RESUMEN
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 CKMB. 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.
Asunto(s)
Venenos de Crotálidos/toxicidad , Crotalus , Corazón/efectos de los fármacos , Animales , Presión Arterial/efectos de los fármacos , Cardiotónicos/toxicidad , Proliferación Celular/efectos de los fármacos , Creatina Quinasa/efectos de los fármacos , Creatina Quinasa/metabolismo , Venenos de Crotálidos/antagonistas & inhibidores , Venenos de Crotálidos/química , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/efectos de los fármacos , Técnicas In Vitro , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Miocardio/enzimología , Miocardio/patología , Miocardio/ultraestructura , Miocitos Cardíacos/efectos de los fármacos , Ratas , Ratas Wistar , Mordeduras de SerpientesRESUMEN
BACKGROUND: The aim of this study was to evaluate the cardiovascular effects of N-phenyl-itaconimide (Imide-1), N-4-methyl-phenyl-itaconimide (Imide-2), N-4-methoxy-phenyl-itaconimide (Imide-3) and N-4-chloro-phenyl-itaconimide (Imide-4), and investigate the mechanisms of action involved in the observed responses. METHODS: The relaxant effect was investigated in rat superior mesenteric arteries by using isometric tension measurements. Additionally, in isolated atria were evaluated the heart rate and force of cardiac contraction and in vivo experiments was evaluated blood pressure and heart rate. RESULTS: Cumulative administration of itaconimides (3 × 10-8 to 3 × 10-4 M) in pre-contracted mesenteric artery rings with phenylephrine, 1 µM, induced endothelium-independent vasorelaxation. The itaconimides showed similar maximum efficacies. Additionally, Imide-3 induced vasorelaxation in rings exposed to a depolarizing-tyrode solution containing 60 mM KCl or 20 mM KCl similar to the control, suggesting the non-participation of K+ channels. Imide-3 attenuated Ca2+ influx in a concentration-dependent manner. As well, imide-3 reduced CaCl2-induced contraction in nominally calcium-free medium, in the presence of cyclopiazonic acid (20 µM), phenylephrine (1 µM) and nifedipine (1 µM), indicating a reduction of Ca2+ influx by receptor-operated channels (ROC) and store-operated channels (SOC). The presence of SKF 96365 (10-5 M), SOC blocker, did not significantly alter the vasorelaxant effect induced by imide-3. Moreover, imide-3 induced a negative inotropic effect. In vivo studies, in non-anesthetized normotensive rats, imide-3 lowered blood pressure and induced bradycardia. CONCLUSIONS: These results suggest that itaconimides have concentration-dependent vascular effects and the vasorelaxation seems to be endothelium-independent. The vasodilatory effect induced by imide-3 may be due to a possible influence on the CaV and ROC. In addition, imide-3 is able to reduce force of cardiac contraction, blood pressure and promote bradycardia.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Imidas/farmacología , Arterias Mesentéricas/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Imidazoles/farmacología , Imidas/química , Masculino , Arterias Mesentéricas/fisiología , Contracción Muscular/fisiología , Nifedipino/farmacología , Técnicas de Cultivo de Órganos , Fenilefrina/farmacología , Ratas , Ratas Wistar , Vasodilatación/fisiologíaRESUMEN
Forty-five individuals with hepatosplenic schistosomiasis mansoni were studied with the aim of measuring levels of von Willebrand factor antigen (vWF:Ag), detecting abnormalities in platelet morphology and aggregation, and identifying changes to surface antigens. Haemograms, platelet aggregation tests, flow cytometry investigations of CD41/CD42b antibody and vWF:Ag assays were performed. Mean platelet counts were low (77,522/mm3) and 82.2% of patients presented thrombocytopenia. An inverse relationship between spleen size and platelet count was seen. Macroplatelets were found in 57.1% of patients, indicating good bone-marrow response, but were insufficient to compensate for the decrease in platelets due to splenomegaly. Decreased or absent platelet aggregation was seen in 50% of patients, probably due to low platelet counts. Markers for GPIIb/IIIa were normal in more than 90% of patients, not supporting the increased capture and destruction of platelets in the spleen that is hypothesized to occur with cirrhosis. Similar to cirrhosis, vWF:Ag levels were high or very high in 70.5% of patients. High levels of vWF:Ag were associated with platelet counts <100,000/mm3, larger spleen diameter and oesophageal varices. In conclusion, hepatosplenic schistosomiasis leads to a lower platelet count due to pooling in the spleen and, consequently, impaired aggregation, but not to increased capture and destruction of platelets in the spleen. High vWF:Ag levels probably promote stabilization of platelet microaggregates and prevent minor manifestations of thrombocytopenia such as petechiae, ecchymosis and gingival bleeding.