Correspondence
Renovascular Hypertension, Endothelial Function, and Oxidative Stress
N Engl J Med 2002; 347:1528-1530November 7, 2002
- Article
To the Editor:
In their elegant study, Higashi et al. (June 20 issue)1 conclude that elevated angiotensin II levels in patients with renovascular hypertension constitute a principal cause of increased oxidative stress that results in impaired endothelium-dependent vasodilatation. Down-regulation of the renin–angiotensin system after angioplasty in conjunction with reduced levels of markers of oxidative stress and improved forearm blood flow is cited as supporting evidence. However, there is an alternative explanation for these findings.
It is well established that total plasma levels of the putative atherothrombotic amino acid homocysteine are inversely related to the glomerular filtration rate.2,3 Thus, as the glomerular filtration rate increases, total homocysteine levels decline. The mechanism through which homocysteine exerts its pernicious effects has not been definitively established. However, recent studies support the premise that homocysteine impairs flow-mediated endothelium-dependent vasodilatation.4,5 Furthermore, as in the study by Higashi et al., this impairment can be attenuated by pretreatment with vitamin C, suggesting involvement of mechanisms mediated by oxidative stress.5
Angioplasty of renal arteries may improve renal perfusion and increase the total glomerular filtration rate, which, in turn, will lower the total plasma homocysteine level. It is plausible to suggest that the improvement in endothelial function and the reductions in markers of oxidative stress after angioplasty are a result of lower plasma total homocysteine levels rather than, or in conjunction with, lower angiotensin II levels. This hypothesis could easily be confirmed by measurement of the glomerular filtration rate and plasma homocysteine levels before and after angioplasty in the study subjects.
5 ReferencesAllon N. Friedman, M.D.
U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111
afriedman@hnrc.tufts. edu 1
Higashi Y ,Sasaki S ,Nakagawa K ,Matsuura H ,Oshima T ,Chayama K . Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med 2002;346:1954-1962
Full Text | Web of Science | Medline2
Arnadottir M ,Hultberg B ,Nilsson-Ehle P ,Thysell H . The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Clin Lab Invest 1996;56:41-46
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Bostom AG ,Kronenberg F ,Jacques PF , et al. Proteinuria and plasma total homocysteine levels in chronic renal disease patients with a normal range serum creatinine: critical impact of true glomerular filtration rate. Atherosclerosis 2001;159:219-223
CrossRef | Web of Science | Medline4
Bellamy MF ,McDowell IFW ,Ramsey MW , et al. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation 1998;98:1848-1852
Web of Science | Medline5
Chambers JC ,McGregor A ,Jean-Marie J ,Obeid OA ,Kooner JS . Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy. Circulation 1999;99:1156-1160
Web of Science | Medline
To the Editor:
The relation observed by Higashi and colleagues might truly be due to the increase in angiotensin II levels observed in patients with renovascular hypertension or might be a response to the high blood pressure itself. Pettit and colleagues1 have demonstrated increased production of free radicals in patients with hypertension (not necessarily renovascular hypertension) due to expression of NADPH oxidase subunit p22. In addition, NADPH oxidase responds to stimuli such as vasoactive factors, growth factors, and cytokines, and some recent data suggest the existence of a genetic background modulating its expression.2 We believe that the relation between oxidative stress and hypertension is a response to several distinct stimuli, not only to an increase in angiotensin II. Investigation of other markers of susceptibility to oxidative stress (e.g., polymorphisms in the p22 gene) in patients with hypertension could be important in the development of new therapeutic approaches that block NADPH oxidase3 in such patients.
3 ReferencesCristiane Ritter, M.D.
José Cláudio F. Moreira, Ph.D.
Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, BrazilFelipe Dal-Pizzol, M.D., Ph.D.
Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, Brazil
pizzol@ez-poa.com. br 1
Pettit AI ,Wong RK ,Lee V ,Jennings S ,Quinn PA ,Ng LL . Increased free radical production in hypertension due to increased expression of the NADPH oxidase subunit p22(phox) in lymphoblast cell lines. J Hypertens 2002;20:677-683
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Zalba G ,San Jose G ,Moreno MU , et al. Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 2001;38:1395-1399
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Wassmann S ,Laufs U ,Stamenkovic D , et al. Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation 2002;105:2083-2091
CrossRef | Web of Science | Medline
To the Editor:
Higashi et al. report that repair of renal-artery stenosis increases the forearm vasodilator response to acetylcholine. Acetylcholine increases endothelial nitric oxide release. Shear stress across the vascular endothelium also increases nitric oxide release1; this is the mechanism responsible for flow-mediated vasodilatation. The amount of nitric oxide released by the endothelium is directly related to systolic blood pressure.2 The subjects with hypertension in the study by Higashi et al. had a systolic blood pressure of 161 mm Hg, whereas the control group had a systolic blood pressure of 115 mm Hg.
Higashi et al. believe that the return of a normal endothelial response to acetylcholine after angioplasty is attributable to diminished oxidative stress. A much simpler explanation is that the systolic blood pressure was decreased from 161 to 124 mm Hg. This decrease in blood pressure should decrease flow-mediated nitric oxide release and permit a greater nitric oxide response to acetylcholine. As the authors note, endothelial function becomes progressively impaired as hypertension worsens. Patients with atherosclerosis, like those in this study, have damaged endothelium. They are unable to make sufficient nitric oxide in response to the combination of a high systolic blood pressure and acetylcholine. Lowering the systolic blood pressure provides some reserve nitric oxide–producing function and thus allows a greater response to infusion of acetylcholine.
Higashi et al. report higher urinary nitrate and nitrite levels after angioplasty. Much of the nitrate and nitrite in urine comes from a normal diet; four days of a restricted diet have been shown to substantially decrease nitrate and nitrite levels.3 Did the subjects in this study follow a special diet?
3 ReferencesMichael G. Ziegler, M.D.
Xuping Bao, M.D.
University of California, San Diego, School of Medicine, San Diego, CA 92103-8341
mziegler@ucsd.edu 1
Bao X ,Lu C ,Frangos JA . Mechanism of temporal gradients in shear-induced ERK1/2 activation and proliferation in endothelial cells. Am J Physiol Heart Circ Physiol 2001;291:H22-H292
Elayan HH ,Kennedy BP ,Ziegler MG . The pressor effect of NO synthase inhibition correlates to pre-existing systolic BP in the rat. Auton Neurosci 2002;95:32-36
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Wang J ,Brown MA ,Tam SH ,Chan MC ,Whitworth JA . Effects of diet on measurement of nitric oxide metabolites. Clin Exp Pharmacol Physiol 1997;24:418-420
CrossRef | Web of Science | Medline
To the Editor:
As Sowers notes in his editorial,1 there is increasing evidence that oxidative stress may be the common pathway in endothelial damage, not only in renovascular hypertension, but also in hyperglycemia.2 This may explain why the beneficial effects of angiotensin-converting–enzyme inhibitors and angiotensin-receptor blockers in delaying progressive nephropathy in patients with diabetes exceed those that would be anticipated on the basis of their hypotensive effects alone.3 Current research indicates that the antioxidant ascorbate not only attenuates vasoconstriction induced by infusion of angiotensin II but also restores endothelium-dependent vasodilatation, which is impaired by hyperglycemia.4
Hyperglycemia has been shown to activate protein kinase C-β (PKC-β), which, in turn, has been demonstrated to decrease endothelium-derived nitric oxide. In addition, an experimental inhibitor (LY333531) of PKC-β has been demonstrated to prevent impairment of endothelium-dependent vasodilatation caused by hyperglycemia in humans.5
