Evidence for endothelin involvement in the response to high salt.

Recent evidence suggests that endothelin-1 (ET-1), perhaps through the ET(B) receptor, may participate in blood pressure regulation through the control of sodium excretion. Mean arterial pressure (MAP) was continuously measured via telemetry implants in male Sprague-Dawley rats. After 1 wk of baseline measurements, rats were given either high (10%) or low (0.08%) NaCl in chow for the remainder of the experiment (n = 5 in each group). MAP was significantly increased in rats on a high-salt diet (115 +/- 2 mmHg) compared with rats on the low-salt diet (103 +/- 2 mmHg; P < 0.05). All rats were then treated with the ET(B) receptor antagonist A-192621 mixed with the food and adjusted daily to ensure a dose of 30 mg x kg(-1) x day(-1). ET(B) blockade produced an increase in MAP within a few hours of treatment and was significantly higher in rats on the high-salt diet over a 1-wk period (170 +/- 3 vs. 115 +/- 3 mmHg, P < 0.01). To determine whether the increase in MAP during A-192621 treatment was due to increased ET(A) receptor activation, all rats were then given the ET(A)-selective antagonist ABT-627 in the drinking water while a low-salt/high-salt diet and ET(B) blockade were continued. ABT-627 decreased MAP within a few hours in rats on either the high-salt (113 +/- 3 mmHg) or low-salt (101 +/- 3 mmHg) diet. These results support the hypothesis that endothelin, through the ET(B) receptor, participates in blood pressure regulation in the response to salt loading.

[1]  J. Garvin,et al.  Endothelin inhibits thick ascending limb chloride flux via ET(B) receptor-mediated NO release. , 2000, American journal of physiology. Renal physiology.

[2]  C. Michel,et al.  Modeling exchange of plasma proteins between microcirculation and interstitium of the renal medulla. , 2000, American journal of physiology. Renal physiology.

[3]  M. Yanagisawa,et al.  Salt-sensitive hypertension in endothelin-B receptor-deficient rats. , 2000, The Journal of clinical investigation.

[4]  D. Pollock.  Renal endothelin in hypertension. , 2000, Current opinion in nephrology and hypertension.

[5]  J. Pollock,et al.  Upregulation of endothelin B receptors in kidneys of DOCA-salt hypertensive rats. , 2000, American journal of physiology. Renal physiology.

[6]  A. Tasker,et al.  Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity. , 1999, Journal of Medicinal Chemistry.

[7]  Z. Abassi,et al.  Differential regulation of renal regional blood flow by endothelin-1. , 1996, The American journal of physiology.

[8]  V. Breu,et al.  The role of ETB receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ETB receptor antagonist Ro 46‐8443 , 1996, FEBS letters.

[9]  A. Tasker,et al.  2,4-Diarylpyrrolidine-3-carboxylic acids--potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. , 1996, Journal of medicinal chemistry.

[10]  E. Schiffrin,et al.  Increased endothelin-1 gene expression in the endothelium of coronary arteries and endocardium in the DOCA-salt hypertensive rat. , 1995, Journal of molecular and cellular cardiology.

[11]  E. Schiffrin,et al.  Antihypertensive effect of an endothelin receptor antagonist in DOCA‐salt spontaneously hypertensive rats , 1995, British journal of pharmacology.

[12]  M. Polokoff,et al.  Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. , 1994, Pharmacological reviews.

[13]  S. Ozaki,et al.  Clearance of circulating endothelin-1 by ETB receptors in rats. , 1994, Biochemical and biophysical research communications.

[14]  K. Lindpaintner,et al.  Characterization of endothelin synthetic pathways and receptor subtypes: physiological and pathophysiological implications. , 1993 .

[15]  A. Davenport,et al.  Novel ligands BQ123 and BQ3020 characterize endothelin receptor subtypes ETA and ETB in human kidney. , 1993, Kidney international.

[16]  E. Schiffrin,et al.  Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats. , 1993, Hypertension.

[17]  J. Keiser,et al.  Induction of water diuresis by endothelin in rats. , 1992, The American journal of physiology.

[18]  P. Harris,et al.  Haemodynamic and renal tubular effects of low doses of endothelin in anaesthetized rats. , 1991, The Journal of physiology.

[19]  J. Vane,et al.  Receptor-mediated release of endothelium-derived relaxing factor and prostacyclin from bovine aortic endothelial cells is coupled. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[20]  D. Webb,et al.  Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. , 1999, Hypertension.

[21]  R. Venema,et al.  ETA receptor blockade attenuates the hypertension but not renal dysfunction in DOCA-salt rats. , 1998, The American journal of physiology.

[22]  T. Rasmussen,et al.  Cardiovascular actions of ET-B activation in vivo and modulation by receptor antagonism. , 1998, The American journal of physiology.

[23]  T. Warner.  Characterization of endothelin synthetic pathways and receptor subtypes: physiological and pathophysiological implications. , 1993, European heart journal.