Apocynin but not allopurinol prevents and reverses adrenocorticotropic hormone-induced hypertension in the rat.
BACKGROUND
Adrenocorticotropic hormone (ACTH)-induced hypertension in the rat is accompanied by increased oxidative stress. This study examines the enzymatic source of reactive oxygen species in ACTH-hypertension.


METHODS
Male Sprague-Dawley rats were divided into 10 groups of 10-20 rats per group. The NAD(P)H oxidase inhibitor apocynin (1.5 mmol/L in drinking water) or the xanthine oxidase inhibitor allopurinol (200 mg/kg/day via food) were administered daily. After 4 days, rats were co-administered ACTH (0.2 mg/kg/day) or saline by subcutaneous injection daily for 11 days (prevention study). In a reversal study, ACTH/saline was administered for 13 days and from day 8, apocynin or allopurinol was added for 5 days. Systolic blood pressure (SBP) was measured by the tail-cuff method and oxidative stress using plasma F2-isoprostane concentrations. Results were expressed as mean+/-SEM.


RESULTS
ACTH increased SBP (P<.001) but apocynin or allopurinol alone had no effect. Apocynin (but not allopurinol) co-treatment prevented (142+/-3 ACTH, 120+/-4 mm Hg apocynin+ACTH, P'<0.001) and reversed ACTH-induced hypertension (133+/-4 to 118+/-5 mm Hg, P<.05). Plasma F2-isoprostane concentrations were increased in ACTH-treated rats compared with saline (11.9+/-1.0 vs 8.2+/-0.8 nmol/L, P<.01), and apocynin attenuated the ACTH-induced rise in plasma F2-isoprostane concentrations. Serum urate concentrations were undetectable in 75% of rats treated with allopurinol and were not affected by ACTH.


CONCLUSIONS
Apocynin but not allopurinol prevented and reversed ACTH-induced hypertension in the rat. These results suggest superoxide production through NAD(P)H oxidase plays a role in ACTH-induced hypertension.
Zhang
Yi
Y
High Blood Pressure Research Unit, John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Canberra, Australia.
Chan
Matthew M K
MM
Andrews
Miles C
MC
Mori
Trevor A
TA
Croft
Kevin D
KD
McKenzie
Katja U S
KU
Schyvens
Christopher G
CG
Whitworth
Judith A
JA
D000098:Acetophenones / Q000627:therapeutic use*; D000324:Adrenocorticotropic Hormone; D000493:Allopurinol / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy*; D028421:Isoprostanes / Q000097:blood; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013950:Thymus Gland / Q000033:anatomy & histology / Q000187:drug effects; D014527:Uric Acid / Q000652:urine; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000098:Acetophenones; D000959:Antihypertensive Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D028421:Isoprostanes; D017382:Reactive Oxygen Species; D013481:Superoxides; D014527:Uric Acid; D000493:Allopurinol; D000324:Adrenocorticotropic Hormone; C056165:acetovanillone; D014969:Xanthine Oxidase; D019255:NADPH Oxidases