Abstract
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.
Highlights
Venom is a functional trait, used by venomous species of snake to subdue prey animals or deter potential predators (Jackson and Fry, 2016)
Inhibition with varespladib significantly attenuated the vasorelaxant effects of three of the venoms (P. nuchalis, textilis and aspidorhyncha), our results indicate that secretory phospholipase A2 (sPLA2) of these species may functionally antagonise vasocontraction in mammalian arteries
In vitro experiments from the same study demonstrated that pseutarin C did not possess any vasorelaxant activity, further reinforcing the role of sPLA2s in the induction of vasorelaxation in mesenteric arteries. These results indicate that multiple components–in this case, a prothrombin activator and sPLA2s–may contribute to the overall cardiovascular symptoms of snake envenomation
Summary
Venom is a functional trait, used by venomous species of snake to subdue prey animals or deter potential predators (Jackson and Fry, 2016). Venom achieves its goal of subjugation or deterrence by virtue of these toxins interfering with the normal functioning of various regulatory (homeostatic) networks. These networks operate in a state of “criticality” (marginal stability—Daniels et al, 2018) and their subversion may lead to a catastrophic failure of homeostasis, either locally (i.e., in the vicinity of the bite site) or systemically. The complexity of the venom cocktail, is in service of the overall function of the trait–venoms typically attack multiple regulatory networks simultaneously and may attack each network on multiple fronts This is highlighted by the complexity of clinical envenoming syndromes in human bite victims (Gutiérrez et al, 2017)
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