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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Systemic arterial pressure response to two weeks of Tempol therapy in SHR: involvement of NO, the RAS, and oxidative stress

Departments of ¹Physiology and Biophysics and ²Medicine, University of Mississippi Medical Center, Jackson, Mississippi; and ³Department of Physiopathology, University of Medicine, Asuncion, Paraguay

Submitted 5 August 2004 ; accepted in final form 15 December 2004

	ABSTRACT

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The roles of nitric oxide (NO) and plasma renin activity (PRA) in the depressor response to chronic administration of Tempol in spontaneously hypertensive rats (SHR) are not clear. The present study was done to determine the effect of 2 wk of Tempol treatment on blood pressure [mean arterial pressure (MAP)], oxidative stress, and PRA in the presence or absence of chronic NO synthase inhibition. SHR were divided into four groups: control, Tempol (1 mmol/l) alone, nitro-L-arginine methyl ester (L-NAME, 4.5 mg·kg^–1·day^–1) alone, and Tempol + L-NAME for 2 wk. With Tempol, MAP decreased by 22%: 191 ± 3 and 162 ± 21 mmHg for control and Tempol, respectively (P < 0.05). L-NAME increased MAP by 16% (222 ± 2 mmHg, P < 0.01), and L-NAME + Tempol abolished the depressor response to Tempol (215 ± 3 mmHg, P < 0.01). PRA was not affected by Tempol but was increased slightly with L-NAME alone and 4.4-fold with L-NAME + Tempol. Urinary nitrate/nitrite increased with Tempol and decreased with L-NAME and L-NAME + Tempol. Tempol significantly reduced oxidative stress in the presence and absence of L-NAME. In conclusion, in SHR, Tempol administration for 2 wk reduces oxidative stress in the presence or absence of NO, but in the absence of NO, Tempol is unable to reduce MAP. Therefore, NO, but not changes in PRA, plays a major role in the blood pressure-lowering effects of Tempol. These data suggest that, in hypertensive individuals with endothelial damage and chronic NO deficiency, antioxidants may be able to reduce oxidative stress but not blood pressure.

nitric oxide; superoxide; antioxidant; renin-angiotensin system

The role of NO in the response to Tempol in SHR is controversial. Schnackenberg and colleagues (19) reported that acute intravenous infusion of Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidininoxyl), a stable membrane-permeable SOD mimetic, caused a significant reduction in blood pressure that was not produced in Wistar-Kyoto (WKY) rats. These data suggested that oxidative stress plays a role in the increased blood pressure of SHR. In these studies, in which nitro-L-arginine methyl ester (L-NAME), the NO synthase (NOS) inhibitor, was acutely infused, the depressor response to Tempol in SHR was abrogated. However, when Kagiyama and colleagues (4) administered Tempol acutely into the lateral ventricle of the brain of SHR, it did not have an effect on blood pressure, nor was the pressor response to L-NAME affected by Tempol. In acute studies in isolated aortic rings or mesenteric vascular beds from SHR, Shastri and colleagues (20) found that Tempol reduced the maximum tension in response to ANG II, and this effect was lost in aorta or mesenteric vascular beds when L-NAME was present or the endothelium was denuded. Although two of these studies (19, 20) suggested a role for NO in the acute response to Tempol, there are no studies in which the role of chronic NO inhibition was studied in chronic scavenging of superoxide by Tempol in SHR.

In addition to its vasodilator activity, endothelium-derived NO has been shown to cause a reduction in renin release (18, 26). In SHR, we showed that blockade of the renin-angiotensin system (RAS) with converting enzyme inhibitors normalizes the blood pressure (15), which suggests that the RAS plays an important role in mediating the hypertension in SHR. Thus Tempol could cause a reduction in blood pressure in SHR by chronically increasing bioavailability of NO, which in turn could reduce renin release and plasma renin activity (PRA). Whether changes in PRA play a role in the depressor response to chronic Tempol in SHR has also not been studied.

