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An analysis of the DOCA-salt model of hypertension in HO-1^–/– mice and the Gunn rat

¹Division of Nephrology and Hypertension and ²Departments of Anesthesiology, ³Molecular Pharmacology and Experimental Therapeutics, and ⁴Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota

Submitted 14 August 2006 ; accepted in final form 6 March 2007

Heme oxygenase-1 (HO-1) is induced in the vasculature in the DOCA-salt model of hypertension in rats. Whereas the HO system and its products may exert vasodilator effects, recent studies have suggested that the HO system may predispose to hypertension. The present study examined the effects of selected components of the HO system, specifically, the HO-1 isozyme and the product bilirubin in the DOCA-salt model of systemic hypertension; the experimental approach employed mutant rodent models, namely, the HO-1^–/– mouse and the hyperbilirubinemic Gunn rat. DOCA-salt induced HO-1 protein in the aorta in HO-1^+/+ mice and provoked a significant rise in systolic arterial pressure in HO-1^–/– mice but not in HO-1^+/+ mice; this effect could not be ascribed to impaired urinary sodium excretion or impaired glomerular filtration rate in the DOCA-salt-treated HO-1^–/– mice. The administration of DOCA salt to uninephrectomized rats significantly increased systolic arterial pressure in wild-type rats, an effect that was attenuated in the mutant Gunn rat; this reduction in systemic hypertension in the DOCA-salt-treated Gunn rat was not due to a greater induction of HO-1 in the vasculature or to a more avid urinary sodium excretion. DOCA-salt impaired endothelium-dependent and endothelium-independent vasorelaxation in wild-type rats but not in Gunn rats; prior exposure to bilirubin repaired the defect in endothelium-dependent vasorelaxation in aortic rings in DOCA-salt-treated rats. DOCA salt stimulated vascular production of superoxide anion in wild-type but not in Gunn rats. We suggest that HO-1 and the product bilirubin may exert a countervailing effect in the DOCA-salt model of systemic hypertension.

superoxide anion; bilirubin; vascular reactivity; oxidative stress

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