Varespladib Attenuates Bothrops jararacussu Venom-Induced Cardiotoxicity in Isolated Hearts Perfused using the Langendorff System

Snake envenomation represents a public health concern in tropical regions and is associated with severe morbidity and high mortality. Venoms from snakes of the family Viperidae can cause local tissue damage, coagulopathies, acute kidney injury, and cardiovascular disturbances. Among these, cardiovascular shock is one of the leading causes of death following envenomation by snakes of the genus Bothrops. Despite their clinical relevance, the direct cardiotoxic effects of these venoms and potential therapeutic strategies remain poorly understood. Therefore, this study aims to investigate the effects of Bothrops jararacussu venom on the function of isolated rat hearts and to evaluate the effects of varespladib, a phospholipase A2 inhibitor, on hemodynamic parameters. All procedures were approved by the Animal Ethics Committee of ICBS/UFRRJ (protocol No. 03/2025). Hearts from male Wistar rats (250–300 g) were excised and subjected to Langendorff perfusion. Following a 10-minute stabilization period with oxygenated Krebs-Henseleit solution (37 °C; pH 7.4), baseline left ventricular developed pressure (LVDP) and left ventricular end-diastolic pressure (LVEDP) were recorded for 20 minutes. Subsequently, the hearts were randomly assigned to two experimental groups (n = 5): B. jararacussu venom (5.0 µg/mL; BJU5) and B. jararacussu venom combined with varespladib (BJU5 + VP20). Hemodynamic parameters were continuously monitored. Data were analyzed using a mixed-effects model followed by Bonferroni's post hoc test, with statistical significance set at p ≤ 0.05. Results are expressed as mean ± standard error of the mean. Venom exposure induced time-dependent changes in LVDP (p = 0.0005). No significant differences were observed between groups in baseline LVDP values; however, significant differences between BJU5 and BJU5 + VP20 emerged after 10 minutes (p < 0.05) and persisted until the cessation of cardiac function. Cardiac activity was maintained for 25 minutes in the BJU5 group and 50 minutes in the BJU5 + VP20 group. Regarding LVEDP, a significant group × time interaction was observed (p = 0.0007). Collectively, these findings indicate that varespladib partially attenuates the hemodynamic alterations induced by B. jararacussu venom and prolongs the maintenance of cardiac function in an isolated heart model, suggesting a potential cardioprotective effect.