Therefore, the present studies were performed to determine the role of NO and changes in renin release in the response to chronic Tempol in SHR. Consistent with the concept that the kidney plays an important role in control of arterial pressure, we also evaluated the effect of Tempol on markers of oxidative stress in this organ. The following questions were addressed: 1) Does Tempol given for 2 wk reduce blood pressure in SHR by affecting the NO system? 2) If so, does an increase in bioavailability of NO associated with Tempol treatment subsequently reduce renin release as measured by PRA and contribute to the Tempol-mediated reduction in blood pressure?

	METHODS

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Experimental protocol. Male SHR (Taconic Farms) were divided into four groups (n = 6–8 rats per group): Controls (group 1) received tap water throughout the experimental protocol. Group 2 was treated with Tempol (1 mmol/l) in drinking water for 2 wk. Group 3 was treated with L-NAME (4.5 mg·kg^–1·day^–1) in drinking water for 2 wk. Group 4 was treated with Tempol (1 mmol/l) + L-NAME (4.5 mg·kg^–1·day^–1) in drinking water for 2 wk. Tempol and L-NAME are readily soluble in water and were prepared fresh daily. Consumption of water was measured daily in all experimental groups. The dose of Tempol was shown in preliminary studies by us and by Schnackenberg and colleagues (19) to reduce blood pressure in male SHR when given chronically for 2 or 6 wk. This low dose of L-NAME was also used by us in normotensive rats and found to effectively block NOS (14). All protocols were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Mississippi Medical Center.

Measurement of blood pressure. On day 13 of treatment, rats were anesthetized by isoflurane gas anesthesia, and a catheter was placed in the femoral artery and exteriorized at the back of the neck, as we previously described (16), for mean arterial pressure (MAP) monitoring. On the next day, animals were placed in restraining cages, and MAP was measured in conscious rats. Rats had been habituated to the restraining cages before catheter placement. MAP was recorded with a pressure transducer connected to a recorder (model 7B-chart, Grass Instrument). After a 60-min stabilization period, results of two 30-min recordings were averaged.

Measurement of urinary nitrate/nitrite. To avoid the contribution of nitrate/nitrite (NOx) in food to NOx excretion, rats were placed on a low-NOx diet throughout the treatment period. NOx was measured daily in 24-h urine specimens by the Griess reagent method, with Escherichia coli used to convert nitrate to nitrite, as we described previously (13). The daily data were averaged for the 14 days and are presented as NOx excreted per 24 h per kilogram body weight.

Measurement of superoxide in kidney homogenates by lucigenin luminescence. In isoflurane-anesthetized rats, kidneys were perfused clear of blood with saline containing 2% heparin. Kidneys were removed and separated into cortex and medulla and homogenized (1:8 wt/vol) in RIPA buffer (PBS, 1% Nonidet P-40 or Igepal CA-630, 0.5% sodium deoxycholate, 0.1% SDS, and a cocktail of protease inhibitors; Sigma Chemical) with a Polytron (model PT10-35). The samples were centrifuged at 12,000 g for 20 min at 4°C. The supernatant was used for measurement of superoxide with lucigenin at a final concentration of 5 µM. The samples were allowed to equilibrate for 3 min in the dark, and luminescence was measured every second for 5 min with a luminometer (Berthold). Luminescence was recorded as relative light units (RLU) per 5 min. An assay blank with no homogenate but containing lucigenin was subtracted from the reading before transformation of the data. Protein concentrations in the kidney homogenates were determined by the method of Lowry et al. (9). The data are expressed as RLU per milligram protein.

Measurement of total antioxidant status. Plasma total antioxidant status (TAS) was measured using a commercially available kit (Calbiochem Novobiochem, San Diego, CA), according to the manufacturer's instructions. Data are presented as millimoles per liter plasma. The TAS assay is based on the ability of antioxidants in the plasma to inhibit the absorbance of the radical cation ABTS⁺ [2,2'-azinobis(3-ethylbenzathiazoline-6-sulfonate)], which has a long-wavelength absorbance, to an extent and on a time scale dependent on the antioxidant capacity of the plasma (17). The TAS assay measures plasma antioxidant levels. The antioxidants determined are not specific and include (among others) selenium, flavonoids, -carotene, carotenoids, vitamins C and E, and thiols.

