Hypothesis: A lack of contraction of cerebral microarterioles to Ang II (“resilience”) depends on cyclooxygenase (COX) and lipocalin type prostaglandin D sythase L-PGDS producing PGD2 that activates prostaglandin D type 1 receptors (DP1Rs) and nitric oxide synthase (NOS). Materials & Methods: Contractions were assessed in isolated, perfused vessels and NO by fluorescence microscopy. Results: The mRNAs of penetrating intraparenchymal cerebral microarterioles versus renal afferent arterioles were >3000-fold greater for L-PGDS and DP1R and 5-fold for NOS III and COX 2. Larger cerebral arteries contracted with Ang II. However, cerebral microarterioles were entirely unresponsive but contracted with endothelin 1 and perfusion pressure. Ang II contractions were evoked in cerebral microarterioles from COX1 –/– mice or after blockade of COX2, L-PGDS or NOS and in deendothelialized vessels but effects of deendothelialization were lost during COX blockade. NO generation with Ang II depended on COX and also was increased by DP1R activation. Conclusion: The resilience of cerebral arterioles to Ang II contractions is specific for intraparenchymal microarterioles and depends on endothelial COX1 and two products that are metabolized by L-PGDS to generate PGD2 that signals via DP1Rs and NO.

AIM:Renal ischaemia-reperfusion injury (IRI) increases angiotensin II (Ang II) and reactive oxygen species (ROS) that are potent modulators of vascular function. However, the roles of individual ROS and their interaction with Ang II are not clear. Here we tested the hypothesis that IRI modulates renal afferent arteriolar responses to Ang II via increasing superoxide (O2-) or hydrogen peroxide (H2 O2 ).METHODS:Renal afferent arterioles were isolated and perfused from C57BL/6 mice 24 h after IRI or sham surgery. Responses to Ang II or noradrenaline were assessed by measuring arteriolar diameter. Production of H2 O2 and O2- was assessed in afferent arterioles and renal cortex. Activity of SOD and catalase, and mRNA expressions of Ang II receptors were assessed in pre-glomerular arterioles and renal cortex.RESULTS:Afferent arterioles from mice after IRI had a reduced maximal contraction to Ang II (-27±2 vs. -42±1%, P < 0.001), but retained a normal contraction to noradrenaline. Arterioles after IRI had a 38% increase in H2 O2 (P < 0.001) and a 45% decrease in catalase activity (P < 0.01). Contractions were reduced in normal arterioles after incubation with H2 O2 (-22±2 vs. -42±1%, P < 0.05) similar to the effects of IRI. However, the impaired contractions were normalized by incubation with PEG catalase despite a reduced AT1 R expression.CONCLUSIONS:Renal IRI in mice selectively impairs afferent arteriolar responses to Ang II because of H2 O2 accumulation that is caused by a reduced catalase activity. This could serve to buffer the effect of Ang II after IRI and may be a protective mechanism.

The glomerular filtration rate (GFR) falls progressively in chronic kidney disease (CKD) which is caused by a reduction in the number of functional nephrons. The dysfunctional nephron exhibits a lower glomerular capillary pressure that is induced by an unbalance between afferent and efferent arteriole. Therefore, we tested the hypothesis that oxidative stress induced by CKD differentially impairs the structure or function of efferent vs. afferent arterioles.

Resistant hypertension is a failure to achieve goal BP (<140/90 mm Hg for the overall population and <130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) in a patient who adheres to maximum tolerated doses of 3 antihypertensive drugs including a diuretic. The kidneys play a critical role in long-term regulation of blood pressure. Blunted pressure natriuresis, with resultant increase in extracellular fluid volume, is an important cause of resistant hypertension. Activation of the renin-angiotensin-aldosterone system, increased renal sympathetic nervous system activity and increased sodium reabsorption are important renal mechanisms. Successful treatment requires identification and reversal of lifestyle factors or drugs contributing to treatment resistance, diagnosis and appropriate treatment of secondary causes of hypertension, use of effective multidrug regimens and optimization of diuretic therapy. Since inappropriate renal salt retention underlies most cases of drug-resistant hypertension, the therapeutic focus should be on improving salt depleting therapy by assessing and, if necessary, reducing dietary salt intake, optimizing diuretic therapy, and adding a mineralocorticoid antagonist if there are no contraindications.

