Vesnarinone prolongs survival and reduces lethality in a murine model of lethal endotoxemia

Vesnarinone (3,4-Dihydro-6-[4(3,4-dimethoxybenzoyl)-1-piperanizyl]-2(1H)-quino linone), a recently synthesized quinolinone derivative with positive inotropic properties, has been reported the survival of patients with chronic congestive heart failure. However, the mechanisms that contribute to this improvement are not yet well understood. There is increasing evidence that vesnarinone has novel immunosuppressive properties related to its inhibition of cytokine production. Cytokines have been shown to play a pivotal role in the pathophysiologic consequences of fatal bacteremic shock. In this study, we investigated the effects of vesnarinone in a murine model of lethal endotoxemia induced by lipopolysaccharide (LPS). Eight-week-old female BALB/c mice were given 300 or 400 micrograms of LPS, and 50 or 100 mg/kg of vesnarinone was administered by oral gavage and/or 10 or 30 micrograms of vesnarinone was given intra peritoneally. Vesnarinone prolonged the median survival time and reduced lethality when given at the same time as the LPS injection. However, vesnarinone did not have a beneficial effect when administered 2 hours after LPS treatment. Plasma TNF-alpha reached a maximum level 1 hour after LPS challenge, and vesnarinone reduced the plasma level of TNF-alpha, when administered at the same time as LPS injection. Vesnarinone had protective effects against lethal endotoxemia; these effects were considered to be due to the suppression of TNF-alpha production. These findings suggest that vesnarinone may be a promising agent for the treatment of bacterial sepsis and shock.