Measurement of PRA. In a separate set of animals (n = 5 per treatment group), rats were untreated or treated with Tempol, L-NAME, or Tempol + L-NAME for 2 wk, as described above, and decapitated for collection of blood into EDTA-containing tubes. PRA in samples of rat plasma was measured by radioimmunoassay as previously described (8).

Measurement of 8-iso-PGF₂ (8-isoprostane). Urine was purified by affinity column, and 8-isoprostane was quantified by a competitive ELISA (Cayman Chemical) according to the manufacturer's instructions. Results are expressed as nanograms of 8-isoprostane per milligram of creatinine. Creatinine was measured by commercially available kit (Sigma).

Statistics. Values are means ± SE. Comparisons among groups were made by ANOVA followed by the Fisher's test. P < 0.05 was considered statistically significant.

	RESULTS

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Effects of Tempol and L-NAME on MAP in SHR. After 2 wk of Tempol administration, MAP was reduced by 22% compared with the control group: 191 ± 3.3 vs. 162 ± 5 mmHg (P < 0.01; Fig. 1). As previously shown (7, 14), chronic L-NAME alone increased MAP by 16% (221 ± 1.9 mmHg) compared with controls (P < 0.01). When the rats were given Tempol + L-NAME (215 ± 3.1 mmHg), the depressor effect of Tempol was abolished, and blood pressure was similar to that of the rats treated with L-NAME alone.

View larger version (10K): [in this window] [in a new window]   Fig. 1. Mean arterial pressure (MAP) in conscious, chronically catheterized spontaneously hypertensive rats (SHR) that were untreated (controls) or treated with Tempol, nitro-L-arginine methyl ester (L-NAME), or Tempol + L-NAME for 2 wk. *P < 0.01 vs. control. P < 0.01 vs. Tempol alone.

View larger version (10K): [in this window] [in a new window]   Fig. 2. Urinary nitrate/nitrite (NOx) excretion in SHR treated chronically with Tempol, L-NAME, or Tempol + L-NAME for 2 wk. *P < 0.05 vs. control. P < 0.05 vs. Tempol alone.

View larger version (14K): [in this window] [in a new window]   Fig. 3. Superoxide anion in kidney cortical homogenates in SHR that were untreated or treated with Tempol, L-NAME, or Tempol + L-NAME for 2 wk. Superoxide was measured by lucigenin assay and expressed as relative light units (RLU) per milligram. *P < 0.001 vs. control.

View larger version (13K): [in this window] [in a new window]   Fig. 4. Superoxide anion in kidney medullary homogenates in SHR that were untreated or treated with Tempol, L-NAME, or Tempol + L-NAME for 2 wk. *P < 0.05 vs. control. P < 0.05 vs. Tempol alone. P < 0.05 vs. L-NAME alone.

View larger version (10K): [in this window] [in a new window]   Fig. 5. Plasma total antioxidant status (TAS) in SHR that were untreated or treated with Tempol, L-NAME, or Tempol + L-NAME for 2 wk. *P < 0.05 vs. control. P < 0.05 vs. Tempol alone. P < 0.05 vs. L-NAME alone.

View larger version (11K): [in this window] [in a new window]   Fig. 6. Urinary excretion of 8-isoprostane in SHR that were untreated or treated with Tempol, L-NAME, or Tempol + L-NAME for 2 wk. *P < 0.05 vs. control. P < 0.05 vs. Tempol alone. P < 0.05 vs. L-NAME alone.

View larger version (10K): [in this window] [in a new window]   Fig. 7. Plasma renin activity in SHR that were treated chronically with Tempol, L-NAME, or Tempol + L-NAME for 2 wk. *P < 0.001 vs. control. P < 0.01 vs. Tempol alone. P < 0.01 vs. L-NAME alone.

