The role of 20-hydroxyeicosatetraenoic acid in adrenocorticotrophic hormone and dexamethasone-induced hypertension.

Abstract

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.

• Authors: Yi Zhang, Jason H Y Wu, Janine J Vickers, Sharon L H Ong, Suzanna E L Temple, Trevor A Mori, Kevin D Croft, Judith A Whitworth
• Journal: Journal of hypertension (J Hypertens) Vol. 27 Issue 8 Pg. 1609-16 (Aug 2009) ISSN: 1473-5598 [Electronic] England
• PMID: 19458537 (Publication Type: Journal Article)

Chemical References

• Amidines
• F2-Isoprostanes
• HET0016
• Hydroxyeicosatetraenoic Acids
• Reactive Nitrogen Species
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Dexamethasone
• Adrenocorticotropic Hormone

Topics

• Adrenocorticotropic Hormone (pharmacology)
• Amidines (pharmacology)
• Animals
• Body Weight (drug effects)
• Dexamethasone (pharmacology)
• F2-Isoprostanes (blood)
• Hydroxyeicosatetraenoic Acids (physiology)
• Hypertension (chemically induced)
• Kidney (drug effects, metabolism)
• Male
• Organ Size (drug effects)
• Rats
• Rats, Sprague-Dawley
• Reactive Nitrogen Species (blood)
• Systole (drug effects)