Background and purpose: We compared the dose‐dependent reductions in cellular superoxide anion (O2‐) by catalytic agents: superoxide dismutase (SOD), polyethylene glycol (PEG)‐SOD and the nitroxide 4‐hydroxy‐2,2,6,6,‐tetramethylpiperidine‐1‐oxyl (tempol) with uncharacterized antioxidants: 5,10,15,20‐tetrakis (4‐sulphonatophenyl) porphyrinate iron (III)(Fe‐TTPS), (‐)‐cis‐3,3′,4′,5,7‐pentahydroxyflavane (2R,3R)‐2‐(3,4‐dihydroxyphenyl)‐3,4‐dihydro‐1(2H)‐benzopyran‐3,5,7‐triol (‐epicatechin), 2‐phenyl‐1,2‐benzisoselenazol‐3(2H)‐one (ebselen) and N‐acetyl‐L‐cysteine (NAC) with the spin trap nitroblue tetrazolium (NBT) and with the vitamins or their analogues: ascorbate, α‐tocopherol and 6‐hydroxy‐2,5,7,8‐tetramethylkroman‐2‐carboxy acid (trolox).Experimental approach: O2‐ was generated in primary cultures of angiotensin II‐stimulated preglomerular vascular smooth muscle cells from spontaneously hypertensive rats and detected by lucigenin‐enhanced chemiluminescence.Key results: SOD, PEG‐SOD, NAC and tempol produced a similar maximum inhibition of O2‐ of 80–90%. ‐Epicatechin, NBT, ebselen and Fe‐TTPS were significantly (P < 0.0125) less effective (50–70%), whereas trolox, α‐tocopherol and ascorbate had little action even over 24 h of incubation (<31%). Effectiveness in disrupted and intact cells was similar for the permeable agents, PEG‐SOD and tempol, but was enhanced for SOD. Generation of O2‐ was increased by NAC and NBT at low concentrations but reduced at high concentrations.Conclusions and implications: Maximum effectiveness against cellular production of O2‐ requires cell membrane permeability and catalytic action as exemplified by PEG‐SOD or tempol. NAC and NBT have biphasic effects on O2‐ production. Vitamins C and E or analogues have low efficacy.

EC-SOD is effective antioxidant, but its role in vascular contractility is unknown. We investigated this in isolated mesenteric arterioles (MAs) from 10 EC-SOD −/ − (−/ −) and 10 EC-SOD +/+ (+/+) mice by using a myograph. Contractions to phenylephrine were similar in two groups, but contractions to endothelin 1 (ET-1) were increased in −/ − mice (100±3% vs 66±5%, p<0.01). ET-1 contractions can be 75% abolished by BQ123 (an ET-Aantagonist) and 25% by BQ788 (an ET-B antagonist) in two groups. Endothelium removal decreased ET-1 contractions in −/ − mice, but unchanged ET-1 contractions in +/+ mice, indicates an endothelium-derived contracting factor (EDCF) released by ET-1in −/ − mice. After intact MAs were incubated with antagonists of O2·− (PEG-SOD), thromboxane prostanoid receptors (TP-Rs, SQ29548), thromboxane A2 synthase (TxA2-S, OKY-046NA), COX-1 (SC-560) or COX-2 (Paracoxib), the augmented ET contraction in−/ − mice were significantly reduced (p<0.01) by PEG-SOD (−64 ± 14%),SC-560 (−61 ± 3%), OKY-046NA (−56 ± 3%), or SQ-29,548 (−71 ± 16%)but notby paracoxib, whereas these agents unaffected ET contractions in +/+ mice. The expression of ET-A, ET-B and COX-1 were increased in MAs from −/ − mice. In conclusion, −/ − mice have selectively enhanced microvascular contractions to ET-1, which duo to O2·− and enhanced ET receptors activating an EDCF that requires COX-1 with generation of TxA2-S activating TP-Rs on the smooth muscle cells. Thus, EC-SOD is a major defense against vascular ET contractility and may defend against hypertension and vasculopathy.

