Zhang, YiWu, Jason H YVickers, JanineOng, SharonTemple, Suzanna E LMori, Trevor ACroft, Kevin DWhitworth, Judith2015-12-070263-6352http://hdl.handle.net/1885/23796OBJECTIVE: 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.Keywords: 20 hydroxyicosatetraenoic acid; corticotropin; cytochrome P450 4A1; dexamethasone; formamidine; het 0016; isoprostane derivative; n hydroxy n' (4 butyl 2 methylphenyl)formamidine; unclassified drug; animal experiment; animal model; article; body weight; c 20-hydroxyeicosatetraenoic acid; Arachidonic acid; Glucocorticoid; Hypertension; N-hydroxy-N0-(4-butyl-2-methylphenyl) formamidine200910.1097/HJH.0b013e32832cc56c2016-02-24