Prothrombin activator-like toxin appears to mediate cardiovascular collapse following envenoming by Pseudonaja textilis

Chaisakul, Janeyuth; O’Leary, Margaret A.; Parkington, Helena C.; Smith, A. Ian; Hodgson, Wayne Clarence; Kuruppu, D M Sanjaya

doi:10.1016/j.toxicon.2015.05.001

Cited by 8 publications

(7 citation statements)

References 29 publications

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“…D. russelii and D. siamensis venom also caused coagulation. D. russelii and D. siamensis venoms are known to contain Factor X 33,34 while both E. ocellatus 35 and P. textilis venom contain prothrombin activators 21,36,37 . Therefore, pro-coagulant activity is unlikely to be directly related to the cardiovascular collapse induced by the venoms.…”

Section: Discussionmentioning

confidence: 99%

An in vivo examination of the differences between rapid cardiovascular collapse and prolonged hypotension induced by snake venom

Kakumanu

Kemp-Harper

Silva

et al. 2019

Sci Rep

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We investigated the cardiovascular effects of venoms from seven medically important species of snakes: Australian Eastern Brown snake (Pseudonaja textilis), Sri Lankan Russell’s viper (Daboia russelii), Javanese Russell’s viper (D. siamensis), Gaboon viper (Bitis gabonica), Uracoan rattlesnake (Crotalus vegrandis), Carpet viper (Echis ocellatus) and Puff adder (Bitis arietans), and identified two distinct patterns of effects: i.e. rapid cardiovascular collapse and prolonged hypotension. P. textilis (5 µg/kg, i.v.) and E. ocellatus (50 µg/kg, i.v.) venoms induced rapid (i.e. within 2 min) cardiovascular collapse in anaesthetised rats. P. textilis (20 mg/kg, i.m.) caused collapse within 10 min. D. russelii (100 µg/kg, i.v.) and D. siamensis (100 µg/kg, i.v.) venoms caused ‘prolonged hypotension’, characterised by a persistent decrease in blood pressure with recovery. D. russelii venom (50 mg/kg and 100 mg/kg, i.m.) also caused prolonged hypotension. A priming dose of P. textilis venom (2 µg/kg, i.v.) prevented collapse by E. ocellatus venom (50 µg/kg, i.v.), but had no significant effect on subsequent addition of D. russelii venom (1 mg/kg, i.v). Two priming doses (1 µg/kg, i.v.) of E. ocellatus venom prevented collapse by E. ocellatus venom (50 µg/kg, i.v.). B. gabonica, C. vegrandis and B. arietans (all at 200 µg/kg, i.v.) induced mild transient hypotension. Artificial respiration prevented D. russelii venom induced prolonged hypotension but not rapid cardiovascular collapse from E. ocellatus venom. D. russelii venom (0.001–1 μg/ml) caused concentration-dependent relaxation (EC50 = 82.2 ± 15.3 ng/ml, Rmax = 91 ± 1%) in pre-contracted mesenteric arteries. In contrast, E. ocellatus venom (1 µg/ml) only produced a maximum relaxant effect of 27 ± 14%, suggesting that rapid cardiovascular collapse is unlikely to be due to peripheral vasodilation. The prevention of rapid cardiovascular collapse, by ‘priming’ doses of venom, supports a role for depletable endogenous mediators in this phenomenon.

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Section: Discussionmentioning

confidence: 99%

An in vivo examination of the differences between rapid cardiovascular collapse and prolonged hypotension induced by snake venom

Kakumanu

Kemp-Harper

Silva

et al. 2019

Sci Rep

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“…Perhaps their most important contribution is to the investigation of the cardiovascular effects of these venoms, which have largely been neglected, despite cardiac arrest being the most common cause of death following snakebite envenoming in Australia ( Allen et al, 2012 ; Johnston et al, 2017 ). Few studies have concentrated on deconvoluting the causes of cardiovascular collapse following brown snake envenoming, with the notable exceptions of in vitro ( Chaisakul et al, 2015 ) and in vivo ( Chaisakul et al, 2013 ) studies of the effects of P. textilis venom. Interestingly, in the present study we found little ( P. inframacula, P. nuchalis and P. textilis ) to no ( P. affinis ) positive inotropic effects, and no effects on chronotropy, induced by the four brown snake venoms tested.…”

Section: Discussionmentioning

confidence: 99%

“…A fraction containing pseutarin C, the procoagulant toxin in P. textilis venom, was also found to induce a significant fall in mean arterial pressure without altering cardiac function ( Chaisakul et al, 2015 ). In vitro experiments from the same study demonstrated that pseutarin C did not possess any vasorelaxant activity, further reinforcing the role of sPLA 2 s in the induction of vasorelaxation in mesenteric arteries.…”

Section: Discussionmentioning

confidence: 99%

“…VICC is the most common severe symptom observed in cases of human envenoming by Pseudonaja spp., though hypotension and subsequent cardiovascular collapse are also potentially life-threatening ( Allen et al, 2012 ). Unlike VICC, which is caused by the prothrombinase toxin pseutarin C interfering with the coagulation cascade ( Rao and Kini, 2002 ), the mechanisms underlying the induction of hypotension and collapse following snakebite remain contentious, although pseutarin C has also been implicated in these pathologies ( Chaisakul et al, 2015 ). Hypotensive effects of snake venoms have also been attributed to the release of dilator autacoids ( Chaisakul et al, 2014 ), blockade of L-type voltage-gated Ca 2+ channels ( Yagami et al, 2013 ), presence of bradykinin-potentiating ( Ferreira et al, 1970 ; Ianzer et al, 2004 ; Camargo et al, 2012 ) and natriuretic ( Fry et al, 2005 ; St Pierre et al, 2005 ) peptides, or as a side effect of disseminated intravascular coagulation ( Tibballs et al, 1992 ).…”