	DISCUSSION

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Our studies follow up on previous investigations of Schnackenberg and colleagues (19) in which Tempol was given acutely by intravenous infusion in graded doses to anesthetized SHR. Tempol (180 µmol·kg^–1·h^–1) was able to reduce blood pressure in the SHR by 22%, and this was abrogated in the presence of acute infusion of L-NAME (11 µmol·kg^–1·min^–1). These data suggested that acute NO deficiency interfered with the depressor response to Tempol in SHR.

With these data in mind, we studied the role of chronic NO inhibition on the depressor response to chronic antioxidants in conscious, chronically catheterized SHR. To support a role for NO in the depressor response to Tempol, we measured urinary NOx excretion in rats fed a low-NOx diet and found that Tempol modestly, but significantly, increased NOx. As expected, L-NAME reduced NOx and abolished the effect of Tempol on NOx. Our data are supported by previous vascular reactivity studies by Shastri et al. (20), who showed that L-NAME treatment of aortae or mesenteries from SHR blocked the Tempol-attenuated response to agonists, ANG II, endothelin, and phenylephrine. Cuzzocrea and colleagues (2) reported similar findings, i.e., that the antihypertensive effect of a superoxide scavenger (M-40403) was blocked by L-NAME in SHR and that M-40403 improved the aortic vascular response to acetylcholine in the presence, but not absence, of the endothelium. In addition, Maffei and colleagues (10) found that aortic rings and mesentery from SHR exhibited higher basal NO production but lower responsiveness to agonist-induced NO release. Ascorbic acid improved the NO release. Taken together, these data and our present data support the hypothesis that there is a balance between NO and ROS that is important in maintaining endothelial function and vascular tone.

Studies using other hypertensive animal models also support the interaction between NO and oxidative stress in maintaining endothelial function. For example, Zhou and colleagues (30) reported that angiotensin AT₁ receptor blockade in Dahl salt-sensitive (DS) rats fed a high-salt diet, a model of reduced NO production and bioavailability, was able to reduce vascular superoxide production and normalize endothelial function but was unable to prevent the salt-induced increase in systolic blood pressure. These investigators then went on to determine that atorvastatin, one of the cholesterol biosynthesis inhibitors, in DS rats fed a high-salt diet prevented the decrease in endothelial NOS (eNOS) activity and the increase in superoxide production and improved endothelial function in response to endothelin and modestly reduced blood pressure (31). These rats were also protected from increased left ventricular hypertrophy and proteinuria. Zhou et al. suggested that protection of vascular eNOS and inhibition of oxidative stress contributed to protection against end-organ damage usually found in DS rats fed a high-salt diet.

We previously showed that blockade of the RAS reduces blood pressure in SHR (15). In the present study, we hypothesized that one mechanism by which Tempol could reduce blood pressure is a reduction in renin release and PRA caused by a chronic increase in NO. As early as 1988, Vidal and colleagues (26) reported that NO could inhibit renin release. Schnackenberg and colleagues (18) reported later that NO caused a reduction in renin release via a macula densa mechanism. However, in our present studies, Tempol treatment and the subsequent increase in systemic NO (as measured by increased urinary NOx) had no effect on PRA; therefore, a reduction in renin release due to increased NO played no role in mediating the depressor response to Tempol.

However, although we anticipated that L-NAME alone would cause an increase in PRA, it was somewhat surprising that Tempol + L-NAME caused an even further increase in PRA. Tubuloglomerular feedback (TGF) is generally thought to be mediated by the macula densa, which detects changes in NaCl concentration reaching the distal tubule and transmits a feedback signal to control afferent arteriolar resistance. SHR reportedly have a diminished TGF response to local or systemic NO inhibition, despite increased neuronal and eNOS expression compared with WKY rats (24, 27). Our data support this theory, because L-NAME alone only slightly increased PRA. Furthermore, Tempol has been shown to restore the TGF response to NO blockade in SHR, suggesting a role for oxidative stress in the reduced TGF in SHR (27). Therefore, the combination of NO inhibition and Tempol should have increased TGF significantly, and this would cause a further increase in renin release compared with NO inhibition alone and could account for the increase in PRA. However, we cannot rule out an effect of Tempol on other components of the RAS in renal tissue. For example, Tempol could have had an effect on renal tissue ANG II or AT₁ receptor levels, leading to a reduction in blood pressure. These changes would not have been evident in measurements of PRA. However, to our knowledge, there have been no studies in which the effect of Tempol on the intrarenal RAS components in SHR has been examined.

