Haemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease.
BACKGROUND
Endothelin-1 (ET-1) has been implicated in the pathophysiology of chronic kidney disease (CKD) and ET receptor blockade has shown renoprotective effects in animals. We examined the haemodynamic and renal effects of an ET receptor antagonist, TAK-044, in patients with CKD.


METHODS
Seven patients with CKD (mean arterial pressure 103 mmHg; mean plasma creatinine 3.5 mg/dl) received three 15 min intravenous infusions, each separated by at least 7 days, of either placebo or TAK-044 (100 or 750 mg) in a randomized, double blind crossover study. Systemic and renal haemodynamics, and plasma immunoreactive ET-1, big ET-1 and C-terminal fragment concentrations, were determined before and after the infusions of placebo and drugs.


RESULTS
Compared with placebo, TAK-044 reduced mean arterial pressure (MAP) (100 mg: 7.4 +/- 1.9 mmHg, 750 mg: 8.4 +/- 2.3 mmHg, P < 0.01) and systemic vascular resistance index (100 mg: 650 +/- 140 dyne.s.cm(-5).m(-2), 750 mg: 829 +/- 141 dyne.s.cm(-5).m(-2), P < 0.01) at both doses. TAK-044 increased cardiac index and heart rate to a similar degree at both doses. With regards to renal haemodynamics, TAK-044 had no significant effect on the glomerular filtration rate at either dose but tended to increase renal plasma flow (100 mg: 9.6 +/- 5.0 ml/min, 750 mg: 25.3 +/- 19.5 ml/min) and decreased the effective filtration fraction (100 mg: 3.6 +/- 1.1%, 750 mg: 4.7 +/- 1.7%, P < 0.01), in a dose-dependent manner. TAK-044 had no significant effect on sodium or lithium clearance, or on fractional excretion of sodium and lithium. Plasma ET-1 concentrations rose more than two-fold after 750 mg TAK-044 while big ET-1 and C-terminal fragment concentrations were unchanged.


CONCLUSIONS
These findings suggest an important role for ET-1 in controlling systemic and renal haemodynamics in patients with CKD. The antihypertensive and potentially renoprotective actions of ET receptor antagonists shown in this study may prove useful in slowing the progression of CKD. Clinical trials are now needed to address these key questions for CKD.
Dhaun
Neeraj
N
Clinical Pharmacology Unit, University of Edinburgh, The Queen's Medical Research Institute, 3rd Floor East, Room E3.23, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. bean.dhaun@ed.ac.uk
Ferro
Charles J
CJ
Davenport
Anthony P
AP
Haynes
William G
WG
Goddard
Jane
J
Webb
David J
DJ
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D017292:Doxazosin / Q000627:therapeutic use; D004656:Enalapril / Q000627:therapeutic use; D065128:Endothelin Receptor Antagonists; D005665:Furosemide / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011446:Prospective Studies
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; C088196:TAK 044; D004656:Enalapril; D005665:Furosemide; D008790:Metoprolol; D017292:Doxazosin