We tested the hypothesis that Superoxide (O2·−) mediates Ang II-dependent increase in expression of smooth muscle α-actin (SMα-actin) gene in cultured renal preglomerular microvascular smooth muscle cells (PGSMCs) from SHR. O2·− quantified by lucigenin method was significantly increased by 85% in intact PGSMCs and by 47% in cell membranes at 12 hr after incubation with Ang II (1uM). Expression of SMα-actin mRNA determined by real time RT-PCR was enhanced by 81% by Ang II and inhibited by 50% in Ang II-treated cells by the thiol antioxidant, N-acetyl-L-cysteine (NAC, 20mM) which also reduced Ang II-induced O2·− generation to 20%. Serum response factor (SRF) and its co-activator, myocardin (Myo) mediate CArG-dependent transcription of SMα-actin gene. Although Ang II treatment did not modify mRNA for SRF, it increased Myo expression by 22%. Promoter repoter assays indicated that Ang II increased SMα-actin promoter activity by 2.3 fold and this was inhibited by 43% by NAC. Site-directed mutations demonstrated that CArG elements are required for SMα-actin promoter activity. Quantitative chromatin immunoprecipitation assay revealed that Ang II increased SRF enrichment of CArG regions in SMα-actin promoter in intact chromatin by 57%, whereas NAC reduced it by 43% without affecting histone 3 (H3) acetylation or histone 3 lysine-9 (H3K9) dimethylation. In conclution; Ang II induces O2·− in SHR PGSMCs that increases SMα-actin gene expression via up-regulation of Myo and enhanced SRF bound to CArG elements without modifications of H3 acetylation and H3K9 methylation in the SMα-actin promoter regions.

We tested the hypothesis that thromboxane-prostaglandin H2 receptors (TP) mediate a blunted NO production in vascular endothelial cells (ENDO) after prolonged exposure to AngII. AngII (10−7M) induces vasoconstriction in isolated mesenteric arteries (MAs) from mice under spontaneous tone, but induces vasodilatation in MAs preconstricted with norepinephrine (+21.5±2.1%; p<0.05). This relaxation response was blunted by endothelium removal (+13.2±2.2%; p<0.05) or by L-NAME (+12.7±2.3%; p<0.05). In mouse endothelioma cells (EOMA), acute AngII (10−7M for 4 hrs) increased NO metabolites (NOx: +3.4±0.5 vs vehicle +2.0±0.2uM; p<0.05, n=6) and NADPH oxidase activity (+24±5%; p<0.05, n=6). This implies that NO release from ENDO during acute AngII may offset the vasoconstriction and oxidative stress. In contrast, EOMA preconditioned with AngII (10−7M) chronically for 6 days (preAngIIEOMA), have a negligible increase in NOx (+0.2±0.4uM; p<0.05, n=4) and an exaggerated increase in NADPH oxidase activity (+36±3%; p<0.05, n=4). PreAngIIEOMA had an unchanged expression of mRNA for eNOS (+7±3%, n=4) but an increase in iNOS (+16±3%; p<0.05, n=4). Supplementation of L-arginine reduced ROS, measured by lucigenin, in untreated EOMA (n=6, p<0.05), but increased ROS in preAngIIEOMA (n=6, p<0.05). PreAngIIEOMA treated with TP antagonist, Ifetroban restored NOx production (+2.2±0.3uM; p<0.05, n=4) and prevented induction of iNOS mRNA (−16±3% vs. preAngII; p<0.05, n=4). In conclusion; acute AngII stimulates eNOS-delived NO that offsets vasoconstriction. However, prolonged AngII upregulates NADPH oxidase and iNOS via activation of TP that prevent bioactive NO and reinforce the vasoconstrictor action of chronic AngII.

The angiotensin II (Ang II) slow-pressor response entails an increase in mean arterial pressure and reactive oxygen species. We used double-stranded interfering RNAs (siRNAs) in Sprague Dawley rats in vivo to test the hypothesis that an increase in the p22phox component of NADPH oxidase is required for this response. Reactive oxygen species were assessed from excretion of 8-isoprostane prostaglandin F2alpha and blood pressure by telemetry. Two siRNA sequences to p22phox (sip22phox) reduced mRNA >85% in cultured vascular smooth muscle cells. Rats received rapid (10 second) IV injections (50 to 100 microg) of 1 of 2 different sip22phox, control siRNA, or vehicle (TransIt in saline) during 14 day SC infusions of Ang II (200 ng.kg(-1).min(-1)) or sham infusions. In both groups, sip22phox, relative to control siRNA, led to significant (P<0.001; approximately 50%) reductions in expression of p22phox mRNA and protein and of NADPH oxidase activity in the kidney cortex. In Ang II-infused rats, sip22phox decreased protein expression for Nox-1, -2, and -4 but increased p47phox. Three days after sip22phox, conscious rats infused with Ang II had a reduced excretion of 8-isoprostane (10+/-1 versus 19+/-2 pg.24 h(-1); P<0.01) and a reduced mean arterial pressure (142+/-5 versus 168+/-4 mm Hg; P<0.005). An increase in p22phox is required for increased renal NADPH oxidase activity, expression of Nox proteins and oxidative stress, and contributes < or =50% to hypertension during an Ang II slow-pressor response.

