Downregulation of angiotensin II type I receptors during sepsis

Our study aimed to characterize the mechanisms underlying the attenuated ca rdiovascular responsiveness toward the renin-angiotensin system during seps is. For this purpose, we determined the effects of experimental Gram-negati ve and Gram-positive sepsis in rats. We found that sepsis led to a ubiquito us upregulation of NO synthase isoform II expression and to pronounced hypo tension. Despite increased plasma renin activity and plasma angiotensin (An g) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rat s. Mimicking the fall of blood pressure during sepsis by short-term infusio n of the NO donor sodium nitroprusside in normal rats did not alter their b lood pressure response to exogenous Ang II. Therefore, we considered the po ssibility of an altered expression of Ang II receptors during sepsis. It tu rned out that Ang II type I receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesan gial cells showed that NO and a combination of proinflammatory cytokines (i nterleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma) downr egulated Ang II type 1 receptor expression in a synergistic fashion. In sum mary, our data suggest that sepsis causes a systemic downregulation of Ang II type I receptors that is likely mediated by proinflammatory cytokines an d NO. We suggest that this downregulation of Ang II type I receptors is the main reason for the attenuated responsiveness of blood pressure and of ald osterone formation to Ang II and, therefore, contributes to the characteris tic septic shock.