The role of indomethacin and tezosentan on renal effects induced by Bothrops moojeni Lys49 myotoxin I (original) (raw)
Related papers
Toxicon, 2005
Bothrops jararacussu myotoxin I (BthTx-I; Lys 49) and II (BthTX-II; Asp 49) were purified by ion-exchange chromatography and reverse phase HPLC. In this work we used the isolated perfused rat kidney method to evaluate the renal effects of B. jararacussu myotoxins I (Lys49 PLA 2 ) and II (Asp49 PLA 2 ) and their possible blockage by indomethacin. BthTX-I (5 mg/ml) and BthTX-II (5 mg/ml) increased perfusion pressure (PP; ct 120 Z110.28G3.70 mmHg; BthTX IZ171.28G 6.30* mmHg; BthTX IIZ175.50G7.20* mmHg), renal vascular resistance (RVR; ct 120 Z5.49 G0.54 mmHg/ml.g K1 min K1 ; BthTX IZ8.62G0.37* mmHg/ml g K1 min K1 ; BthTX IIZ8.9G0.36* mmHg/ml g K1 min K1 ), urinary flow (UF; ct 120 Z 0.14G0.01 ml g K1 min K1 ; BthTX IZ0.32G0.05* ml g K1 min K1 ; BthTX IIZ0.37G0.01* ml g K1 min K1 ) and glomerular filtration rate (GFR; ct 120 Z0.72G0.10 ml g K1 min K1 ; BthTX IZ0.85G0.13* ml g K1 min K1 ; BthTX IIZ1.22G 0.28* ml g K1 min K1 ). In contrast decreased the percent of sodium tubular transport (%TNa C ; ct 120 Z79,76G0.56; BthTX IZ62.23G4.12*; BthTX IIZ70.96G2.93*) and percent of potassium tubular transport (%TK C ;ct 120 Z66.80G3.69; BthTX IZ55.76G5.57*; BthTX IIZ50.86G6.16*). Indomethacin antagonized the vascular, glomerular and tubular effects promoted by BthTX I and it's partially blocked the effects of BthTX II. In this work also evaluated the antibacterial effects of BthTx-I and BthTx-II against Xanthomonas axonopodis. pv. passiflorae (Gram-negative bacteria) and we observed that both PLA2 showed antibacterial activity. Also we observed that proteins Also we observed that proteins chemically modified with 4bromophenacyl bromide (r-BPB) decrease significantly the antibacterial effect of both PLA 2 . In conclusion, BthTx I and BthTX II caused renal alteration and presented activity antimicrobial. The indomethacin was able to antagonize totally the renal effects induced by BthTx I and partially the effects promoted by BthTx II, suggesting involvement of inflammatory mediators in (H.S.A. Monteiro). the renal effects caused by myotoxins. In the other hand, other effects could be independently of the enzymatic activity of the BthTX II and the C-terminal domain could be involved in both effects promoted for PLA 2 .
Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity
Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) sub-cutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Re-nal polymyxin B concentrations were found to be 3.6 0.4 g/g, 9.9 1.5 g/g, and 21.7 4.8 g/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged , but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity.
Renal effects and injury induced by animal toxins
Toxicon, 2012
Animal toxins are well recognized for their hazards to man. Consisting of peptides, enzymes, chemicals and proteins, animal toxins can cause cellular injury with a broad spectrum of clinical manifestations. The kidney, as a highly vascularized organ, is vulnerable to toxin injury by either hemodynamic alterations which lead to renal ischemia or by direct kidney injury. Hemodynamic changes can be induced by toxin effects on ion channels, or by peptides and enzymes. Hemodynamic changes, inflammatory and vasoactive mediators and direct nephrotoxicity are tightly intregrated in causing renal injury. Several animal toxin components are involved in renal injury. Effects of toxins on renal tubular epithelial transport, a rather neglected area, and serum electrolyte changes in the victims are brought to attention. Toxicon 60 (2012) 943-953 RVR: renal vascular resistance. GFR: glomerular filtration rate. V: urine volume. FENa: fractional excretion of sodium. V. Sitprija, S. Sitprija / Toxicon 60 (2012) 943-953 944
Renal effects of Bunodosoma caissarum crude extract: Prostaglandin and endothelin involvement
Toxicon : official journal of the International Society on Toxinology, 2017
Sea anemones contain a variety of interesting biologically active compounds, including some potent toxins. PLA2 from Bunodosoma caissarum, a sea anemone endemic in the Brazilian southern coast, has shown renal alterations on isolated kidney. The aim of this study was to evaluate the renal and vascular effects of B. caissarum crude extract (BcE) on isolated perfused kidney and arteriolar mesenteric bed, as well the involvement of prostaglandins and endothelin. BcE did not show any effect on arteriolar mesenteric bed, but increased perfusion pressure, renal vascular resistance, urinary flow, glomerular filtration rate and decreased the percentage of sodium tubular transport on isolated perfused kidney. Indomethacin blocked the renal effects induced by BcE and tezosentan only partially blocked these effects. These results demonstrate the effects of BcE on kidney in situ, suggesting the involvement of prostaglandins and endothelin.