Dopamine receptors (DR) regulate blood pressure, in part, by inhibiting the production of reactive oxygen species (ROS). To determine whether increased ROS production affects DR protein expression, we studied in ecSOD knockout (ecSOD−/−) mice and wild type littermates (ecSOD+/+), protein expression (immunoblotting) of the five DRs in the kidney and relaxation response in isolated mesentery artery to DR agonists: D1R/D5R(Fenoldpam), D2R(PPHT), D3R(PD128907) and D4R(PD168077). ecSOD−/ − (n=6) and ecSOD+/+ littermates (n=6) (male, 4–6 months) were fed 0.4% Na diet with ad libitum water and food intake. In the whole kidney, D1R protein expression was similar in ecSOD−/ − and ecSOD+/+ (ecSOD+/+: 100±14, ecSOD−/ − mice: 85±15%, expressed as M± E percentage of ecSOD+/+, set at 100%). D5R protein at 55kDa was also similar in the two mouse strains but the 70 kDa band (possibly glycosylated receptor) was decreased in ecSOD−/ − (47±6 %) relative to ecSOD+/+ (100±20%). Compared to ecSOD+/+, all D2-like receptors were decreased in ecSOD−/ − (D2R: 49±9; D3R: 28±6; and D4R: 82±3%). Relative to ecSOD+/+, relaxation of isolated mesentery arteries caused by D3R and D4R agonists was decreased in ecSOD−/ − but the relaxation response to D1/D5R and D2R agonists was similar in ecSOD−/ − and ecSOD. Furthermore, D4R protein was also decreased in ecSOD−/ − (61%) while D5R was similar in the two mouse strains. The decreased renal protein expression of D2R, D3R, D4R, and D5R and decreased D3R and D4R vascular protein expression and relaxation caused by ROS contribute to the dysregulation of blood pressure and renal function in ecSOD−/ − mice.

Hydrogen peroxide (H2O2) can function as an endothelium-derived hyperpolarizing factor (EDHF) and thromboxane A2, as an endothelium-derived constricting factor (EDCF). However, their interaction has not been studied previously. Recent studies have shown that H2O2 stabilizes the thromboxane A2 (TP) receptor by translocating it to the Golgi complex. Therefore, we investigated mouse cremaster arterioles in vivo (n=8) before and after 15–20 min of H2O2. Exposure to H2O2 reduced basal vascular tone of mouse cremaster arterioles in vivo (baseline diameter increased by 10±4%). H2O2 (10−5M) inhibited constriction to U46619 (10−7 to 10−5M). At the maximal concentration, U46619-induced constriction was reduced by 78±14% (p < 0.001) compared to the control. In contrast, H2O2 did not significantly attenuate the vasoconstrictor responses to angiotensin II (−7±6%) or phenylephrine (−3±13%). These results demonstrate a selective inhibition of the response of vascular TP receptors by H2O2. Thus, in addition to facilitating vascular relaxation via EDHF, at high concentrations, H2O2 can block vasoconstriction via EDCF by selectively inhibiting the effect of vasoconstrictor prostaglandins. (Supported by AHA 0230308N and HL 68686-01)

BACKGROUND We used apocynin to test the hypothesis that superoxide anion (O(-) (2)) from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase underlies the development of diabetic nephropathy in the rat. METHODS Rats received apocynin (16 mg/kg/day) from 2 to 8 weeks after inducing diabetes mellitus (DM) with streptozotocin. RESULTS DM increased excretion of hydrogen peroxide (H(2)O(2)), lipid peroxidation products (LPO), nitric oxide products (NOx), and protein. The kidneys of rats with DM had increased expression of p47phox and gp91phox and endothelial nitric oxide synthase (eNOS), and increased mesangial matrix with expression of fibronectin and collagen I. Apocynin prevented the increase in excretion of H(2)O(2), LPO, and protein in diabetic rats, increased renal NOx generation, and prevented the increased renal expression of gp91phox and the membrane fraction of p47phox, and reverted the mesangial matrix expansion. CONCLUSION Activation of NADPH oxidase with translocation of p47phox to the membrane underlies the oxidative stress and limited NO generation, despite enhanced eNOS expression in a model of diabetic nephropathy. Apocynin prevents these changes and the associated proteinuria.

