AUTHOR=Vuong Nhi Thuc , Jackson Timothy N. W. , Wright Christine E. 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.754304

DOI=10.3389/fphar.2021.754304

ISSN=1663-9812

ABSTRACT=<p>Human envenoming by Australian brown snakes (<italic>Pseudonaja</italic> 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 <italic>Pseudonaja</italic> spp. venoms. In this study, we have examined the effects of venom from five brown snake species—<italic>P. affinis</italic>, <italic>aspidorhyncha, inframacula, nuchalis,</italic> and <italic>textilis</italic>—on cardiac inotropic and chronotropic responses, vascular tone, and sympathetic nerve-induced vascular contractions in rat isolated tissues. The role of phospholipases A<sub>2</sub> (PLA<sub>2</sub>s) in venom-induced effects was assessed with the sPLA<sub>2</sub> inhibitor varespladib. In rat isolated left and right atria, there were no physiologically relevant effects of <italic>Pseudonaja</italic> 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 <italic>P. aspidorhyncha</italic>, <italic>P. nuchalis,</italic> and <italic>P. textilis</italic> venoms. Electrically induced sympathetic nerve-mediated contractions of mesenteric arteries were significantly attenuated by only <italic>P. textilis</italic>, and <italic>P. affinis</italic> venoms (30 µg/ml) and these sympatholytic effects were inhibited by varespladib (1 µM). Based on their inhibition with the sPLA<sub>2</sub> inhibitor varespladib, we conclude that PLA<sub>2</sub> toxins in <italic>P. aspidorhyncha</italic>, <italic>P. nuchalis</italic>, and <italic>P. textilis</italic> venoms are involved in brown snake venom-induced vasorelaxation and the sympatholytic effects of <italic>P. affinis</italic>, and <italic>P. textilis</italic> 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.</p>