Aldosterone is a mineral corticoid hormone that is produced in response to angiotensin-II, and like angiotensin-II, stimulates inflammation, oxidative stress, and fibrosis by activating nuclear factor-κB and activating protein-1. Recent evidence, however, indicates that aldosterone stimulates phospholipase C and activates nuclear factor-κB and activating protein-1. Although the heme oxygenase system is cytoprotective, its effects on aldosterone–phospholipase C signaling in deoxycorticosterone acetate (DOCA-salt) hypertension, a model of aldosteronism, and spontaneously hypertensive rat, a genetic model of human essential hypertension, have not been fully characterized.
In the present study, the heme oxygenase inducer, hemin, was given to spontaneously hypertensive and deoxycorticosterone acetate hypertensive rats, and the effects on blood pressure, aldosterone, nuclear factor-κB, activating protein-1, phospholipase C, and inositol 1,4,5-triphosphate were examined.
Hemin therapy restored physiological blood pressure to spontaneously hypertensive rats (209.9 ± 0.9 to 127.3 ± 0.85 mmHg, n = 10, P < 0.01) and to deoxycorticosterone acetate salt hypertensive rats (195.7 ± 1.8 vs.132.5 ± 2.1 mmHg; P < 0.01, n = 10), but had no effect on age-matched normotensive Wistar–Kyoto or Sprague–Dawley strains. The antihypertensive effect was accompanied by enhanced heme oxygenase activity, upregulated cyclic guanosine monophosphate-protein kinase G signaling, increased superoxide dismutase activity, and the potentiation of total antioxidant capacity, whereas aldosterone, activating protein-1, and nuclear factor-κB were reduced. Furthermore, hemin suppressed phospholipase C activity, attenuated inositol 1,4,5-triphosphate, and reduced resting intracellular calcium in the aorta.
Collectively, our results suggest that the concomitant depletion of aldosterone, phospholipase C-inositol 1,4,5-triphosphate activity, resting intracellular calcium and the corresponding decline of inflammatory, and oxidative insults may account for the antihypertensive effects of hemin in deoxycorticosterone acetate hypertension and spontaneously hypertensive rats.
Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Received 10 September, 2007
Revised 13 January, 2008
Accepted 30 January, 2008
Correspondence to Dr Joseph Fomusi Ndisang, PhD, Department of Physiology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5 Tel: +1 306 966 6533; fax: +1 306 966 6532; e-mail: email@example.com