Published online before print February 23, 2004, doi: 10.1161/01.CIR.0000118499.69469.51
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(Circulation. 2004;109:1186-1193.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Endothelin-A Receptor Antagonism Reduces Blood Pressure and Increases Renal Blood Flow in Hypertensive Patients With Chronic Renal Failure
A Comparison of Selective and Combined Endothelin Receptor Blockade
From the Centre for Cardiovascular Science (J.G., N.R.J., A.D.C., D.J.W.), University of Edinburgh, Edinburgh, United Kingdom; Monklands Hospital (M.F.H.), Airdrie, Lanarkshire, United Kingdom; Department of Nephrology & Hypertension (T.J.R.), University Hospital, Utrecht, Netherlands; and Pfizer Global Research & Development (A.J.R.), Sandwich, United Kingdom.
Correspondence to Professor D.J. Webb, Clinical Research Centre, Centre for Cardiovascular Science, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom. E-mail d.j.webb{at}ed.ac.uk
Received July 28, 2003; revision received November 12, 2003; accepted November 25, 2003.
Background— Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade.
Methods and Results— We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls -4±2%, CRF -13±2%, P<0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8±23.9%, P<0.01 versus placebo) and reduced renal vascular resistance (-44.5±11.3%, P<0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls.
Conclusions— ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.
Key Words: blood flow • blood pressure • endothelin • kidney • hemodynamics
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