We also measured the effect of Tempol and L-NAME on oxidative stress. As expected, Tempol reduced urinary 8-isoprostane, decreased renal cortical superoxide, and increased plasma TAS. In contrast, Tempol had no effect on medullary superoxide production. L-NAME alone, on the other hand, had no effect on urinary 8-isoprotanes, cortical superoxide production, or TAS compared with controls. L-NAME significantly increased medullary superoxide production. NO concentration is high in the medulla compared with the cortex. Therefore, inhibition of NO production with L-NAME would leave superoxide unquenched in the medulla, leading to high levels of superoxide. However, in the presence of Tempol and L-NAME, medullary superoxide levels were reduced to control.

Although we are satisfied that the mechanism by which Tempol reduces blood pressure in the SHR is linked to increases in NO and reductions in oxidative stress, other investigators have suggested that Tempol may reduce blood pressure by inhibiting sympathetic nervous system activity. Shohogi and colleagues (21) reported that acute infusion of Tempol and another superoxide scavenger, diethyldithiocarbamic acid, reduced renal sympathetic nerve activity (RSNA) in SHR and WKY rats but reduced blood pressure in SHR only. Intracerebroventricular infusion had no effect on the RSNA or blood pressure. These investigators suggested that superoxide may stimulate RSNA in SHR. The SHR is a model of increased RSNA, and it is possible that Tempol is capable of reducing blood pressure via this mechanism. However, these findings are not consistent in other models of hypertension. For example, Xu and colleagues (29) reported that Tempol, but no other antioxidant, including apocynin, polyethylene glycol-SOD, or SOD alone, reduced RSNA in deoxycorticosterone acetate-salt-treated rats. However, despite the effect on RSNA, Tempol had no effect on blood pressure or measurements of oxidative stress in aorta or vena cava, suggesting that Tempol reduced RSNA independent of an effect on oxidative stress. Both of these studies, in which RSNA was measured, were performed with acute infusion of Tempol at high doses in anesthetized animals (21, 29). Furthermore, ROS may play a more important role in mediating hypertension in SHR than in other models, because, in contrast to the deoxycorticosterone acetate-salt-treated rats, we have preliminary data that apocynin decreases blood pressure in male SHR (unpublished results). Therefore, future studies are needed to determine whether RSNA is indeed modulated chronically by oxidative stress.

Despite many studies that have shown that oxidative stress is elevated in hypertensive individuals compared with normotensive controls (5, 6, 25, 28), few studies have shown that a reduction in oxidative stress was associated with a reduction in blood pressure and cardiovascular disease risk in hypertensive humans. For example, Ascherio and colleagues (1) reported no effect of vitamin E and C supplementation on stroke in 40- to 75-yr-old men. Similarly, in the Heart Outcomes Prevention Evaluation (HOPE) study, treatment with antioxidants in hypertensive patients in whom blood pressure was controlled by other medications did not result in further reductions in blood pressure (11). Our present studies shed light on why antioxidants may not have been efficacious in hypertensive humans. Hypertension is a disease associated with chronic endothelial dysfunction and, therefore, chronically reduced NO. If chronic endothelial injury reduces NO independent of oxidative stress, antioxidants will not be able to reduce blood pressure and protect against cardiovascular disease risk. Therefore, future studies are necessary to determine whether increasing NO in the presence of antioxidants would have a better effect than antioxidants alone in lowering blood pressure in hypertensive individuals.

