Improvement in myocardial contractility by toborinone in sepsis

Study Objectives: Cardiovascular depression commonly occurs in sepsis and appears to be mediated, in part by inflammatory cytokines. Toborinone is a novel inotropic agent related to vesnaranone that has been shown to have potent anti-cytokine effects in vitro. The objectives were to test the hypothesis that toborinone might be beneficial to LV performance in sepsis and to evaluate its potential effects on the specific cytokine, tumor necrosis factor-a (TNF-α). Design: Fourteen anesthetized pigs were instrumented with conductance and high fidelity pressure catheters to assess left ventricular (LV) performance in a relatively load-independent manner. After baseline measurements, septic pathophysiology was induced in all pigs by infusion of endotoxin (50 mg/kg E. coli lipopolysaccharide). Pigs then randomly received either toborinone treatment or vehicle (control). Interventions and Measurements: Eight pigs received 5 mg/kg/min toborinone infusion beginning 1 hour after the start of endotoxin and 6 pigs did not Measures of end-systolic pressure-volume relations (ESPVR) and preload recruitable stroke work (PRSW) were used to assess LV performance. Plasma TNF-α levels were assayed serially by ELISA. Results: LV performance progressively decreased in control animals. Toborinone treated animals had a relative increase in LV performance: group mean ESPVR increased 24%* and PRSW increased 22%* by hour 6 (*p<0.05 vs. control). TNF-α levels increased to a similar degree in both groups at 1 hour and returned to baseline values by 3 hours in both groups. Conclusions: Toborinone attenuated myocardial depression independent of an effect on circulating TNF-α levels in this swine model and may potentially be useful to treat myocardial depression in human sepsis.