(Hypertension. 2000;35:732.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis
Role of ETB Receptors
From the Department of Vascular Surgery (A.H., Z.A.A.), Rambam Medical Center, Haifa, Israel; Department of Physiology and Biophysics (Z.A.A., S.B., J.W.), The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; and Department of Nephrology (R.R.), Poriah Government Hospital, Tiberias, Israel.
Correspondence to Aaron Hoffman, MD, Department of Vascular Surgery, Rambam Medical Center, POB 9602, 31096 Haifa, Israel. E-mail ahofman{at}rambam.health.gov.il
Abstract—Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and antinatriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms underlying the excretory effects of big ET-1 have not been fully elucidated. To explore these mechanisms, we examined the effects of a highly selective ETB antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal actions of big ET-1 in anesthetized rats. An intravenous bolus injection of incremental doses of big ET-1 (0.3, 1.0, and 3.0 nmol/kg) produced a significant hypertensive effect that was dose dependent and prolonged (from 113±7 mm Hg to a maximum of 148±6 mm Hg). The administration of big ET-1 induced marked diuretic and natriuretic responses (urinary flow rate increased from 8.5±1 to 110±14 µL/min, and fractional excretion of sodium increased from 0.38±0.13% to 7.51±1.24%). Glomerular filtration rate and renal plasma flow significantly decreased only at the highest dose of big ET-1. Pretreatment with A-192621.1 (3 mg/kg plus 3 mg · kg-1 · h-1) significantly abolished the diuretic (17±5 µL/min to a maximum of 19±3 µL/min) and natriuretic (0.29±0.1% to a maximum of 1.93±0.37%) responses induced by big ET-1. Moreover, A-192621.1 potentiated the decline in glomerular filtration rate and renal plasma flow and the increase in mean arterial blood pressure produced by the low doses of big ET-1. Similar to A-192621.1, pretreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg · kg-1 · h-1) significantly and comparably reduced the diuretic and natriuretic actions of big ET-1 and augmented the hypoperfusion/hypofiltration and systemic vasoconstriction induced by high doses of the peptide. Pretreatment with verapamil (2 mg · kg-1 · h-1) slightly inhibited the diuretic/natriuretic effects of the high-dose big ET-1 and completely prevented the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associated with significant natriuretic/diuretic responses and did not influence the pressor effect and renal actions of big ET-1. Taken together, these results suggest that big ET-1–induced diuretic and natriuretic responses are mediated mainly by stimulation of nitric oxide production coupled to ETB receptor subtype activation.
Key Words: endothelin • receptors, endothelin • nitric oxide • verapamil • prostaglandins • diuretics
This article has been cited by other articles:
 |
|
 |
|
  L. R. Stow, M. L. Gumz, I. J. Lynch, M. M. Greenlee, A. Rudin, B. D. Cain, and C. S. Wingo Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1) J. Biol. Chem., October 30, 2009; 284(44): 30087 - 30096. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhou, Y. Zhu, M. Cheng, D. Dinesh, T. Thorne, K. K. Poh, D. Liu, C. Botros, Y. L. Tang, N. Reisdorph, et al. Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor Circulation, September 29, 2009; 120(13): 1213 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Abassi, B. Bishara, T. Karram, S. Khatib, J. Winaver, and A. Hoffman Adverse effects of pneumoperitoneum on renal function: involvement of the endothelin and nitric oxide systems Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R842 - R850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Heyman, S. Rosen, and C. Rosenberger Renal Parenchymal Hypoxia, Hypoxia Adaptation, and the Pathogenesis of Radiocontrast Nephropathy Clin. J. Am. Soc. Nephrol., January 1, 2008; 3(1): 288 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wendel, L. Knels, W. Kummer, and T. Koch Distribution of Endothelin Receptor Subtypes ETA and ETB in the Rat Kidney J. Histochem. Cytochem., November 1, 2006; 54(11): 1193 - 1203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Bagnall, N. F. Kelland, F. Gulliver-Sloan, A. P. Davenport, G. A. Gray, M. Yanagisawa, D. J. Webb, and Y. V. Kotelevtsev Deletion of Endothelial Cell Endothelin B Receptors Does Not Affect Blood Pressure or Sensitivity to Salt Hypertension, August 1, 2006; 48(2): 286 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Guo and T. Yang Endothelin B receptor antagonism in the rat renal medulla reduces urine flow rate and sodium excretion. Experimental Biology and Medicine, June 1, 2006; 231(6): 1001 - 1005. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Fryer, P. A. Rakestraw, P. N. Banfor, B. F. Cox, T. J. Opgenorth, and G. A. Reinhart Blood pressure regulation by ETA and ETB receptors in conscious, telemetry-instrumented mice and role of ETA in hypertension produced by selective ETB blockade Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2554 - H2559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Ovcharenko, Z. Abassi, I. Rubinstein, A. Kaballa, A. Hoffman, and J. Winaver Renal effects of human urotensin-II in rats with experimental congestive heart failure Nephrol. Dial. Transplant., May 1, 2006; 21(5): 1205 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. del Villar, C. J. G. Alonso, C. A. Feldstein, L. A. Juncos, and J. C. Romero Role of Endothelin in the Pathogenesis of Hypertension Mayo Clin. Proc., January 1, 2005; 80(1): 84 - 96. [Abstract] [PDF]
|
|
|
|
|
|
J. L. Tycho Vuurmans, P. Boer, and H. A. Koomans Effects of endothelin-1 and endothelin-1-receptor blockade on renal function in humans Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2742 - 2746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Goddard, C. Eckhart, N. R. Johnston, A. D. Cumming, A. J. Rankin, and D. J. Webb Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor-Mediated and Nitric Oxide-Dependent Mechanism J. Am. Soc. Nephrol., October 1, 2004; 15(10): 2601 - 2610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Vassileva, C. Mountain, and D. M. Pollock Functional Role of ETB Receptors in the Renal Medulla Hypertension, June 1, 2003; 41(6): 1359 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Reinhart, L. C. Preusser, S. E. Burke, J. L. Wessale, C. D. Wegner, T. J. Opgenorth, and B. F. Cox Hypertension induced by blockade of ETB receptors in conscious nonhuman primates: role of ETA receptors Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1555 - H1561. [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]
|
|
|
|
 |
|
 Y. Kotelevtsev and D. J Webb Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide Cardiovasc Res, August 15, 2001; 51(3): 481 - 488. [Full Text] [PDF]
|
|
|
|
 |
|
 Z. A. Abassi, S. Ellahham, J. Winaver, and A. Hoffman The Intrarenal Endothelin System and Hypertension Physiology, August 1, 2001; 16(4): 152 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Riggleman, J. Harvey, and C. Baylis Endothelin Mediates Some of the Renal Actions of Acutely Administered Angiotensin II Hypertension, July 1, 2001; 38(1): 105 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. POLLOCK Contrasting pharmacological ETB receptor blockade with genetic ETB deficiency in renal responses to big ET-1 Physiol Genomics, June 6, 2001; 6(1): 39 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Park and E. L. Schiffrin ETA Receptor Antagonist Prevents Blood Pressure Elevation and Vascular Remodeling in Aldosterone-Infused Rats Hypertension, June 1, 2001; 37(6): 1444 - 1449. [Abstract] [Full Text] [PDF]
|
|