Tempol is an amphipathic radical nitroxide (N) that acutely reduces blood pressure (BP) and heart rate (HR) in the spontaneously hypertensive rat (SHR). We investigated the hypothesis that the response to nitroxides is determined by SOD mimetic activity or lipophilicity. Groups (n = 6-10) of anesthetized SHRs received graded intravenous doses of Ns: tempol (T), 4-amino-tempo (AT), 4-oxo-tempo (OT), 4-trimethylammonium-2,2,6,6-tetramethylpiperidine-1-oxyl iodide (CAT-1), 3-carbamoyl-proxyl (3-CP), or 3-carboxy-proxyl (3-CTPY). Others received native or liposomal (L) Cu/Zn SOD. T and OT are uncharged, AT is positively charged and cell-permeable, and CAT-1 is positively charged and cell-impermeable. 3-CP and 3-CTPY have five-member pyrrolidine rings, whereas T, AT, OT, and CAT-1 have six-member piperidine rings. T and AT reduced mean arterial pressure (MAP) similarly (-48 +/- 2 mmHg and -55 +/- 8 mmHg) but more (P < 0.05) than OT and CAT-1. 3-CP and 3-CTPY were ineffective. The group mean change in MAP with piperidine Ns correlated with SOD activity (r = -0.94), whereas their ED(50) correlated with lipophilicity (r = 0.89). SOD and L-SOD did not lower BP acutely but reduced it after 90 min (-32 +/- 5 and -31 +/- 6 mmHg; P < 0.05 vs. vehicle). Pyrrolidine nitroxides are ineffective antihypertensive agents. The antihypertensive response to piperidine Ns is predicted by SOD mimetic action, and the sensitivity of response is by hydrophilicity. SOD exerts a delayed hypotensive action that is not enhanced by liposome encapsulation, suggesting it must diffuse to an extravascular site.

We tested the hypothesis that superoxide anion (O(2)(-).) generated in the kidney by prolonged angiotensin II (ANG II) reduces renal cortical Po(2) and the use of O(2) for tubular sodium transport (T(Na):Q(O(2))). Groups (n = 8-11) of rats received angiotensin II (ANG II, 200 ng.kg(-1).min(-1) sc) or vehicle for 2 wk with concurrent infusions of a permeant nitroxide SOD mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol, 200 nmol.kg(-1).min(-1)) or vehicle. Rats were studied under anesthesia with measurements of renal oxygen usage and Po(2) in the cortex and tubules with a glass electrode. Compared with vehicle, ANG II increased mean arterial pressure (107 +/- 4 vs. 146 +/- 6 mmHg; P < 0.001), renal vascular resistance (42 +/- 3 vs. 65 +/- 7 mmHg.ml(-1).min(-1).100 g(-1); P < 0.001), renal cortical NADPH oxidase activity (2.3 +/- 0.2 vs. 3.6 +/- 0.4 nmol O(2)(-)..min(-1).mg(-1) protein; P < 0.05), mRNA and protein expression for p22(phox) (2.1- and 1.8-fold respectively; P < 0.05) and reduced the mRNA for extracellular (EC)-SOD (-1.8 fold; P < 0.05). ANG II reduced the Po(2) in the proximal tubule (39 +/- 1 vs. 34 +/- 2 mmHg; P < 0.05) and throughout the cortex and reduced the T(Na):Q(O(2)) (17 +/- 1 vs. 9 +/- 2 mumol/mumol; P < 0.001). Tempol blunted or prevented all these effects of ANG II. The effects of prolonged ANG II to cause hypertension, renal vasoconstriction, renal cortical hypoxia, and reduced efficiency of O(2) usage for Na(+) transport, activation of NADPH oxidase, increased expression of p22(phox), and reduced expression of EC-SOD can be ascribed to O(2)(-). generation because they are prevented by an SOD mimetic.

