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.


CONCLUSIONS
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.
Zhang
Yi
Y
High Blood Pressure Research Unit, John Curtin School of Medical Research, Building 131, Garran Road, Australian National University, Canberra, ACT 0200, Australia. yi.zhang@anu.edu.au
Wu
Jason H Y
JH
Vickers
Janine J
JJ
Ong
Sharon L H
SL
Temple
Suzanna E L
SE
Mori
Trevor A
TA
Croft
Kevin D
KD
Whitworth
Judith A
JA
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D028441:F2-Isoprostanes / Q000097:blood; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology*; D006973:Hypertension / Q000139:chemically induced*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000097:blood; D013599:Systole / Q000187:drug effects
D000578:Amidines; D028441:F2-Isoprostanes; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D026361:Reactive Nitrogen Species; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone