N-Acetylcysteine prevents but does not reverse dexamethasone-induced hypertension

1. We have shown previously that N-acetylcysteine (NAC) prevents the increase in blood pressure induced by adrenocorticotropin treatment. The present study investigated the effect of NAC on dexamethasone (Dex)-induced hypertension. 2. Male Sprague-Dawle

Quaternary geology of Bluegoose Prairie, Baffin Island, Nunavut

The surficial geology and glacial history of Bluegoose Prairie (NTS 36H/1-8) are described, and the first surficial geology map of the area is presented. Four phases of ice flow occurred in Bluegoose Prairie since the Last Glacial Maximum. Collapse of the Foxe Dome ca. 6.2 - 6.5 14C ka BP initiated deglaciation of Foxe Basin. Deglaciation of Bluegoose Prairie and subsequent isostatic rebound were rapid, as evidenced by a relative sea level curve constructed using marine mollusc 14C ages. Diverse macrofossil assemblages show deglacial climate was as warmer or warmer than today. Contemporaneous pairs of terrestrial and marine macrofossils allow for the measurement of deglacial marine reservoir age for Bluegoose Prairie. This new value of 985 ± 10 14C years, 265 14C years older than previously thought, can be applied to deglacial marine 14C ages in Foxe Basin and Hudson Strait. Application of this value allows more accurate palaeogeographic reconstructions

The glucocorticoid receptor is required for experimental adrenocorticotrophic hormone-induced hypertension in mice

1. In the present study, we have (i) measured basal blood pressure by telemetry in wild-type (WT) and glucocorticoid receptor knockout (GRKO) mice; (ii) investigated whether or not adrenocorticotrophic hormone (ACTH) can induce hypertension in GRKO mice

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 μmol/L (P < 0.001) in saline and from 84 ± 13 to 28 ± 2 μmol/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

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

Effects of Sepiapterin Supplementation and NOS Inhibition on Glucocorticoid-Induced Hypertension

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.MethodsMale Sprague-Dawley (SD) rats (n = 7-13\group) were treated with either sepiapterin (5mg\kg\day, IP) or saline (sham) 4 days before and during ACTH (0.2mg\kg\day, SC), dexamethasone (0.03mg\kg\day, SC), or saline treatment. NOLA (0.4mg\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.ResultsBoth ACTH (116 2 to 135 3mmHg (mean s.e.m.), P 0.001) and dexamethasone (114 4 to 133 3mmHg, P 0.0005) increased SBP. Sepiapterin alone did not alter SBP. Sepiapterin did not prevent ACTH-(129 4mmHg, NS) or dexamethasone-induced hypertension (135 3mmHg, 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 3mmHg, P 0.05) and dexamethasone-treated rats (135 5 to 170 6mmHg, P 0.05). ACTH and dexamethasone increased plasma F 2-isoprostane concentrations. Neither sepiapterin nor NOLA significantly affected this marker of oxidative stress.ConclusionSepiapterin 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

26 th, and a Nuffield College seminar. I am grateful to many individuals for helpful discussions of

Martin Wolf, and other members of the various seminars. Responsibility for views expressed is mine entirely. I am grateful for support to the Joseph Rowntree Foundation. 1