Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in DOCA-salt rats

Xu, Hui; Fink, Gregory D.; Galligan, James J.

doi:10.1152/ajpheart.00134.2002

Cited by 69 publications

(79 citation statements)

References 32 publications

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“…In the SHR, tempol decreased both BP and renal vascular resistance (RVR) through NO-mediated mechanisms, whereas shortterm infusions had, in addition, NO-independent effects, likely through inhibition of renal sympathetic nerve activity (373). Reductions in RVR and BP lead to increased diuresis and natriuresis, even when simultaneous NOS blockade is instituted (199).…”

Section: Nephron Handling Of Ros and Hypertension: Redox Control Omentioning

confidence: 99%

Redox Control of Renal Function and Hypertension

Nistala

Whaley‐Connell

Sowers

2008

Antioxidants & Redox Signaling

136

123

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Section: Nephron Handling Of Ros and Hypertension: Redox Control Omentioning

confidence: 99%

Redox Control of Renal Function and Hypertension

Nistala

Whaley‐Connell

Sowers

2008

Antioxidants & Redox Signaling

136

123

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“…1 4-Hydroxy 2,2,6,6,-tetramethyl piperidine 1-oxyl (tempol), a superoxide dismutase (SOD) mimetic, lowers blood pressure in normotensive and hypertensive rats by multiple mechanisms. [2][3][4][5] Acute tempol treatment of normotensive, DOCA-salt and spontaneously hypertensive rats (SHRs) inhibits sympathetic nerve activity and this effect is not prevented by nitric oxide synthase (NOS) inhibition. [2][3][4][5][6] Local application of tempol onto renal sympathetic nerves decreased nerve activity without changing blood pressure (BP) or heart rate (HR).…”

Section: S Uperoxide Anion (Omentioning

confidence: 99%

“…Sham operated and DOCA-salt hypertensive rats (male, 170 to 225 grams; Charles River Laboratories) were prepared as previously de-scribed. 2,6 Blood pressure was measured in conscious animals by tail-cuff plethysmography 4 weeks after DOCA implantation.…”

Section: Animalsmentioning

confidence: 99%

Activation of Vascular BK Channel by Tempol in DOCA-Salt Hypertensive Rats

Bian

Watts

et al. 2005

Hypertension

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Abstract-Large-conductance Ca 2ϩ -activated potassium (BK) channels modulate vascular smooth muscle tone. Tempol, a superoxide dismutase (SOD) mimetic, lowers blood pressure and inhibits sympathetic nerve activity in normotensive and hypertensive rats. In the present study, we tested the hypotheses depressor responses caused by tempol are partly mediated by vasodilation. It was found that tempol, but not tiron (a superoxide scavenger), dose-dependently relaxed mesenteric arteries (MA) in anesthetized sham and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Tempol also reduced perfusion pressure in isolated, norepinephrine (NE) preconstricted MA from sham and DOCA-salt hypertensive rats. Maximal responses in DOCA-salt rats were twice as large as those in sham rats. The vasodilation caused by tempol was blocked by iberiotoxin (IBTX, BK channel antagonist, 0.1 mol/L) and tetraethylammonium chloride (TEA) (1 mmol/L). Tempol did not relax KCl preconstricted arteries in sham or DOCA-salt rats, and N -nitro-L-arginine methyl ester (L-NAME), apamin, or glibenclamide did not alter tempol-induced vasodilation. IBTX constricted MA and this response was larger in DOCA-salt compared with sham rats. Western blots and immunohistochemical analysis revealed increased expression of BK channel ␣ subunit protein in DOCA-salt arteries compared with sham arteries. Whole-cell patch clamp studies revealed that tempol enhanced BK channel currents in HEK-293 cells transiently transfected with mslo, the murine BK channel a subunit. These currents were blocked by IBTX. The data indicate that tempol activates BK channels and this effect contributes to depressor responses caused by tempol. Upregulation of the BK channel ␣ subunit contributes to the enhanced depressor response caused by tempol in DOCA-salt hypertension. Ϫ ) increases blood pressure in hypertensive animals and humans in part by reducing the vascular bioavailability of nitric oxide (NO). 1 4-Hydroxy 2,2,6,6,-tetramethyl piperidine 1-oxyl (tempol), a superoxide dismutase (SOD) mimetic, lowers blood pressure in normotensive and hypertensive rats by multiple mechanisms. [2][3][4][5] Acute tempol treatment of normotensive, DOCA-salt and spontaneously hypertensive rats (SHRs) inhibits sympathetic nerve activity and this effect is not prevented by nitric oxide synthase (NOS) inhibition. 2-6 Local application of tempol onto renal sympathetic nerves decreased nerve activity without changing blood pressure (BP) or heart rate (HR). 7 The results suggested that changes in K ϩ channel activity might contribute to sympatho-inhibition caused by tempol. Central administration of tempol in normotensive rats reduced sympathetic nerve discharge 8,9 and attenuated sympathetic excitation caused by central angiotensin II administration. 9 Therefore, it is possible that tempol-induced vasodilation in vivo is masked by its sympatho-inhibitory effects. 9 Chronic tempol treatment attenuates blood pressure increases in hypertensive animals, an effect attributed to improvement in endothelium f...

