AT1 receptors play a role in sepsis-induced vasoplegia by increasing iNOS expression in the perivascular adipose tissue.

Sepsis enhances the anticontractile effect of perivascular adipose tissue (PVAT), which contributes to a reduced response to vasoconstrictor agents. In the early stages of sepsis, the renin-angiotensin-aldosterone system (RAAS) is activated, and this response can lead to poorer clinical outcomes. We hypothesized that AT₁ receptors (AT₁R) contribute to vascular hyporesponsiveness during sepsis by increasing the expression of inducible nitric oxide synthase (iNOS) in the periaortic PVAT, resulting in elevated nitric oxide (NO) production. In our study, male Wistar Hannover rats underwent lethal sepsis via a cecal ligation and puncture (CLP) model. We evaluated the role of AT₁R in sepsis-induced PVAT dysfunction by administering a single dose of losartan (a selective AT₁R antagonist; 10 mg/kg, gavage) to the rats 1 h prior to the CLP surgery. We observed increased levels of circulating angiotensin II in septic rats. Functional analyses revealed that AT₁R blockade prevented the enhanced anticontractile effect of PVAT and the resulting vascular hyporesponsiveness to phenylephrine during sepsis. Additionally, losartan inhibited sepsis-induced iNOS expression and the overproduction of NO in both the PVAT and the aorta. Experiments using 1400W, a selective iNOS inhibitor, indicated that iNOS plays a crucial role in the sepsis-induced increase in the anticontractile effect of PVAT. In summary, AT₁R mediate iNOS expression in PVAT, leading to the overproduction of NO, which ultimately contributes to sepsis-induced vasoplegia. Furthermore, AT₁R-mediated iNOS expression is an important mechanism related to vasoplegia in the vasculature. The present results implicate AT₁R as active players in sepsis-induced PVAT and vascular dysfunction.