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.
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.


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.
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
Jane
J
Goddard
Neil R
NR
Johnston
Malcolm F
MF
Hand
Allan D
AD
Cumming
Ton J
TJ
Rabelink
Andrew J
AJ
Rankin
David J
DJ
Webb
D000959:Antihypertensive Agents / Q000097:blood / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000097:blood / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D011507:Proteinuria / Q000175:diagnosis; D012079:Renal Circulation / Q000187:drug effects*; D012964:Sodium / Q000652:urine
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C086539:BQ 788; D012964:Sodium; C072247:cyclo(Trp-Asp-Pro-Val-Leu)