Comparison of the effects of selective endothelin ETA and ETB receptor antagonists in congestive heart failure

First Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Japan. wada@belle.shiga-med.ac.jp

OBJECTIVES: This study was designed 1) to determine the extent to which endogenous endothelin (ET) affects hemodynamic, hormonal and body fluid balance through ETA and ETB receptors in congestive heart failure (CHF); and 2) to assess the therapeutic benefits and adverse effects of ET receptor antagonists for ETA and ETB on cardiorenal and neurohormonal variables. BACKGROUND: ET has two receptors, ETA and ETB, both of which are distributed in various tissues and cells. In vascular beds, ETA receptors mediate vasoconstriction, whereas ETB receptors mediate vasorelaxation. However, ETB receptors also exist in smooth muscle and mediate vasoconstriction. METHODS: We administered either the ETA receptor antagonist FR139317 (FR [n = 8], 1 and 10 mg/kg body weight) or the ETB receptor antagonist RES-701-1 (RES [n = 8], 0.2 and 1.5 mg/kg) to dogs with CHF induced by rapid ventricular pacing. The effects of both antagonists on cardiorenal and hormonal functions were studied. RESULTS: FR decreased cardiac pressures and the plasma atrial natriuretic peptide (ANP) level and increased cardiac output (CO). Urinary flow rate and urinary sodium excretion increased in association with an increase in the glomerular filtration rate and renal plasma flow (RPF). In contrast, RES increased cardiac pressures and decreased CO. It also decreased the plasma aldosterone level and RPF. Neither antagonist affected plasma norepinephrine levels. CONCLUSIONS: Endogenous ETs increase cardiac pressures and the retention of body fluid through ETA receptors in CHF. The vasodilative action through ETB receptors is overall functionally more important than the constrictive action through ETB receptors. ETs may regulate the secretion of ANP and aldosterone. Our findings suggest that selective ETA receptor antagonists have potential therapeutic benefits affecting both hemodynamic variables and diuresis, whereas ETB receptor antagonists have adverse hemodynamic effects, with the possibility of preventing fluid retention through suppression of aldosterone secretion in dogs with CHF.

This article has been cited by other articles:

				N. F. Kelland and D. J. Webb Clinical Trials of Endothelin Antagonists in Heart Failure: A Question of Dose? Exp Biol Med, June 1, 2006; 231(6): 696 - 699. [Abstract] [Full Text] [PDF]

				P. J. Cowburn, J. G.F. Cleland, T. A. McDonagh, J. D. McArthur, H. J. Dargie, and J. J. Morton Comparison of selective ETA and ETB receptor antagonists in patients with chronic heart failure Eur J Heart Fail, January 1, 2005; 7(1): 37 - 42. [Abstract] [Full Text] [PDF]

				T. J.L. Vuurmans, P. Boer, and H. A. Koomans Effects of Endothelin-1 and Endothelin-1 Receptor Blockade on Cardiac Output, Aortic Pressure, and Pulse Wave Velocity in Humans Hypertension, June 1, 2003; 41(6): 1253 - 1258. [Abstract] [Full Text] [PDF]

				S. Vanni, G. Polidori, I. Cecioni, S. Serni, M. Carini, and P. A. Modesti ETB Receptor in Renal Medulla Is Enhanced by Local Sodium During Low Salt Intake Hypertension, August 1, 2002; 40(2): 179 - 185. [Abstract] [Full Text] [PDF]

				P.J. Cowburn and J.G.F. Cleland Endothelin antagonists for chronic heart failure: do they have a role? Eur. Heart J., October 1, 2001; 22(19): 1772 - 1784. [PDF]

				Y. Oikawa, K. Maehara, T. Saito, K. Tamagawa, and Y. Maruyama Attenuation of angiotensin II-mediated coronary vasoconstriction and vasodilatory action of angiotensin-converting enzyme inhibitor in pacing-induced heart failure in dogs J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1188 - 1194. [Abstract] [Full Text] [PDF]

				K. Tadano, J. Suzuki, K. Hanada, M. Nakao, R. Nakao, S. Uehara, H. Ohta, T. Miyauchi, and M. Nishikibe Pathophysiological Roles of Endogenous Endothelin-1 in Dogs with Chronic Heart Failure Produced by Rapid Right Ventricular Pacing J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 729 - 736. [Abstract] [Full Text] [PDF]

				S. Eddahibi and S. Adnot Endothelins and pulmonary hypertension, what directions for the near future? Eur. Respir. J., July 1, 2001; 18(1): 1 - 4. [Full Text] [PDF]

