| Angiotensin II (Ang II) is involved critically in the development and maintenance of hypertension in both human and animal models. Ang II also is known to stimulate interleukin 6 (IL-6) release, and a recent study by our laboratory demonstrated that Ang II hypertension was attenuated in IL-6 knockout (KO) mice. These data suggest that IL-6 mediates part of the hypertensive actions of Ang II. In addition, Ang II also stimulates production and release of aldosterone, which also has hypertensive actions. Ang II also stimulates the proinflammatory cytokine tumor necrosis factor-alpha (TNF-(alpha), which can stimulate IL-6 secretion. Therefore, the aim of this project was to determine whether the dependence of Ang II hypertension on II-6 is due to a direct link between Ang II and IL-6 or whether aldosterone and/or TNF-alpha are important intermediate factors. In separate studies, we determined whether mineralocorticoid hypertension is IL-6 dependent, the role of IL-6 bioactivity verses IL-6 plasma concentration, and the role of TNF-alpha in Ang II hypertension. Mineralocorticoid hypertension was induced by implanting a deoxycorticosterone acetate (DOCA) pellet (1 g/kg) subcutaneously and giving all animals a solution of 1% sodium chloride (NaCl) and 0.2% potassium chloride (KCl) to dink for a 14 day experimental period. DOCA-salt treatment increased the mean arterial pressure (MAP) similarly by ∼30 mm Hg in both the WT and IL-6 KO mice. However, DOCA-salt treatment did not increase plasma IL-6 concentration in wildtype (WT) mice nor did it increase IL-6 bioavailability using a bioassay on day 14 of treatment. There was, however, a transient increase in plasma IL-6 concentration and bioactivity on day 7 of DOCA-salt treatment in the WT mice. Treating WT mice with Ang II and the mineralocorticoid receptor antagonist, spironolactone, significantly attenuated the Ang II mediated increase in plasma IL-6 concentration on day 7 and day 14 of treatment. These data suggest that aldosterone might play a role in the initial increase in plasma IL-6 concentration during Ang II hypertension, but not the sustained increase. Similarly, Ang II increased MAP by -30 mm Hg in both the WT and TNF-alpha KO mice by day 14 of treatment. In WT mice Ang II treatment did not increase plasma levels of TNF-alpha. Ang II-induced hypertension is characterized by increased plasma levels of Ang II, aldosterone and IL-6 but not TNF-alpha. These data suggest that Ang II may work through an aldosterone but not TNF-alpha mediated mechanism to increase plasma IL-6 concentration in Ang II hypertension. However, these results suggest that the role of IL-6 in mediating Ang II hypertension may be independent of the interaction with aldosterone and TNF-alpha. |
