Nephrol Dial Transplant Vol. 19 No. 11 © ERA-EDTA 2004; all rights reserved
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Sir,We thank Luigi Vernaglione for his critical comments on our paper on the role of nitric oxide (NO) in the regulation of renal haemodynamics in humans [1]. He expresses some concern about standardization of dietary factors, data analysis and interpretation. We are fully aware of the fact that diet may have an important impact on renal haemodynamics. While we have already discussed a potential confounding role of sodium intake on the response of renal haemodynamics to NO synthase inhibition in our paper [1,2], Vernaglione highlights possible effects of uncontrolled protein intake and potential differences between normotensive and hypertensive subjects. Unfortunately, self-reported protein intake and calculation of protein intake from urine urea excretion do not accurately reflect dietary protein intake and administration of a standardized formula diet over 8 weeks to control for protein intake appears not feasible. Thus, theoretical considerations, such as detailed dietary control, cannot be put into practice reasonably. However, we asked patients not to change their dietary habits during their participation in this study, which should exclude dramatic changes in protein intake. Although we cannot rule out a difference in protein intake between normotensive and hypertensive study participants, we want to point out that the main findings of our study derive from the relatively homogenous group of hypertensive subjects and not from a comparison between normotensive and hypertensive subjects.
We also may reassure Vernaglione that parametric tests have been applied only after formal testing of our data for normal distribution. However, Vernaglione is right in that non-parametric tests may, nevertheless, be useful in the analysis of data with SDs greater than the average. We have also performed non-parametric tests on all data and did not find any relevant change of results compared with the data reported in our paper [1].
Vernaglione's interpretation of renal haemodynamic changes in response to NG-monomethyl-L-arginine (L-NMMA) may be devised from our study. An increase in filtration fraction in response to L-NMMA may be interpreted as a more substantial contribution of NO to efferent than to afferent arteriolar tone. However, this rather simplistic approach contradicts more recent work that the regulation of glomerular filtration is due to the fact of several confounding determinants, of which glomerular pressure is just one. Experimental work mentioned by Vernaglione [3] supports this notion, but other data from animal models indicate a more pronounced role of NO in the regulation of afferent than of efferent arteriolar tone under basal conditions [4]. Strikingly enough, although an increase of filtration fraction due to L-NMMA is a common finding, a decrease of glomerular filtration rate in response to L-NMMA is reported in other studies [2,5], in contrast to our present findings [1] and would be in line with a predominant action of NO on the afferent glomerular arteriole.
Differences in the effect of L-NMMA on renal haemodynamics reported in the literature may derive from differences in study participants and confounding factors, such as sodium (and possibly protein) intake [2]. These contradictory results of experimental and human studies led us to design the current study using pharmacological modification of afferent and efferent arteriolar tone as a new approach to the examination of the contribution of NO to renal haemodynamics in human subjects [1]. As already discussed in our paper, this approach is an indirect one. Discrepancies between our findings on the change or absence of change in the response of renal plasma flow to L-NMMA after amlodipine or valsartan treatment, respectively, and Vernaglione's interpretation of the response of filtration rate to L-NMMA in our study participants clearly demonstrate that evaluation of such data proves to be difficult. While we appreciate Vernaglione's interpretation of a prevalent effect of NO on the efferent arteriole, one cannot neglect the results from our pharmacologically driven approach and data from other authors also pointing towards the afferent arteriole as the major target for NO. Certainly, our study is not the last word about the role of NO in the regulation of glomerular haemodynamics in humans.
Conflict of interest statement. None declared.
Department of Medicine IV University of Erlangen-Nürnberg Erlangen, Germany Email: markus.schneider{at}rzmail.uni-erlangen.de
References
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[Abstract/Free Full Text] - Bech JN, Nielsen CB, Ivarsen P, Jensen KT, Pedersen EB. Dietary sodium affects systemic and renal hemodynamic response to NO inhibition in healthy humans. Am J Physiol 1998; 274: F914–F923
- Tolins JP, Shultz PJ, Westberg G, Raij L. Renal hemodynamic effects of dietary protein in the rat: role of nitric oxide. J Lab Clin Med 1995; 125: 228–236[Web of Science][Medline]
- Edwards RM, Trizna W. Modulation of glomerular arteriolar tone by nitric oxide synthase inhibitors. J Am Soc Nephrol 1993; 4: 1127–1132[Abstract]
- Schmidt A, Bayerle-Eder M, Pleiner H et al. The renal and systemic hemodynamic effects of a nitric oxide-synthase inhibitor are reversed by a selective endothelin(a) receptor antagonist in men. Nitric Oxide 2001; 5: 370–376[CrossRef][Web of Science][Medline]
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