Abstract

Russell’s viper (Daboia russelii) venom causes a range of clinical effects in humans. Hypotension is an uncommon but severe complication of Russell’s viper envenoming. The mechanism(s) responsible for this effect are unclear. In this study, we examined the cardiovascular effects of Sri Lankan D. russelii venom in anaesthetised rats and in isolated mesenteric arteries. D. russelii venom (100 μg/kg, i.v.) caused a 45 ± 8% decrease in blood pressure within 10 min of administration in anaesthetised (100 μg/kg ketamine/xylazine 10:1 ratio, i.p.) rats. Venom (1 ng/mL–1 μg/mL) caused concentration-dependent relaxation (EC50 = 145.4 ± 63.6 ng/mL, Rmax = 92 ± 2%) in U46619 pre-contracted rat small mesenteric arteries mounted in a myograph. Vasorelaxant potency of venom was unchanged in the presence of the nitric oxide synthase inhibitor, L-NAME (100 µM), or removal of the endothelium. In the presence of high K+ (30 mM), the vasorelaxant response to venom was abolished. Similarly, blocking voltage-dependent (Kv: 4-aminopryidine; 1000 µM) and Ca2+-activated (KCa: tetraethylammonium (TEA; 1000 µM); SKCa: apamin (0.1 µM); IKCa: TRAM-34 (1 µM); BKCa; iberiotoxin (0.1 µM)) K+ channels markedly attenuated venom-induced relaxation. Responses were unchanged in the presence of the ATP-sensitive K+ channel blocker glibenclamide (10 µM), or H1 receptor antagonist, mepyramine (0.1 µM). Venom-induced vasorelaxtion was also markedly decreased in the presence of the transient receptor potential cation channel subfamily V member 4 (TRPV4) antagonist, RN-1734 (10 µM). In conclusion, D. russelii-venom-induced hypotension in rodents may be due to activation of Kv and KCa channels, leading to vasorelaxation predominantly via an endothelium-independent mechanism. Further investigation is required to identify the toxin(s) responsible for this effect.

Highlights

  • Snake bite is a globally important health issue [1,2]

  • We examined in more detail the hypotensive effects of snake venom and pharmacologically characterized the vasodilatory effects of Sri Lankan Russell’s viper (D. russelii) venom

  • We investigated the prolonged hypotensive effect of D. russelii venom both in vivo and in vitro in rodents

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Summary

Introduction

Snake bite is a globally important health issue [1,2]. Snake venom has three purposes: a defensive mechanism against predators, an aid to capture prey, and/or a tool to deter/challenge competitors [3].Toxins 2019, 11, 197; doi:10.3390/toxins11040197 www.mdpi.com/journal/toxinsVenom is a complex cocktail of toxins and enzymes that have a wide range of biological activities targeting major physiological pathways and organs [4]. Ninety to ninety-five percent of snake venom consists of proteins and peptides, many of which are toxic to humans [5]. These components often possess enzymatic activity and ligand binding abilities that, in combination and/or separately, result in the clinical envenoming symptoms in humans and other organisms [3,6]. While most components of snake venom, such as neurotoxins [7,8,9], myotoxins [10,11,12], pro-coagulants, and anticoagulant, haemolytic and local tissue necrotic factors [13,14,15] have been studied in detail, toxins targeting the cardiovascular system are less well understood

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