Advertisement

Endothelin type A receptor antagonism restores myocardial perfusion response to adenosine in experimental hypercholesterolemia

      Abstract

      Experimental hypercholesterolemia is characterized by increased endothelin-1 (ET-1) activity and is associated with an attenuated myocardial perfusion response and an inappropriate increase in coronary microvascular permeability during episodes of increased myocardial demand. This study was designed to determine the effect of chronic selective ET type A (ETA) receptor antagonism on coronary vascular response to simulated cardiac stress in experimental hypercholesterolemia. Twenty-one pigs were randomized to three groups: normal diet (N), high-cholesterol diet (HC), and HC diet plus ABT-627, a selective ETA receptor antagonist, (HC+ABT-627). After 12 weeks, cardiac electron beam computed tomography (EBCT) was performed before and during intravenous infusion of adenosine, and myocardial perfusion (ml/min per g) and coronary microvascular permeability index (arbitrary units) were calculated. Basal myocardial perfusion was similar in all groups (N: 0.91±0.10; HC: 0.95±0.08; HC+ABT-627: 1.03±0.09; P=0.64). Adenosine infusion led to a significant increase in myocardial perfusion in the N (1.32±0.15; P<0.001) but not in the HC (0.95±0.07) group. However, in the HC+ABT-627 group, adenosine also significantly increased myocardial perfusion (1.33±0.12; P=0.001). Basal permeability index did not differ between the groups (N: 1.56±0.13; HC: 1.34±0.19; HC+ABT-627: 1.62±0.10; P=0.38). Adenosine infusion significantly increased permeability index in HC pigs (2.29±0.22; P<0.001) but not in N (1.71±0.21) and HC+ABT-627 (1.82±0.08) pigs. We conclude that chronic selective ETA receptor antagonism preserves myocardial perfusion response and coronary microvascular integrity during episodes of increased myocardial demand in experimental hypercholesterolemia, indicating an important role for the endogenous endothelin system in this disorder.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Levin E.R.
        Endothelins.
        New Engl. J. Med. 1995; 333: 356-363
        • Lüscher T.F.
        • Barton M.
        Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs.
        Circulation. 2000; 102: 2434-2440
        • Lerman A.
        • Webster M.W.
        • Chesebro J.H.
        • Edwards W.D.
        • Wei C.M.
        • Fuster V.
        • Burnett J.C.J.r
        Circulating and tissue endothelin immunoreactivity in hypercholesterolemic pigs.
        Circulation. 1993; 88: 2923-2928
        • Rodriguez-Porcel M.
        • Lerman A.
        • Best P.J.M.
        • Krier J.D.
        • Napoli C.
        • Lerman L.O.
        Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity.
        J. Am. Coll. Cardiol. 2001; 37: 608-615
        • Rumberger J.A.
        • Feiring A.J.
        • Lipton M.J.
        • Higgins C.B.
        • Ell S.R.
        • Marcus M.L.
        Use of ultrafast computed tomography to quantitate regional myocardial perfusion: a preliminary report.
        J. Am. Coll. Cardiol. 1987; 9: 59-69
        • Schmermund A.
        • Lerman L.O.
        • Rumberger J.A.
        • Lund P.E.
        • Pfeifer E.A.
        • Sheedy 2nd, P.F.
        • Ritman E.L.
        Effects of acute and chronic angiotensin receptor blockade on myocardial vascular BV and perfusion in a pig model of coronary microembolization.
        Am. J. Hypertens. 2000; 13: 827-837
        • Möhlenkamp S.
        • Lerman L.O.
        • Lerman A.
        • Behrenbeck T.R.
        • Katusic Z.S.
        • Sheedy 2nd, P.F.
        • Ritman E.L.
        Minimally invasive evaluation of coronary microvascular function by electron beam computed tomography.
        Circulation. 2000; 102: 2411-2416
        • Möhlenkamp S.
        • Behrenbeck T.R.
        • Lerman A.
        • Pankratz V.S.
        • Sheedy 2nd, P.F.
        • Weaver A.L.
        • Ritman E.L.
        Coronary microvascular functional reserve: quantification of long-term changes with electron-beam CT—preliminary results in a porcine model.
        Radiology. 2001; 221: 229-236
        • Bell M.R.
        • Lerman L.O.
        • Rumberger J.A.
        Validation of minimally invasive measurement of myocardial perfusion using electron beam computed tomography and application in human volunteers.
        Heart. 1999; 81: 628-635
        • Best P.J.M.
        • McKenna C.J.
        • Hasdai D.