We used cyclooxygenase-1 (COX-1)-deficient mice to test the hypothesis that COX-1 regulates blood pressure (BP) and renal hemodynamics. The awake time (AT) mean arterial pressures (MAPs) measured by telemetry were not different between COX-1(+/+) and COX-1(-/-) (131+/-2 versus 126+/-3 mm Hg; NS). However, COX-1(-/-) had higher sleep time (ST) MAP (93+/-1 versus 97+/-2 mm Hg; P<0.05) and sleep-to-awake BP ratio (+8.6%; P<0.05). Under anesthesia with moderate sodium loading, COX-1(-/-) had higher MAP (109+/-5 versus 124+/-4 mm Hg; P<0.05), renal vascular resistance (23.5+/-1.6 versus 30.7+/-1.7 mm Hg . mL(-1) . min(-1) . g(-1); P<0.05) and filtration fraction (33.7+/-2.1 versus 40.2+/-2.0%; P<0.05). COX-1(-/-) had a 89% reduction (P<0.0001) in the excretion of TxB2, a 76% reduction (P<0.01) in PGE2, a 40% reduction (P<0.0002) in 6-ketoPGF1alpha (6keto), a 27% reduction (P<0.02) in 11-betaPGF2alpha (11beta), a 35% reduction (P<0.01) in nitrate plus nitrite (NOx), and a 52% increase in metanephrine (P<0.02). The excretion of normetanephrine, a marker for sympathetic nervous activity, was reduced during ST in COX-1(+/+) (6.9+/-0.9 versus 3.2+/-0.6 g . g(-1) creatinine . 10(-3); P<0.01). This was blunted in COX-1(-/-) (5.1+/-0.9 versus 4.9+/-0.7 g . g(-1) creatinine . 10(-3); NS). Urine collection during ST showed lower excretion of 6keto, 11beta, NOx, aldosterone, sodium, and potassium than during AT in both COX-1(+/+) and COX-1(-/-), and there were positive correlations among these parameters (6keto versus NOx; P<0.005; 11beta versus NOx; P<0.005; and NOx versus sodium; P<0.005). In conclusion, COX-1 mediates a suppressed sympathetic nervous activity and enhanced NO, which may contribute to renal vasodilatation and a reduced MAP while asleep or under anesthesia. COX-1 contributes to the normal nocturnal BP dipping phenomenon.

INTRODUCTION:Tempol is a permeant nitroxide superoxide dismutase (SOD) mimetic that lowers mean arterial pressure (MAP) in spontaneously hypertensive rats (SHRs). We investigated the hypothesis that the antihypertensive response entails a negative salt balance, blunting of plasma renin activity (PRA), endothelin-1 (ET-1), or catecholamines or correction of oxidative stress as indexed by 8-isoprostane prostaglandin F(2alpha) (PGF(2alpha)) (8-Iso).METHODS:Groups (N= 6 to 8) of SHRs were infused for 2 weeks with vehicle or tempol (200 nmol/kg/min) or given tempol (2 mmol/L) in drinking water.RESULTS:Tempol infusion reduced the MAP of anesthetized SHRs (150 +/- 5 vs. 126 +/- 6 mm Hg) (P < 0.005). Oral tempol did not change the heart rate but reduced the MAP of conscious SHRs (-23 +/- 6 mm Hg) (P < 0.01) but not Wistar-Kyoto (WKY) rats. Tempol infusion increased the PRA (2.2 +/- 0.2 vs. 5.0 +/- 0.9 ng/mL/hour) (P < 0.005), did not change excretion of nitric oxide (NO) [NO(2)+ NO(3) (NOx)], ET-1, or catecholamines but reduced excretion of 8-Iso (13.2 +/- 1.4 vs. 9.6 +/- 0.9 ng/24 hours; P < 0.01). Cumulative Na(+) balance and gain in body weight were unaltered by tempol infusion. Tempol prevented a rise in MAP with high salt intake.CONCLUSION:Tempol corrects hypertension without a compensatory sympathoadrenal activation or salt retention. The response is independent of nitric oxide, endothelin, or catecholamines and occurs despite increased PRA. It is accompanied by a reduction in oxidative stress and is maintained during increased salt intake.