida S.
        • Nishikibe M.
        • Ikemoto F.
        • Okada K.
        • et al.
        Inhibition of biological actions of big endothelin-1 by phosphoramidon.
        Biochem. Biophys. Res. Comm. 1990; 172: 390-395
        • Pernow J.
        • Böhm F.
        • Johansson B.-L.
        • Hedin U.
        • Rydén L.
        Enhanced vasoconstrictor response to endothelin B receptor stimulation in patients with atherosclerosis.
        J. Cardiovasc. Pharmacol. 2000; 36: S418-S420
        • Kido H.
        • Nakano A.
        • Okishima N.
        • et al.
        Human chymase, an enzyme forming novel bioactive 31-amino acid length endothelins.
        J. Biol. Chem. 1998; 379: 885-891
        • Kaartinen M.
        • Penttila A.
        • Kovanen P.T.
        Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the predilection site of atheromatous rupture.
        Circulation. 1994; 90: 1669-1678
        • Kovanen P.T.
        • Kaartinen M.
        • Paavonen T.
        Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction.
        Circulation. 1995; 92: 1084-1088
        • Kishi F.
        • Minami K.
        • Okishima N.
        • et al.
        Novel 31-amino-acid-length endothelins cause constriction of vascular smooth muscle.
        Biochem. Biophys. Res. Commun. 1998; 248: 387-390
        • Sorensen K.E.
        • Kristensen I.B.
        • Celermajer D.S.
        Atherosclerosis in the human brachial artery.
        J. Am. Coll. Cardiol. 1997; 29: 318-322
        • DeNucci G.
        • Thomas R.
        • D′Orleans-Juste P.
        • Antunes E.
        • Walder C.
        • Warner T.D.
        • et al.
        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. USA. 1988; 85: 9797-9800