        • Holmes Jr, D.R.
        • Lerman A.
        Chronic endothelin antagonism preserves coronary endothelial function in experimental hypercholesterolemia.
        Circulation. 1999; 99: 1747-1752
        • Best P.J.M.
        • Lerman L.O.L.
        • Romero J.C.
        • Richardson D.
        • Holmes Jr, D.R.
        • Lerman A.
        Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2769-2775
        • Lerman L.O.
        • Siripornpitak S.
        • Maffei N.L.
        • Sheedy 2nd, P.F.
        • Ritman E.L.
        Measurement of in vivo myocardial microcirculatory function with electron beam CT.
        J. Comput. Assist. Tomogr. 1999; 23: 390-398
        • Garrett J.S.
        • Lanzer P.
        • Jaschke W.
        • Botvinick E.
        • Sievers R.
        • Higgins C.B.
        • Lipton M.J.
        Measurement of cardiac output by cine computed tomography.
        Am. J. Cardiol. 1985; 56: 657-661
        • 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
        • Best P.J.M.
        • Lerman A.
        Endothelin in cardiovascular disease: from atherosclerosis to heart failure.
        J. Cardiovasc. Pharmacol. 2000; 35: S61-S63
        • Hasdai D.
        • Sangiorgi G.
        • Spagnoli L.G.
        • Simari R.D.
        • Holmes Jr, D.R.
        • Kwon H.M.
        • Carlson P.J.
        • Schwartz R.S.
        • Lerman A.
        Coronary artery apoptosis in experimental hypercholesterolemia.
        Atherosclerosis. 1999; 142: 317-325
        • Schächinger V.
        • Zeiher A.M.
        Alterations of coronary blood flow and myocardial perfusion in hypercholesterolemia.
        Heart. 1996; 76: 295-298
        • Verhaar M.C.
        • Grahn A.Y.
        • van Weerdt A.W.M.
        • Honing M.L.
        • Morrison P.J.
        • Yang Y.P.
        • Padley R.J.
        • Rabelink T.J.
        Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humans.
        Br. J. Clin. Pharmacol. 2000; 49: 562-573
        • Mathew V.
        • Cannan C.R.
        • Miller V.M.
        • Barber D.A.
        • Hasdai D.
        • Schwartz R.S.
        • Holmes D.R.J.r
        • Lerman A.
        Enhanced endothelin-mediated coronary vasoconstriction and attenuated basal nitric oxide activity in experimental hypercholesterolemia.
        Circulation. 1997; 96: 1930-1936
        • Olsson R.A.
        • Pearson J.D.
        Cardiovascular purinoreceptors.
        Physiol. Rev. 1990; 70: 761-845
        • Schiele J.O.
        • Schwabe U.
        Characterization of the adenosine receptor in microvascular coronary endothelial cells.
        Eur. J. Pharmacol. 1994; 269: 51-58
        • Hein T.W.
        • Kuo L.
        cAMP-independent dilation of coronary arterioles to adenosine: role of nitric oxide, G proteins, and KATP channels.
        Circ. Res. 1999; 85: 634-642
        • Smits P.
        • Williams S.B.
        • Lipson D.E.
        • Banitt P.
        • Rongen G.A.
        • Creager M.A.
        Endothelial release of nitric oxide contributes to the vasodilator effect of adenosine in humans.
        Circulation. 1995; 92: 2135-2141
        • Buus N.H.
        • Bøttcher M.
        • Hermansen F.
        • Sander M.
        • Nielsen T.T.
        • Mulvany M.J.
        Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia.
        Circulation. 2001; 104: 2305-2310
        • Embrey R.P.
        • Brooks L.A.
        • Dellsperger K.C.
        Mechanism of coronary microvascular responses to metabolic stimulation.
        Cardiovasc. Res. 1997; 35: 148-157
        • Wilson R.F.
        • Wyche K.
        • Christensen B.V.
        • Zimmer S.
        • Laxson D.D.
        Effects of adenosine on human coronary arterial circulation.
        Circulation. 1990; 82: 1595-1606
        • Filep J.G.
        • Foldes-Filep E.
        • Rousseau A.
        • Fournier A.
        • Sirois P.
        • Yano M.
        Endothelin-1 enhances vascular permeability in the rat heart through the ETA receptor.
        Eur. J. Pharmacol. 1992; 219: 343-344
        • Victorino G.P.
        • Wisner D.H.
        • Tucker V.L.
        Basal release of endothelin-1 and the influence of the ETB receptor on single vessel hydraulic permeability.
        J. Trauma. 2000; 49: 314-319
        • Wu C.C.
        • Chang S.W.
        • Chen M.S.
        • Lee Y.T.
        Early change of vascular permeability in hypercholesterolemic rabbits.
        Arterioscler. Thromb. Vasc. Biol. 1995; 15: 529-533