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.

How do glucocorticoids cause hypertension: role of nitric oxide deficiency, oxidative stress, and eicosanoids.

The exact mechanism by which glucocorticoid induces hypertension is unclear. Several mechanisms have been proposed, although there is evidence against the role of sodium and water retention as well as sympathetic nerve activation. This review highlights the role of nitric oxide-redox imbalance and their interactions with arachidonic acid metabolism in glucocorticoid-induced hypertension in humans and experimental animal models.

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.

The role of 20-hydroxyeicosatetraenoic acid in adrenocorticotrophic hormone and dexamethasone-induced hypertension.

OBJECTIVE: 20-hydroxyeicosatetraenoic acid (20-HETE) is a potent constrictor in small arteries and also has natriuretic properties. Urinary 20-HETE excretion is increased in adrenocorticotrophic hormone (ACTH)-induced hypertensive rats. In the present study, we investigated the effect of a specific enzyme inhibitor of 20-HETE production, N-hydroxy-N'-(4-butyl-2-methylphenyl) formamidine (HET0016), on glucocorticoid-induced hypertension in rats, a sodium-independent model. METHODS: Male Sprague-Dawley rats were treated with physiological saline (0.9% NaCl), ACTH (0.2 mg/kg per day) or dexamethasone (0.03 mg/rat per day) subcutaneously for 13 days. HET0016 (10 mg/kg per day) or its vehicle (10% lecithin in physiological saline) was coadministered (intraperitoneally) a day before (prevention study) or at day 8 of treatment (reversal studies). Systolic blood pressure was measured by the tail-cuff method. RESULTS: Relative to physiological saline, systolic blood pressure was increased by ACTH (P < 0.001) and dexamethasone (P < 0.01). HET0016 reversed ACTH-induced (P < 0.01) but not dexamethasone-induced hypertension. HET0016 also prevented the development of hypertension induced by ACTH (P < 0.01). ACTH, but not dexamethasone, increased renal microsome 20-HETE formation and plasma F2-isoprostane concentrations. HET0016 inhibited renal 20-HETE formation but had no effect on plasma F2-isoprostane concentrations or renal cytochrome P450 4A1 expression. CONCLUSION: Inhibition of 20-HETE production by HET0016 prevents and reverses ACTH-induced but not dexamethasone-induced hypertension. These results suggest that 20-HETE may play a role in the genesis of ACTH-induced hypertension but not in dexamethasone-induced hypertension.

Blood pressure measurement in pregnancy: the effect of arm circumference and sphygmomanometer cuff size.

This study aimed to assess the difference in blood pressure readings between the standard and large cuff and to determine if such a difference applies over a range of arm circumferences (ACs) in pregnancy. We measured blood pressure on 219 antenatal women. Six blood pressure readings were taken, three with a standard 'adult' and three with a 'large' cuff, in random order. A random zero sphygmomanometer was used by a trained observer. Women with an AC >33 cm were similar in age, gestational age and parity but were heavier and had more hypertension than those with AC ≤33 cm. There was a systematic difference between the standard and large cuff of 5-7 mmHg with little effect due to AC. We were unable to demonstrate an association between the standard and large cuff blood pressure difference and increasing blood pressure. Our study has shown that both systolic and diastolic blood pressure measurements are more dependent on the cuff size used than AC and for the individual it is difficult to predict the magnitude of effect the different cuff sizes will have on blood pressure measurements. This study has shown the presence of an average difference in blood pressure measurement between standard and large cuffs in pregnancy, and does not support the arbitrary 33 cm 'cut-off' recommended in guidelines for the use of a large cuff in pregnancy.

Reactive oxygen species and glucocorticoid-induced hypertension.

1. There is increasing evidence for a role of oxidative stress and nitric oxide deficiency in experimental glucocorticoid-induced hypertension, as evidenced by increased biomarkers of oxidative stress; the effectiveness of antioxidants or reduced NADPH oxidase antagonists in lowering blood pressure; and secondary upregulation of endogenous antioxidant enzymes in response to oxidative stress. 2. In the vasculature, the main sources of superoxide are NADPH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase (eNOS) and mitochondria. 3. NADPH oxidase plays a significant role in the pathogenesis of glucocorticoid-induced hypertension in the rats, but xanthine oxidase and uncoupled eNOS pathways are not important sources of reactive oxygen species in these models. The role of mitochondrial reactive oxygen species in glucocorticoid-induced hypertension remains to be clarified.

Role of xanthine oxidase in dexamethasone-induced hypertension in rats.

1. Glucocorticoid-induced hypertension (GC-HT) in the rat is associated with nitric oxide-redox imbalance. 2. We studied the role of xanthine oxidase (XO), which is implicated in the production of reactive oxygen species, in dexamethasone-induced hypertension (dex-HT). 3. Thirty male Sprague-Dawley rats were divided randomly into four treatment groups: saline, dexamethasone (dex), allopurinol plus saline, and allopurinol plus dex. 4. Systolic blood pressures (SBP) and bodyweights were recorded each alternate day. Thymus weight was used as a marker of glucocorticoid activity, and serum urate to assess XO inhibition. 5. Dex increased SBP (110 +/- 2-126 +/- 3 mmHg; P < 0.001) and decreased thymus (P < 0.001) and bodyweights (P" < 0.01). Allopurinol decreased serum urate from 76 +/- 5 to 30 +/- 3 micromol/L (P < 0.001) in saline and from 84 +/- 13 to 28 +/- 2 micromol/L in dex-treated (P < 0.01) groups. 6. Allopurinol did not prevent dex-HT. This, together with our previous findings that allopurinol failed to prevent adrenocorticotrophic hormone induced hypertension, suggests that XO activity is not a major determinant of GC-HT in the rat.