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Russell&#8217;s viper (<i>Daboia russelii</i>) venom causes a range of clinical effects in humans. Hypotension is an uncommon but severe complication of Russell&#8217;s viper envenoming. The mechanism(s) responsible for this effect are unclear. In this study, we examined the cardiovascular effects of Sri Lankan <i>D. russelii</i> venom in anaesthetised rats and in isolated mesenteric arteries. <i>D. russelii</i> venom (100 &#956;g/kg, i.v.) caused a 45 &#177; 8% decrease in blood pressure within 10 min of administration in anaesthetised (100 &#956;g/kg ketamine/xylazine 10:1 ratio, i.p.) rats. Venom (1 ng/mL&#8211;1 &#956;g/mL) caused concentration-dependent relaxation (EC₅₀ = 145.4 &#177; 63.6 ng/mL, R_max = 92 &#177; 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 &#181;M), or removal of the endothelium. In the presence of high K⁺ (30 mM), the vasorelaxant response to venom was abolished. Similarly, blocking voltage-dependent (K_v: 4-aminopryidine; 1000 &#181;M) and Ca²⁺-activated (K_Ca: tetraethylammonium (TEA; 1000 &#181;M); SK_Ca: apamin (0.1 &#181;M); IK_Ca: TRAM-34 (1 &#181;M); BK_Ca; iberiotoxin (0.1 &#181;M)) K⁺ channels markedly attenuated venom-induced relaxation. Responses were unchanged in the presence of the ATP-sensitive K⁺ channel blocker glibenclamide (10 &#181;M), or H1 receptor antagonist, mepyramine (0.1 &#181;M). 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 &#181;M). In conclusion, <i>D. russelii</i>-venom-induced hypotension in rodents may be due to activation of K_v and K_Ca channels, leading to vasorelaxation predominantly via an endothelium-independent mechanism. Further investigation is required to identify the toxin(s) responsible for this effect.