Envenoming, resulting from snake bites, is a global public health problem. The present study was undertaken to investigate the influence of Crotalus durissus cascavella (Cdcas) venom on cardiac activity and the mechanisms of action underlying its effect. To investigate the inotropic and chronotropic effects induced by Cdcas, studies were performed on the left and right atria. A series of tests were conducted to investigate whether the negative inotropic effect, induced by Cdcas, was related to cardiac damage. Cdcas venom (0.1-30 µg/mL) elicited a significant negative inotropic effect. The addition of Cdcas crude venom (7.5, 15 and 30 μg/mL) did not induce significant alterations in cell proliferation, nor in the enzymatic activity of total-CK and CK-MB. Ultrastructural evaluation demonstrated that cardiac cells from isoproterenol and Cdcas groups revealed discreet swelling and displaced intermyofibrillar mitochondria with disorganization of the cristae. No change was observed in cardiac electrical activity in perfused isolated rat hearts with Cdcas. In addition, Cdcas reduced contractility in isolated cardiomyocytes from the rat left ventricle. The negative inotropic effect of Cdcas was reduced by L-NAME (100 μM), PTIO (100 μM), ODQ (10 μM) and KT5823 (1 μM), suggesting the participation of NO/cGMP/PKG pathway due to Cdcas. In non-anesthetized rats, Cdcas induced hypotension followed by bradycardia, the latter was also observed by ECG (anesthetized animals). Our results suggest that the negative inotropic effect induced by Cdcas venom is unrelated to cardiac toxicity, at least, at the concentrations tested; and occurs through of NO/cGMP/PKG pathway, likely leading to hypotension and bradycardia when administered in vivo.

中文翻译：

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Crotalus durissus cascavella 毒液诱导的心脏效应：形态功能证据和作用机制

由蛇咬伤引起的中毒是一个全球性的公共卫生问题。本研究旨在调查 Crotalus durissus cascavella (Cdcas) 毒液对心脏活动的影响及其作用机制。为了研究 Cdcas 引起的变力和变时作用，对左心房和右心房进行了研究。进行了一系列测试以研究由 Cdcas 引起的负性肌力作用是否与心脏损伤有关。Cdcas 毒液 (0.1-30 µg/mL) 引起显着的负性肌力作用。添加 Cdcas 粗毒液（7.5、15 和 30 μg/mL）不会引起细胞增殖的显着改变，也不会引起总 CK 和 CK-MB 的酶活性的显着改变。超微结构评估表明，来自异丙肾上腺素和 Cdcas 组的心肌细胞表现出谨慎的肿胀和肌原纤维间线粒体的移位，同时伴有嵴的解体。在用 Cdcas 灌注的离体大鼠心脏中未观察到心脏电活动的变化。此外，Cdcas 降低了来自大鼠左心室的分离心肌细胞的收缩力。L-NAME (100 μM)、PTIO (100 μM)、ODQ (10 μM) 和 KT5823 (1 μM) 降低了 Cdcas 的负性肌力作用，表明 Cdcas 参与了 NO/cGMP/PKG 通路。在非麻醉大鼠中，Cdcas 引起低血压，然后是心动过缓，后者也可通过 ECG（麻醉动物）观察到。我们的结果表明，由 Cdcas 毒液诱导的负性肌力作用与心脏毒性无关，至少，在测试的浓度下；并且通过 NO/cGMP/PKG 途径发生，在体内给药时可能导致低血压和心动过缓。