Maitotoxin induces biphasic interleukin-1β secretion and membrane blebbing in murine macrophages
Molecular …, 2004
Maitotoxin (MTX) is a potent shellfish toxin widely used as an in vitro tool for increasing intracellular Ca 2ϩ and studying Ca 2ϩdependent processes. MTX also induces membrane blebbing and nonselective pores similar to those elicited by the P2X7 receptor (P2X7R), an ATP-gated cation channel expressed in inflammatory leukocytes. We therefore tested whether MTX treatment of lipopolysaccharide-primed murine macrophages would mimic the ability of activated P2X7R to induce secretion of the proinflammatory cytokine interleukin-1 (IL-1). MTX at Յ0.6 nM predominantly induced processing and nonlytic release of mature IL-1 (mIL-1), whereas Ͼ0.6 nM of MTX induced cytolytic release of unprocessed proIL-1. MTX-dependent release of mIL-1 (but not cytolysis) was inhibited by the elimination of the trans-plasma membrane K ϩ gradient. MTX-induced cytokine release and cytolysis were both abrogated in the absence of extracellular Ca 2ϩ. On the other hand, extracellular glycine (5 mM) blocked MTX-induced cytolytic release of proIL-1 without affecting regulated secretion of mIL-1. Because MTX has profound effects on plasma membrane permeability, we used time-lapse videography to examine the morphologic response of individual macrophages to MTX. MTX treatment led to biphasic propidium dye uptake and dilated blebbing coincident with cytolysis. Glycine completely blocked the second, lytic phase of dye uptake and prevented MTX-induced bleb dilation. These results indicate that the inflammatory macrophage can assemble the necessary signaling components to initiate both regulated and lytic release of IL-1 in response to MTX. This suggests that the hyperactivation of proinflammatory cytokine secretion may be a significant component of the in vivo response to MTX during shellfish seafood poisoning. Maitotoxin (MTX), from the dinoflagellate Gambierdiscus toxicus, is among the most potent marine toxins known and plays a significant role in ciguatera seafood poisoning (Takahashi et al., 1982). MTX at doses as low as 0.2 g/kg can kill mice, and sublethal doses induce marked abnormalities in all tissues examined (Legrand et al., 1982; Terao et al., 1988, 1989). MTX has been extensively studied for its ability to stimulate increases in intracellular Ca 2ϩ via activation of Ca 2ϩ-permeable, nonselective cation channels (CaNSC) (Gusovsky and Daly, 1990; Dietl and Volkl, 1994; Bielfeld-Ackermann et al., 1998). Electrophysiological analysis of patch-clamped fibroblasts has revealed that Na ϩ , K ϩ , and Ca 2ϩ can all permeate the MTX-induced cation channels (Martinez-Francois et al., 2002). MTX has also been shown to mediate formation of a cytolytic/oncotic pore (COP) with properties identical to that facilitated by the activation of the P2X7 nucleotide receptor (P2X7R), as measured by vital dye uptake (Schilling et al., 1999a,b). In addition, MTX induces formation of dilated membrane blebs in endothelial cells similar to the blebs observed in macrophages upon ATP activation of the P2X7R (Estacion and Schilling, 2001; Verhoef et al., 2003). MTX-dependent pore formation and blebbing is biphasic: the initial phase is slow and allows the passage of molecules Ͻ800 Da, and the blebs are small (1-3 m), whereas the second phase represents cytolysis as measured by rapid dye uptake, LDH release, and massive expansion of the blebs (Estacion and Schilling, 2001, 2002). This
Toxicon, 1993
C. Díaz, J. M. Gutiérrez, B. Lomonte and J. Núñez. p-Bromophenacyl bromide modification of Bothrops asper myotoxin II, a lysine-49 phospholipase A2, affects its pharmacological activities. Toxicon31, 1202–1206, 1993.—Modification of Bothrops asper myotoxin II, a lysine-49 phospholipase A2 variant, was carried out with p-bromophenacyl bromide. Modified toxin did not show changes in its charge and immunological properties but two of its pharmacological activities were modified. Myotoxic activity, measured by histology and by increment of creatine kinase levels in plasma of mice, was significantly reduced after toxin modification. In addition, liposome disruption activity was also significantly lower with the modified toxin both at 3 and 24 hr of incubation with the alkylating reagent. Some of the implications of these results on the structure-function relationship of myotoxins are discussed.
Nephrotoxicity Of Polymyxin B: Experimental Study In Cells And Implications For Nursing Practice
Revista da Escola de Enfermagem da USP, 2014
The aim of the study was to characterize the cell damage mechanisms involved in the pathophysiology of cytotoxicity of polymyxin B in proximal tubular cells (LLC - PK1) and discuss about the nurses interventions to identify at risk patients and consider prevention or treatment of nephrotoxicity acute kidney injury. This is a quantitative experimental in vitro study, in which the cells were exposed to 375μM polymyxin B sulfate concentration. Cell viability was determined by exclusion of fluorescent dyes and morphological method with visualization of apoptotic bodies for fluorescence microscopy. Cells exposed to polymyxin B showed reduced viability, increased number of apoptotic cells and a higher concentration of the enzyme lactate dehydrogenase. The administration of polymyxin B in vitro showed the need for actions to minimize adverse effects such as nephrotoxicity.
Experimental and Toxicologic Pathology, 2006
As a first step to investigate the structure-function relationship of bothropstoxin-I (BthTX-I), a myotoxin from Bothrops jararacussu snake venom, our group previously cloned a recombinant toxin (rBthTX-I) in Escherichia coli. The aim of this work was to characterize the biological activities of this rBthTX-I (1.0 mM) in both phrenic-diaphragm and extensor digitorum longus preparations in vitro, by means of myographic and morphologic techniques. Native BthTX-I (1.0 mM) was used as a standard. The influence of heparin (27.5 mg/ml) upon the biological activities of both toxins was also investigated. rBthTX-I had similar effects to the native toxin inducing blockage of both directly and indirectly evoked contractions in phrenic-diaphragm preparations, and muscle damage characterized by edema, round fibers, and cell areas devoid of myofibrils. Interestingly the paralyzing activity of rBthTX-I was slightly more potent than the native toxin. Heparin prevented paralyzing and myotoxic effects of both the native and recombinant toxins. This work shows that rBthTX-I was expressed in a fully active form, and presents a biological profile similar to the native toxin.