				J.-L. Liu, R. U. Pliquett, E. Brewer, K. G. Cornish, Y.-T. Shen, and I. H. Zucker Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1906 - R1913. [Abstract] [Full Text] [PDF]

				L. E. Spieker, G. Noll, F. T. Ruschitzka, and T. F. Luscher Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1493 - 1505. [Abstract] [Full Text] [PDF]

				W. Boemke, B. Hocher, N. Schleyer, M. O. Krebs, and G. Kaczmarczyk Hemodynamic, renal, and endocrine responses to acute ETA blockade at different ANG II plasma levels Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1322 - R1331. [Abstract] [Full Text] [PDF]

				T. Suzuki and T. Miyauchi A novel pharmacological action of ET-1 to prevent the cytotoxicity of doxorubicin in cardiomyocytes Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1399 - R1406. [Abstract] [Full Text] [PDF]

				J.-F. Jasmin, M. Lucas, P. Cernacek, and J. Dupuis Effectiveness of a Nonselective ETA/B and a Selective ETA Antagonist in Rats With Monocrotaline-Induced Pulmonary Hypertension Circulation, January 16, 2001; 103(2): 314 - 318. [Abstract] [Full Text] [PDF]

				T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]

				Y.-T. Shen, P. S Buie, J. J Lynch, S. M Krause, and X.-L. Ma Chronic therapy with an ETA/B receptor antagonist in conscious dogs during progression of congestive heart failure: Intracellular Ca2+ regulation and nitric oxide mediated coronary relaxation Cardiovasc Res, November 1, 2000; 48(2): 332 - 345. [Abstract] [Full Text] [PDF]

				D. L. Moraes, W. S. Colucci, and M. M. Givertz Secondary Pulmonary Hypertension in Chronic Heart Failure : The Role of the Endothelium in Pathophysiology and Management Circulation, October 3, 2000; 102(14): 1718 - 1723. [Abstract] [Full Text] [PDF]

				E. Thorin, M. Lucas, P. Cernacek, and J. Dupuis Role of ETA receptors in the regulation of vascular reactivity in rats with congestive heart failure Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H844 - H851. [Abstract] [Full Text] [PDF]

				M. P Love, C. J Ferro, W. G Haynes, C. Plumpton, A. P Davenport, D. J Webb, and J. J.V McMurray Endothelin receptor antagonism in patients with chronic heart failure Cardiovasc Res, July 1, 2000; 47(1): 166 - 172. [Abstract] [Full Text] [PDF]

				L. E. Spieker, V. Mitrovic, G. Noll, R. Pacher, M. R. Schulze, J.o. Muntwyler, C. Schalcher, W. Kiowski, T. F. Luscher, and on behalf of the ET 003 Investigators Acute hemodynamic and neurohumoral effects of selective ETA receptor blockade in patients with congestive heart failure J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1745 - 1752. [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]

				P. J. Cowburn, J. G. F. Cleland, J. D. McArthur, M. R. MacLean, J. J. V. McMurray, H. J. Dargie, and J. J. Morton EndothelinB receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction J. Am. Coll. Cardiol., March 15, 1999; 33(4): 932 - 938. [Abstract] [Full Text] [PDF]

				A. Wada, T. Tsutamoto, M. Ohnishi, M. Sawaki, D. Fukai, Y. Maeda, and M. Kinoshita Effects of a Specific Endothelin-Converting Enzyme Inhibitor on Cardiac, Renal, and Neurohumoral Functions in Congestive Heart Failure : Comparison of Effects With Those of Endothelin A Receptor Antagonism Circulation, February 2, 1999; 99(4): 570 - 577. [Abstract] [Full Text] [PDF]

				J. Dupuis, J.-L. Rouleau, and P. Cernacek Reduced Pulmonary Clearance of Endothelin-1 Contributes to the Increase of Circulating Levels in Heart Failure Secondary to Myocardial Infarction Circulation, October 20, 1998; 98(16): 1684 - 1687. [Abstract] [Full Text] [PDF]

				J. Dupuis, G. W Moe, and P. Cernacek Reduced pulmonary metabolism of endothelin-1 in canine tachycardia-induced heart failure Cardiovasc Res, September 1, 1998; 39(3): 609 - 616. [Abstract] [Full Text] [PDF]

				M. Ohnishi, A. Wada, T. Tsutamoto, D. Fukai, and M. Kinoshita Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure Cardiovasc Res, September 1, 1998; 39(3): 617 - 624. [Abstract] [Full Text] [PDF]