doi: 10.1161/01.ATV.0000193890.94720.1a
© 2005 American Heart Association, Inc.
Letters to the Editor |
Letter to the Editor
Dissociation Between the Short-Term Effects of Nocturnal Hemodialysis on Endothelium Dependent Vasodilation and Plasma ADMA
Department of Medicine, University Health Network and Mount Sinai Hospital University of Toronto, Ontario, Canada
Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology Center of Experimental Medicine University Hospital Hamburg–Eppendorf, Germany
Humber River Regional Hospital University of Toronto, Ontario, Canada
Department of Medicine, University Health Network and Mount Sinai Hospital University of Toronto, Ontario, Canada
To the Editor,
Cardiovascular mortality remains the leading cause of death in ESRD patients.1 Several of the abnormalities that accrue in ESRD have the potential to attenuate endothelium-dependent vasodilation (EDV).2 These include, but are not restricted to, uremia, hypertension, and increased plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase3,4 that has been recently associated independently with increased cardiovascular event rates.5
Nocturnal hemodialysis (NHD) (5 to 6 sessions per week, 8 hours per session) is a novel mode of renal replacement therapy that increases both the frequency and dose of dialysis.6 Within 1 to 2 months after ESRD patients are converted from CHD to NHD, hypertension resolves, EDV improves markedly, and vasodilator responsiveness to sublingual glyceryl trinitrate (GTN) is enhanced.7
ADMA inhibits competitively all 3 isoforms of NO synthase.8 When infused into healthy humans, ADMA decreases forearm blood flow and cardiac output and increases systemic vascular resistance.9,10 ADMA accumulates with renal failure.11 Its plasma concentrations are elevated in patients receiving CHD.12 We therefore tested the hypotheses that NHD improves EDV by lowering plasma concentrations of ADMA.
Seventeen nonsmoking ESRD patients (10 men; mean age, 41±2 years) were studied, after informed written consent, according to methods detailed in the online supplement (available at http://atvb.ahajournals.org). While on CHD, these patients required, on average, 2.6 antihypertensive drugs for blood pressure control. Hyperemia did not elicit a consistent increase in flow-mediated dilation of the brachial artery (–2.9±2.0% change in diameter). Furthermore, the vasodilator response to GTN was less than half that anticipated from prior studies in healthy volunteers (6.5±3.0%).13
After conversion to NHD, there was a significant increase in dialysis dose (from 1.23±0.06 [CHD] to 2.04±0.09 [NHD], P=0.02) and a significant reduction in blood pressure despite withdrawal of antihypertensive therapy. After 1 month, there were significant improvements in both EDV (4.7±1.9%, P<0.05) and GTN-mediated dilation (7.3±1.8%, P<0.05). Mean values for both EDV (8.4±1.5%) and GTN-mediated dilation (15.8±1.8%) doubled after a second month of NHD (P<0.05). In contrast, mean plasma ADMA levels were approximately twice those reported in healthy subjects14 yet unaffected by NHD (from 1.06±0.05 [CHD] to 1.02±0.08 [1 month of NHD] and 1.06±0.11 [2 months of NHD] µmol/L; Table).
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Increasing the dose and frequency of dialysis by NHD has been demonstrated, in both short- and long-term studies, to reverse several important risk factors for adverse cardiovascular events in ESRD patients.15 One mechanism by which this might occur is by lowering the plasma concentrations of the NO synthase inhibitor, ADMA. Our key and novel finding effectively refutes this hypothesis. NHD had no effect on plasma concentrations of the NOS inhibitor ADMA yet increased both EDV and EIV. This dissociation was present within 1 month of commencing NHD.
This interpretation is consistent with several previous in vivo and in vitro findings. In CHD patients, endothelial NO generation is not decreased, when compared with control subjects, despite higher circulating ADMA concentrations.16,17 Cross et al18 hypothesized that exogenous administration of L-arginine might improve endothelial function in patients with chronic kidney failure by overcoming inhibition of endothelial NO synthases by AMDA. However, acute local or systemic administration of L-arginine did not improve EDV in patients’ resistance or conduit arteries. Another group examined responses to acetylcholine in vessels isolated from ESRD patients. Endothelial responsiveness was inhibited by calcium gated potassium channel blockade but not by inhibitors of NOS (ie, NG-monomethyl-L-aginine [L-NMMA] or ADMA).19 Thus, substances other than inhibitors of NOS appear to be primarily responsible for the profound attenuation of EDV in ESRD patients.
The ability of more sustained dialysis to clear ADMA from the circulation has been questioned. Kielstein et al20 studied 30 ESRD patients and analyzed the removal rates of ADMA by conventional and extended hemodialysis. These investigators found the dialysance of ADMA to be much lower than anticipated on the basis of its molecular weight, because of significant protein binding; its behavior therefore appeared similar to that of middle or large molecules.
This is the first study to demonstrate that improvement in endothelial and vascular smooth muscle vasodilator responsiveness in ESRD occurs independently of any concurrent changes in circulating ADMA. This finding therefore calls into question the concept that increased plasma ADMA concentrations contribute importantly to the profound impairment of endothelium-dependent vasodilation in ESRD patients receiving CHD.
Acknowledgments
Dr John Floras holds the Canada Research Chair in Integrative Cardiovascular Biology and is the recipient of a Career Investigator Award from the Heart and Stroke Foundation of Ontario. This study was supported by Canadian Institutes of Health Research Operating grant MOP53284.
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