5 ReferencesRobert Matz, M.D.
Mount Sinai School of Medicine, New York, NY 10029-6574
robert.matz@mountsinai. org 1
Sowers JR . Hypertension, angiotensin II, and oxidative stress. N Engl J Med 2002;346:1999-2001
Full Text | Web of Science | Medline2
Cosentino F ,Hishikawa K ,Katusic ZS ,Luscher TF . High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 1997;96:25-28
Web of Science | Medline3
Brenner BM ,Cooper ME ,de Zeeuw D , et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869
Full Text | Web of Science | Medline4
Beckman JA ,Goldfine AB ,Gordon MB ,Creager MB . Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 2001;103:1618-1623
Web of Science | Medline5
Beckman JA ,Goldfine AB ,Gordon MB ,Garrett LA ,Creager MA . Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res 2002;90:107-111
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Friedman's hypothesis that the improvement of endothelial function and reduction in oxidative stress after angioplasty are due to reduced plasma total homocysteine levels caused by an increased glomerular filtration rate is interesting and well conceived. However, we found no significant difference between the mean (±SD) total glomerular filtration rate as measured by inulin clearance before and after angioplasty (68.5±12.3 vs. 71.2±11.4 ml per minute per 1.48 m2 of body-surface area, P=0.26) in 7 of the 15 patients with renovascular hypertension, although we did not measure the plasma total homocysteine levels. There have been conflicting findings concerning the effects of angioplasty on the glomerular filtration rate in patients with renovascular hypertension.1,2
We agree with the comment of Dr. Ritter et al. that other stimuli besides increased angiotensin II levels activate NADPH oxidase. In addition, xanthine oxidase, endothelial nitric oxide synthase uncoupled by the depletion of tetrahydrobiopterin, and cyclooxygenase may contribute to the production of the reactive oxygen species in patients with hypertension. The development of new antioxidant therapies that avoid the pleiotropic effects of agents such as statins and angiotensin-converting–enzyme inhibitors is awaited with great interest.
Indeed, as Drs. Ziegler and Bao suggest, the amount of nitric oxide released from vascular endothelial cells is directly related to systolic blood pressure, although the precise mechanisms by which shear stress stimulates nitric oxide release from the endothelium are not known. On the other hand, shear stress activates NADPH and NADH oxidases, leading to an increase in reactive oxygen species. The endothelium is sensitive to shear stress and can respond to changes in shear stress associated with several factors, including fluid viscosity.3 High blood pressure (high shear stress) does not always increase the bioavailability of nitric oxide. We believe that an imbalance between nitric oxide production and increased reactive oxygen species in patients with hypertension decreases the bioavailability of nitric oxide, resulting in endothelial dysfunction. Further studies are needed to determine whether the reduction in blood pressure itself is directly related to the improvement in endothelial function.
In our study, the subjects followed a regular diet that contained 170 mmol of sodium chloride per day, 100 mmol of potassium per day, 40 mmol of calcium per day, and a total intake of 40 calories per kilogram of body weight per day throughout the study. In a previous study, we confirmed that the day-to-day variation in the intake of nitrate and nitrite by a given subject was small (coefficient of variation, 7.2 percent).4
4 ReferencesYukihito Higashi, M.D., Ph.D.
Kazuaki Chayama, M.D., Ph.D.
Masao Yoshizumi, M.D., Ph.D.
Hiroshima University, Hiroshima 734-8551, Japan
yhigashi@hiroshima-u.ac. jp 1
Farmer CKT ,Reidy J ,Kalra PA ,Cook GJR ,Scoble J . Individual kidney function before and after renal angioplasty. Lancet 1998;352:288-289
CrossRef | Web of Science | Medline2
La Batide-Alanore A ,Azizi M ,Froissart M ,Raynaud A ,Plouin PF . Split renal function outcome after renal angioplasty in patients with unilateral renal artery stenosis. J Am Soc Nephrol 2001;12:1235-1241
Web of Science | Medline3
Pinsky DJ ,Patton S ,Mesaros S , et al. Mechanical transduction of nitric oxide synthesis in the beating heart. Circ Res 1997;81:372-379
Web of Science | Medline4
Higashi Y ,Oshima T ,Sasaki S , et al. Angiotensin-converting enzyme inhibition, but not calcium antagonism, improves a response of the renal vasculature to L-arginine in patients with essential hypertension. Hypertension 1998;32:16-24
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