Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study.
BACKGROUND
Endothelial dysfunction occurs in patients with end-stage renal disease (ESRD) and is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) contributes to endothelial dysfunction in ESRD. In the general population, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease ADMA levels, but no study has compared the effect of these drugs in patients with ESRD on maintenance hemodialysis (MHD).


METHODS
We evaluated the effect of 1-week treatment with ramipril (5 mg/d), valsartan (160 mg/d), and placebo on ADMA levels in 15 patients on MHD in a double-blind, placebo-controlled, three x three cross-over study.


RESULTS
We found that ADMA levels were increased at baseline and throughout the dialysis session during ramipril treatment (p < 0.001 compared to both, placebo and valsartan). Ramipril did not increase ADMA levels in a study of patients without ESRD, suggesting that factors related to ESRD or hemodialysis contribute to the ACE inhibitor-induced increase in ADMA. We have previously shown that ACE inhibition increases bradykinin (BK) levels during hemodialysis. We therefore evaluated the effect of bradykinin on ADMA production in A549 cells; a cell line that expresses BK receptors. Incubation with BK increased intracellular ADMA concentration through BK B2-receptor stimulation.


CONCLUSIONS
These data indicate that short-term ACE inhibition increases ADMA in patients on MHD whereas ARBs do not. In vitro studies further suggest that this may occur through BK-mediated increase in ADMA production during ACE inhibition.


BACKGROUND
Clinicaltrials.gov NCT00732069 August 6 2008 and NCT00607672 February 4 2008.
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2222 Pierce Avenue, 561-B PRB, Nashville, TN, 37232, USA. jorge.gamboa@vanderbilt.edu.
Jorge L
JL
Gamboa
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA. mias.pretorius@vanderbilt.edu.
Mias
M
Pretorius
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2222 Pierce Avenue, 561-B PRB, Nashville, TN, 37232, USA. katie.c.sprinkel@vanderbilt.edu.
Katie C
KC
Sprinkel
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2222 Pierce Avenue, 561-B PRB, Nashville, TN, 37232, USA. nancy.j.brown@vanderbilt.edu.
Nancy J
NJ
Brown
Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. alp.ikizler@vanderbilt.edu.
T Alp
TA
Ikizler
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D002460:Cell Line; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D017257:Ramipril / Q000494:pharmacology*; D006435:Renal Dialysis; D000068756:Valsartan / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; C018524:N,N-dimethylarginine; D000068756:Valsartan; D001120:Arginine; D017257:Ramipril; D001920:Bradykinin