	GRANTS

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This work was supported by National Heart, Lung, and Blood Institute Grants HL-66072 and HL-69194.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. F. Reckelhoff, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216-4505 (E-mail: jreckelhoff{at}physiology.umsmed.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

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1. Ascherio A, Rimm EB, Hernan MA, Giovannucci E, Kawachi I, Stampfer MJ, and Willett WC. Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann Intern Med 130: 963–970, 1999.[Abstract/Free Full Text]
2. Cuzzocrea S, Mazzon E, Dugo L, Di Paola R, Caputi AP, and Salvemini D. Superoxide: a key player in hypertension. FASEB J 18: 94–101, 2004.[Abstract/Free Full Text]
3. Grunfeld S, Hamilton CA, Mesaros S, McClain SW, Dominiczak AF, Bohr T, and Malinski T. Role of superoxide in the depressed nitric oxide production by endothelium of genetically hypertensive rats. Hypertension 26: 854–857, 1995.[Abstract/Free Full Text]
4. Kagiyama S, Tsuchihashi T, Abe I, Matsumura K, and Fujishima M. Central infusion of L-arginine or superoxide dismutase does not alter arterial pressure in SHR. Hypertens Res 23: 339–343, 2000.[Web of Science][Medline]
5. Kumar DV and Das UN. Are free radicals involved in the pathobiology of human essential hypertension? Free Radic Res Commun 19: 59–66, 1993.[Web of Science][Medline]
6. Lacy F, O'Conner DT, and Schmid-Schonbein GW. Plasma hydrogen peroxide production in hypertensive and normotensive subjects at genetic risk of hypertension. J Hypertens 16: 291–303, 1998.[CrossRef][Web of Science][Medline]
7. Lahera V, Salom MG, Miranda-Guardiola F, Moncada S, and Romero JC. Effects of N-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol Renal Fluid Electrolyte Physiol 261: F1033–F1037, 1991.[Abstract/Free Full Text]
8. Lohmeier TE, Mizelle HL, Reinhart GA, and Montani JP. Influence of angiotensin on the early progression of heart failure. Am J Physiol Regul Integr Comp Physiol 278: R74–R86, 2000.[Abstract/Free Full Text]
9. Lowry OH, Rosebrough NJ, Farr AL, and Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275, 1951.[Free Full Text]
10. Maffei A, Poulet R, Vecchione C, Colella S, Fratta L, Frati G, Trimarco V, Trimarco B, and Lembo G. Increased basal nitric oxide release despite enhanced free radical production in hypertension. J Hypertens 20: 1135–1142, 2002.[CrossRef][Web of Science][Medline]
11. Marchioli R, Schweiger C, Levantesi G, Tavazzi L, and Valagussa F. Antioxidant vitamins and prevention of cardiovascular disease: epidemiology and clinical trial data. Lipids 36: S53–S63, 2001.
12. Pryor WA and Squadrito GL. Chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol Lung Cell Mol Physiol 268: L699–L722, 1995.[Abstract/Free Full Text]
13. Reckelhoff JF, Kellum JA, Blanchard EJ, Bacon EE, Wesley AJ, and Kruckeberg WC. Changes in nitric oxide precursor, L-arginine, and metabolites, nitrate and nitrite, with aging. Life Sci 24: 1895–1902, 1994.
14. Reckelhoff JF and Manning RD Jr. Role of endothelium-derived nitric oxide in control of renal microvasculature in aging male rats. Am J Physiol Regul Integr Comp Physiol 265: R1126–R1131, 1993.[Abstract/Free Full Text]
15. Reckelhoff JF, Zhang H, and Srivastava K. Gender differences in development of hypertension in spontaneously hypertensive rats. Role of the renin-angiotensin system. Hypertension 35: 480–483, 2000.[Abstract/Free Full Text]