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“…13 In contrast, ET B receptors have been shown to mediate the protective effect against vascular and renal injuries in DOCA-salt hypertension. 17 On the other hand, our most recent studies have demonstrated that venous O 2 Ϫ levels are also increased in DOCA-salt hypertension, 18 and ET-1 and its receptors play important roles in maintaining venous tone in this model. 19,20 However, the effect of increased venous O 2 Ϫ on ET-1-induced venoconstriction remains unknown.…”

mentioning

confidence: 91%

NADPH Oxidase–Derived Superoxide Augments Endothelin-1–Induced Venoconstriction in Mineralocorticoid Hypertension

Watts

Banes

et al. 2003

Hypertension

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Abstract-Deoxycorticosterone acetate (DOCA)-salt hypertension is characterized by low renin/angiotensin but increased arterial superoxide levels. We have recently reported that the arterial endothelin-1 (ET-1) level is increased, resulting in NADPH oxidase activation and superoxide generation. However, the effect of ET-1 on venous superoxide production and its relation to venoconstriction are unknown. The present study tested the hypotheses that ET-1 stimulates venous NADPH oxidase and superoxide via its ET A receptors, resulting in enhanced venoconstriction in DOCA-salt hypertensive rats. Treatment with ET-1 (0.01 to 1 nmol/L), but not the selective ET B receptor agonist sarafotoxin s6c, of vena cavas of normal rats concentration-dependently increased superoxide levels, an effect that was abolished by the selective ET A receptor antagonist ABT-627. Although the ET-1 level was not increased in the vena cava and plasma, both venous NADPH oxidase activity and superoxide levels were significantly higher in DOCA-salt compared with sham rats. Moreover, ET-1 treatment (10 Ϫ9 mol/L, 10 minutes) of isolated vena cavas further elevated superoxide levels in DOCA-salt rats only but not sham rats, an effect that was abrogated by the superoxide scavenger tempol. Similarly, ET-1-induced contractions of isolated vena cavas of DOCA-salt but not sham rats were significantly inhibited by tempol. The NADPH oxidase inhibitor apocynin significantly reduced superoxide levels in vena cavas of DOCA-salt rats and in ET-1-treated vena cavas of normal rats. Finally, in vivo ET A receptor blockade by ABT-627 significantly lowered venous superoxide levels and blood pressure in DOCA-salt but not sham rats. These results suggest that superoxide contributes to ET-1-induced venoconstriction through an elevated venous NADPH oxidase activity in mineralocorticoid hypertension. Ϫ ) contributes to hypertension development in both animals and humans by inactivating nitric oxide (NO) and impairing arterial endothelium-dependent relaxation. 1-3 An increase in venous O 2 Ϫ might also inactivate NO and alter venous functions (eg, impaired relaxation or augmented constriction). However, the role of venous O 2 Ϫ production in hypertension and its effect on venoconstriction are unknown. Because hypertension involves multifactorial hemodynamic alterations, venoconstriction augmented by O 2 Ϫ might contribute to increased blood pressure by enhancing cardiac output and shifting blood from the veins to arteries. 4 -6 Consistent with this notion, endothelin-1 (ET-1) stimulates venous constriction, resulting in significant changes in blood volume distribution, cardiac output, and blood pressure. 5,6 The factors controlling venoconstriction are complex and include both neural and humoral mechanisms. The increased sympathetic nerve activity results in augmented venoconstriction, which predominates in the development of spontaneous hypertension. 4 Various humoral factors, such as angiotensin II (Ang II) and ET-1, also induce venoconstriction. 7 Ang II causes impair...

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Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in DOCA-salt rats

Cited by 69 publications

References 32 publications

Redox Control of Renal Function and Hypertension

Redox Control of Renal Function and Hypertension

Activation of Vascular BK Channel by Tempol in DOCA-Salt Hypertensive Rats

NADPH Oxidase–Derived Superoxide Augments Endothelin-1–Induced Venoconstriction in Mineralocorticoid Hypertension

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