The High Blood Pressure Research Unit, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
Am J Hypertens. 2010 May;23(5):569-74. doi: 10.1038/ajh.2010.27. Epub 2010 Feb 25.
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.
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.
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.
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.
糖皮质激素诱导的高血压与一氧化氮（NO）和超氧化物之间的失衡有关。导致这种失衡的途径之一是内皮型一氧化氮合酶（eNOS）解偶联。在本研究中，用促肾上腺皮质激素（ACTH）和地塞米松治疗的大鼠进一步用四氢生物蝶呤前体蝶酸或一氧化氮合酶抑制剂 N-硝基-L-精氨酸（NOLA）治疗，以研究 eNOS 解偶联在糖皮质激素诱导的高血压中的作用。
雄性 Sprague-Dawley（SD）大鼠（每组 7-13 只）在 ACTH（0.2 mg/kg/天，SC）、地塞米松（0.03 mg/kg/天，SC）或生理盐水治疗前 4 天和期间每天用蝶酸（5 mg/kg/天，IP）或生理盐水（假手术）处理。NOLA（0.4 mg/ml 在饮用水中）在给予地塞米松前 4 天和期间给予大鼠。通过尾套法测量收缩压（SBP）。
ACTH（116 +/- 2 至 135 +/- 3 mmHg（平均值 +/- s.e.m.），P < 0.001）和地塞米松（114 +/- 4 至 133 +/- 3 mmHg，P < 0.0005）均升高 SBP。蝶酸单独处理不会改变 SBP。蝶酸不能预防 ACTH-（129 +/- 4 mmHg，NS）或地塞米松诱导的高血压（135 +/- 3 mmHg，NS），尽管血浆总生物蝶呤浓度升高。NOLA 在给予地塞米松或生理盐水之前增加了大鼠的 SBP。NOLA 进一步增加了生理盐水-（133 +/- 4 至 157 +/- 3 mmHg，P < 0.05）和地塞米松处理的大鼠（135 +/- 5 至 170 +/- 6 mmHg，P < 0.05）的 SBP。ACTH 和地塞米松增加了血浆 F(2)-异前列腺素浓度。蝶酸和 NOLA 均未显著影响这种氧化应激标志物。
蝶酸不能预防 ACTH 或地塞米松诱导的高血压。NOLA 加重了地塞米松诱导的高血压。这些数据表明，eNOS 解偶联在大鼠糖皮质激素诱导的高血压的发生中不起主要作用。
