(Circulation. 2000;102:e37.)
© 2000 American Heart Association, Inc.
Correspondence |
Nitric Oxide Synthesis and Congestive Heart Failure
Department of Clinical Pharmacology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London, England
Because body weights were not reported, we assumed that the
nitrate volume of distribution was 37 liters2 ; however,
this figure probably underestimates the actual total body water in
patients with CHF. Because the urine was collected for 24 hours,
62.5% (1.5 half-lives) of urinary
[15N]nitrate was recovered in patients with CHF
compared with 80% (2.6 half-lives) in the control group. It is likely
that these dissimilar recoveries of
[15N]nitrate could have had an important
contribution to the observed difference of nitric oxide
production.
Third, the authors stated: "in agreement with a previous study
in hypertensive patients that used similar isotope-labeling
techniques,5 urinary nitrate excretion of
[15N]nitrate was completed within 24 hours
after the infusion of
L-[15N2]arginine."
This statement is incorrect and misleading. We did measure
[15N]nitrate enrichment in urine at 0.4260%
during the period between 24 and 36 hours.5 Katz et al
emphasized that they did not detect any levels of
[15N]nitrate in urine after 24 hours. This is
not surprising if we consider that the precision of their mass
spectrometer was rarely better than 0.01%. The mass spectrometer used
in our study has a very high sensitivity (±0.0004), which allows for
the recovery of >90% of the [15N]nitrate
excreted in urine.
References
-
Katz SD, Khan T, Zeballos GA, et al.
Decreased activity of the L-arginine–nitric
oxide metabolic pathway in patients with congestive heart
failure. Circulation. 1999;99:2113–2117.
[Abstract/Free Full Text]
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Wennmalm A, Benthin G, Edlund A, et al.
Metabolism and excretion of nitric oxide in humans: an
experimental and clinical study. Circ Res. 1993;73:1121–1127.
[Abstract/Free Full Text]
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Levey AS, Berg RL, Gassman JJ, et al.
Creatinine filtration, secretion and excretion during
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Forte P, Copland M, Smith LM, et al. Basal
nitric oxide synthesis in essential hypertension. Lancet.. 1997;349:837–842.[Medline]
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Response
Division of Circulatory Physiology, Columbia University, 630 West 168th St, New York, NY 10032
Drs Forte and Benjamin suggest that differences in renal nitrate clearance can account for our reported findings.R1 We disagree for several reasons.
First, if nitrate clearance was the principal determinant of our findings, then the differences in nitrate clearance reported in our article would predict that [15N]nitrate concentrations in plasma would be greater in patients with heart failure than in normal controls. In fact, in a small subset of 11 patients with heart failure and 4 normal subjects for whom plasma data are available, plasma [15N]nitrate concentrations tended to be nearly 2-fold higher in normal subjects compared with patients with heart failure (250±140 versus 140±50 nmol/L; P=NS). Second, if nitrate clearance was the principal determinant of our findings, we would expect to see a correlation between nitrate clearance and [15N]nitrate excretion. In fact, no association was found between nitrate clearance and [15N]nitrate excretion (r=0.41; P=NS). Finally, differences in nitrate clearance cannot account for the reported disparate response to exercise in normal subjects and in patients with heart failure.
Our statement regarding the Forte et al’sR2 published study in hypertensive patients was based on data published in Table 2 of that article, which indicates that only 8% to 15% of total [15N]nitrate urinary excretion was detected in the urine collected between 24 and 36 hours after the administration of L-[15N]arginine. Given the nearly 4-fold difference in [15N]nitrate excretion between heart failure patients and normal subjects reported in our study, the relatively small changes in total [15N]nitrate excretion that may have been detected by extending our urine collection to 36 hours would not alter our original conclusions.
In summary, we maintain that decreased activity of the L-arginine–nitric oxide metabolic pathway is the most likely explanation for our observations and that small differences in renal clearance of nitrates cannot account for our findings. Our original conclusions are supported by the recently published study by Agnoletti et al,R3 which demonstrated that serum from patients with heart failure downregulates endothelial nitric oxide synthase expression in cultured human umbilical vein endothelial cells.
References
-
Katz SD, Khan T, Zeballos GA, et al.
Decreased activity of the L-arginine–nitric
oxide metabolic pathway in patients with congestive heart
failure. Circulation. 1999;99:2113–2117.
-
Forte P, Copland M, Smith LM, et al. Basal
nitric oxide synthesis in essential hypertension. Lancet. 1997;349:837–842.
-
Agnoletti L, Curello S, Bachetti T, et al. Serum
from patients with severe heart failure downregulates eNOS and is
proapoptotic: role of tumor necrosis factor-
.
Circulation. 1999;100:1983–1991.[Abstract/Free Full Text]
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