β3-Adrenergic receptor antagonism improves cardiac and vascular functions but did not modulate survival in a murine resuscitated septic shock model.

Abstract

Background: Recent findings suggest that β3-adrenergic receptors (β3-AR) could play a role in the hemodynamic regulation, but their function in septic shock remains unclear. This study investigates the modulation of β3-AR in an experimental murine model of resuscitated septic shock on in vivo hemodynamic, ex vivo vasoreactivity, inflammation and survival.

Method: Wild-type mice were used, undergoing cecal ligation and puncture (CLP) to induce septic shock, with SHAM as controls. Mice were treated with β3-AR agonist or antagonist three hours post-CLP, followed by resuscitation with fluids and antibiotics. Hemodynamic parameters were measured at 18 h following the surgery, and the expression of β-ARs in heart and aorta was assessed via immunostaining and western blot. Vascular reactivity was studied using myography, and inflammatory markers were analyzed through PCR and western blots. A 5-day survival study was conducted, documenting clinical severity scores and survival rates.

Results: β3-AR was expressed in both endothelial and myocardial cells in healthy and septic mice. During septic shock model, β3-AR density on endothelial cells increased post-CLP, while β1- and β2-AR decreased or remained constant. β3-AR antagonist treatment improved hemodynamic parameters, increasing mean arterial pressure and cardiac index, unlike the agonist. Vascular reactivity to phenylephrine was enhanced in aortic rings from both β3-AR agonist and antagonist-treated mice. However, no significant differences in inducible NO synthase expression were observed among treated groups. Despite improved hemodynamic parameters with β3-AR antagonist treatment, survival rates in treated groups remained similar to CLP group.

Conclusions: In an experimental murine model of resuscitated septic shock, β3-AR is resistant to desensitization and its inhibition improves cardiac and vascular function without affecting the short-term survival.