Submitted on August 14, 2006
Accepted on March 6, 2007
An Analysis of the DOCA-salt Model of Hypertension in HO-1-/- Mice and the Gunn Rat
Karl A. Nath1*, Livius V. d'Uscio2, Julio P. Juncos1, Anthony J. Croatt3, Melissa C. Manriquez4, Siobhan T. Pittock5, and Zvonimir S. Katusic6
1 Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
2 Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
3 Rochester, Minnesota, United States; Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
4 Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, United States; Rochester, Minnesota, United States; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States
5 Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
6 Rochester, Minnesota, United States; Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
* To whom correspondence should be addressed. E-mail: nath.karl{at}mayo.edu.
Heme oxygenase-1 (HO-1) is induced in the vasculature in the DOCA-salt model of hypertension in rats. While 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 GFR in the DOCA-salt-treated HO-1-/- mice. The administration of DOCA-salt to uninephrectomized rats significantly increased systolic arterial pressure in wildtype 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 greater induction of HO-1 in the vasculature, or to more avid urinary sodium excretion. DOCA-salt impaired endothelium-dependent and endothelium-independent vasorelaxation in wildtype 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 wildtype 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.