Section: Introductionmentioning

confidence: 99%

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Role of Phospholipases A2 in Vascular Relaxation and Sympatholytic Effects of Five Australian Brown Snake, Pseudonaja spp., Venoms in Rat Isolated Tissues

2021

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Human envenoming by Australian brown snakes (Pseudonaja spp.) may result in potentially life-threatening hypotension and subsequent cardiovascular collapse. There have been relatively few studies of the cardiovascular and sympathetic effects of Pseudonaja spp. venoms. In this study, we have examined the effects of venom from five brown snake species—P. affinis, aspidorhyncha, inframacula, nuchalis, and textilis—on cardiac inotropic and chronotropic responses, vascular tone, and sympathetic nerve-induced vascular contractions in rat isolated tissues. The role of phospholipases A2 (PLA2s) in venom-induced effects was assessed with the sPLA2 inhibitor varespladib. In rat isolated left and right atria, there were no physiologically relevant effects of Pseudonaja venoms (0.1–30 µg/ml) on left atrial force of contraction (inotropy) or right atrial rate (chronotropy). In contrast, in isolated small mesenteric arteries precontracted with a thromboxane mimetic, each of the five brown snake venoms (at 30 µg/ml) caused marked vasorelaxation (−60 to –90% of contractile tone). Pretreatment with varespladib (1 µM) significantly inhibited the vasorelaxation caused by P. aspidorhyncha, P. nuchalis, and P. textilis venoms. Electrically induced sympathetic nerve-mediated contractions of mesenteric arteries were significantly attenuated by only P. textilis, and P. affinis venoms (30 µg/ml) and these sympatholytic effects were inhibited by varespladib (1 µM). Based on their inhibition with the sPLA2 inhibitor varespladib, we conclude that PLA2 toxins in P. aspidorhyncha, P. nuchalis, and P. textilis venoms are involved in brown snake venom-induced vasorelaxation and the sympatholytic effects of P. affinis, and P. textilis venoms. Our study supports the promising potential role of varespladib as an initial (pre-referral) and/or adjunct (in combination with antivenom) therapeutic agent for brown snake envenoming.

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“…The effect of venom on blood pressure and heart rate was determined using the previously described anesthetised rat preparation [ 34 ]. This procedure was approved by the Monash Animal Research Platform (MARP) Animal Ethics Committee, Monash University, Australia MARP/2014/97 (approved in December 2014).…”

Section: Methodsmentioning

confidence: 99%

The Cardiovascular and Neurotoxic Effects of the Venoms of Six Bony and Cartilaginous Fish Species

Han

Baumann

Casewell

et al. 2017

Toxins

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Fish venoms are often poorly studied, in part due to the difficulty in obtaining, extracting, and storing them. In this study, we characterize the cardiovascular and neurotoxic effects of the venoms from the following six species of fish: the cartilaginous stingrays Neotrygon kuhlii and Himantura toshi, and the bony fish Platycephalus fucus, Girella tricuspidata, Mugil cephalus, and Dentex tumifrons. All venoms (10–100 µg/kg, i.v.), except G. tricuspidata and P. fuscus, induced a biphasic response on mean arterial pressure (MAP) in the anesthetised rat. P. fucus venom exhibited a hypotensive response, while venom from G. tricuspidata displayed a single depressor response. All venoms induced cardiovascular collapse at 200 µg/kg, i.v. The in vitro neurotoxic effects of venom were examined using the chick biventer cervicis nerve-muscle (CBCNM) preparation. N. kuhlii, H. toshi, and P. fucus venoms caused concentration-dependent inhibition of indirect twitches in the CBCNM preparation. These three venoms also inhibited responses to exogenous acetylcholine (ACh) and carbachol (CCh), but not potassium chloride (KCl), indicating a post-synaptic mode of action. Venom from G. tricuspidata, M. cephalus, and D. tumifrons had no significant effect on indirect twitches or agonist responses in the CBCNM. Our results demonstrate that envenoming by these species of fish may result in moderate cardiovascular and/or neurotoxic effects. Future studies aimed at identifying the molecules responsible for these effects could uncover potentially novel lead compounds for future pharmaceuticals, in addition to generating new knowledge about the evolutionary relationships between venomous animals.

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Prothrombin activator-like toxin appears to mediate cardiovascular collapse following envenoming by Pseudonaja textilis

Cited by 8 publications

References 29 publications

An in vivo examination of the differences between rapid cardiovascular collapse and prolonged hypotension induced by snake venom

An in vivo examination of the differences between rapid cardiovascular collapse and prolonged hypotension induced by snake venom

Role of Phospholipases A2 in Vascular Relaxation and Sympatholytic Effects of Five Australian Brown Snake, Pseudonaja spp., Venoms in Rat Isolated Tissues

The Cardiovascular and Neurotoxic Effects of the Venoms of Six Bony and Cartilaginous Fish Species

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