16. Reckelhoff JF, Zhang H, Srivastava K, Roberts LJ II, Morrow JD, and Romero JC. Subpressor doses of angiotensin II increase plasma F₂-isoprostanes in rats. Hypertension 35: 476–479, 2000.[Abstract/Free Full Text]
17. Rice-Evans C and Miller NJ. Total antioxidant status in plasma and body fluids. Methods Enzymol 234: 279–293, 1994.[Web of Science][Medline]
18. Schnackenberg CG, Tabor BL, Strong MH, and Granger JP. Inhibition of intrarenal nitric oxide stimulates renin secretion through a macula densa-mediated mechanism. Am J Physiol Regul Integr Comp Physiol 272: R879–R886, 1997.[Abstract/Free Full Text]
19. Schnackenberg CG, Welch WJ, and Wilcox CS. Normalization of blood pressure and renal vascular resistance in SHR with membrane-permeable superoxide dismutase mimetic: role of nitric oxide. Hypertension 32: 59–64, 1998.[Abstract/Free Full Text]
20. Shastri S, Gopalakrishnan V, Poduri R, and Di Wang H. Tempol selectively attenuates angiotensin II-evoked vasoconstrictor responses in spontaneously hypertensive rats. J Hypertens 20: 1381–1391, 2002.[CrossRef][Web of Science][Medline]
21. Shohogi T, Nishiyama A, Fujisawa Y, Hitomi H, Kiyomoto H, Takahashi N, Kimura S, Kohno M, and Abe Y. Renal sympathetic nerve responses to Tempol in spontaneously hypertensive rats. Hypertension 41: 266–273, 2003.[Abstract/Free Full Text]
22. Suzuki H, DeLano FA, Parks DA, Jamshidi N, Granger DN, Ishii H, Suematsu M, Zweifach BW, and Schmid-Schonbein GW. Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats. Proc Natl Acad Sci USA 95: 4754–4759, 1998.[Abstract/Free Full Text]
23. Suzuki H, Swei A, Zweifach BW, and Schmid-Schonbein GW. In vivo evidence for microvascular oxidative stress in spontaneously hypertensive rats: hydroethidine microfluorography. Hypertension 25: 1083–1089, 1995.[Abstract/Free Full Text]
24. Thorup C and Persson AE. Impaired effect of nitric oxide synthesis inhibition on tubuloglomerular feedback in hypertensive rats. Am J Physiol Renal Fluid Electrolyte Physiol 271: F246–F252, 1996.[Abstract/Free Full Text]
25. Tse WY, Maxwell SR, Thomason H, Blann A, Thorpe GH, Waite M, and Holder R. Antioxidant status in controlled and uncontrolled hypertension and its relationship to endothelial damage. J Hum Hypertens 8: 843–849, 1994.[Web of Science][Medline]
26. Vidal MJ, Romero JC, and Van Houtte PM. Endothelial-derived relaxing factor inhibits renin release. Eur J Pharmacol 149: 401–402, 1988.[CrossRef][Web of Science][Medline]
27. Welch WJ, Tojo A, Lee JU, Kang DG, Schnackenberg CG, and Wilcox CS. Nitric oxide synthase in the JGA of the SHR: expression and role of tubuloglomerular feedback. Am J Physiol Renal Physiol 277: F130–F138, 1999.[Abstract/Free Full Text]
28. Wen Y, Killalea S, McGettigan P, and Freely J. Lipid peroxidation and antioxidant vitamins C and E in hypertensive patients. Ir J Med Sci 165: 210–1212, 1996.[Web of Science][Medline]
29. Xu H, Fink GD, and Galligan JJ. Tempol lowers blood pressure and sympathetic nerve activity but not vascular O₂^– in DOCA-salt rats. Hypertension 43: 329–334, 2004.[Abstract/Free Full Text]
30. Zhou MS, Adam AG, Jaimes EA, and Raij L. In salt-sensitive hypertension, increased superoxide production is linked to functional upregulation of angiotensin II. Hypertension 42: 945–951, 2003.[Abstract/Free Full Text]
31. Zhou MS, Jaimes EA, and Raij L. Atorvastatin prevents end-organ injury in salt-sensitive hypertension. Role of eNOS and oxidant stress. Hypertension 44: 186–190, 2004.[Abstract/Free Full Text]

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