The effect of alpha-lipoic acid on mitochondrial superoxide and glucocorticoid-induced hypertension.

AIMS: To examine the effect of alpha-lipoic acid, an antioxidant with mitochondrial superoxide inhibitory properties, on adrenocorticotrophic hormone- (ACTH-HT) and dexamethasone-induced hypertensions (DEX-HT) in rats and if any antihypertensive effect is mediated via mitochondrial superoxide inhibition. METHODS: In a prevention study, rats received ground food or alpha-lipoic-acid-laced food (10 mg/rat/day) for 15 nights. Saline, adrenocorticotrophic hormone (ACTH, 0.2 mg/kg/day), or dexamethasone (DEX, 10 µ g/rat/day) was injected subcutaneously from day 5 to day 11. In a reversal study, rats received alpha-lipoic-acid-laced food 4 days after commencement of saline or DEX. Tail-cuff systolic blood pressure (SBP) was measured second daily. Kidney mitochondrial superoxide was examined using (MitoSOX) Red (MitoSOX) via flow cytometry. RESULTS: SBP was increased by ACTH (P < 0.0005) and DEX (P < 0.0005). Alpha-lipoic acid alone did not alter SBP. With alpha-lipoic acid pretreatment, SBP was increased by ACTH (P' < 0.005) but not by DEX. Alpha-lipoic partially prevented ACTH-HT (P' < 0.0005) and fully prevented DEX-HT (P' < 0.0005) but failed to reverse DEX-HT. ACTH and DEX did not increase MitoSOX signal. In ACTH-hypertensive rats, high-dose alpha-lipoic acid (100 mg/rat/day) did not decrease SBP further but raised MitoSOX signal (P < 0.001), suggesting prooxidant activity. CONCLUSION: Glucocorticoid-induced hypertension in rats is prevented by alpha-lipoic acid via mechanisms other than mitochondrial superoxide reduction.

Effects of sepiapterin supplementation and NOS inhibition on glucocorticoid-induced hypertension.

BACKGROUND: Glucocorticoid-induced hypertension is associated with imbalance between nitric oxide (NO) and superoxide. One of the pathways that causes this imbalance is endothelial NO synthase (eNOS) uncoupling. In the present study, adrenocorticotrophic hormone (ACTH)- and dexamethasone-treated rats were further treated with sepiapterin, a precursor of tetrahydrobiopterin, or N-nitro-L-arginine (NOLA), an inhibitor of NOS, to investigate the role of eNOS uncoupling in glucocorticoid-induced hypertension. METHODS: Male Sprague-Dawley (SD) rats (n = 7-13/group) were treated with either sepiapterin (5 mg/kg/day, IP) or saline (sham) 4 days before and during ACTH (0.2 mg/kg/day, SC), dexamethasone (0.03 mg/kg/day, SC), or saline treatment. NOLA (0.4 mg/ml in drinking water) was given to rats 4 days before and during dexamethasone treatment. Systolic blood pressure (SBP) was measured by the tail-cuff method. RESULTS: Both ACTH (116 +/- 2 to 135 +/- 3 mm Hg (mean +/- s.e.m.), P < 0.001) and dexamethasone (114 +/- 4 to 133 +/- 3 mm Hg, P < 0.0005) increased SBP. Sepiapterin alone did not alter SBP. Sepiapterin did not prevent ACTH- (129 +/- 4 mm Hg, NS) or dexamethasone-induced hypertension (135 +/- 3 mm Hg, NS), although plasma total biopterin concentrations were increased. NOLA increased SBP in rats prior to dexamethasone or saline treatment. NOLA further increased SBP in both saline- (133 +/- 4 to 157 +/- 3 mm Hg, P < 0.05) and dexamethasone-treated rats (135 +/- 5 to 170 +/- 6 mm Hg, P < 0.05). ACTH and dexamethasone increased plasma F(2)-isoprostane concentrations. Neither sepiapterin nor NOLA significantly affected this marker of oxidative stress. CONCLUSION: Sepiapterin did not prevent ACTH- or dexamethasone-induced hypertension. NOLA exacerbated dexamethasone-induced hypertension. These data suggest that eNOS uncoupling does not play a major role in the genesis of glucocorticoid-induced hypertension in the rat.

Role of tetrahydrobiopterin in adrenocorticotropic hormone-induced hypertension in the rat.

Adrenocorticotropic hormone (ACTH)-induced hypertension in the rat is characterized by nitric oxide deficiency. Tetrahydrobiopterin (BH4) is an essential cofactor for the enzyme nitric oxide synthase and glucocorticoids have been reported to reduce cytokine-induced BH4 production. Accordingly we hypothesized that ACTH-induced hypertension would be reversed by BH4 supplementation. Male Sprague-Dawley rats (n = 33) were treated with BH4 in vehicle (10 mg/kg/day i.p.) or vehicle alone (5 mg/kg/day i.p. of ascorbic acid in 4 mM HCl) for 10 days. ACTH (0.2 mg/kg s.c.) or saline daily injection was started 2 days after BH4 or vehicle treatment and continued for 8 days. Systolic blood pressure (SBP) was measured on alternate days using the tail cuff method. Treatment with HCl, ascorbic acid or BH4 alone had no effect on SBP. In saline treated rats, neither BH4 nor its vehicle modified SBP. In ACTH treated rats, SBP was increased in both BH4 (from 128 +/- 6 to 142 +/- 4 mmHg, T0 to T10, P < 0.0005, one way ANOVA) and vehicle groups (from 127 +/- 3 to 158 +/- 7 mmHg, T0 to T10, P < 0.001, one way ANOVA). There was no significant difference in SBP between BH4 + ACTH treated and vehicle + ACTH treated rats. Thus, daily injection of BH4 (10 mg/kg i.p.) failed to prevent the development of ACTH-induced hypertension in rat.

World health organisation-international society of hypertension (WHO/ISH) hypertension guidelines.

Hypertension is now recognised as a very major contributor to disease burden globally. The close working relationship between the World Health Organisation (WHO) and the International Society of Hypertension (ISH) has existed for several decades and led to the production of a number of guidelines and statements. Since the publication of the 1999 WHO/ISH Guidelines for the Management of Hypertension, WHO determined in 2000 that in future the evidence base for all of its guidelines will be explicitly documented according to a defined methodology. In 2002 the World Health Report on Reducing Risks and Promoting Health Life documented the burden of disease (4.5%) related to blood pressure, and subsequently decided to establish comprehensive guidelines to help bring about a paradigm shift to a holistic multiple risk factor approach and facilitate policy development for implementation of population based strategies. ISH will be part of this process. The 2003 WHO/ISH Statement on Management of Hypertension focuses on key areas where new information has become available since the 1999 Guidelines, including establishment of thresholds and goals, treatment strategies and cost-effectiveness. It will be published in the Journal of Hypertension during 2003.