Sudden collapse following envenomation by some Australasian elapids is a poorly understood cause of mortality. We have previously shown that Oxyuranus scutellatus venom causes cardiovascular collapse in anaesthetized rats. Prior administration of a sub lethal dose of venom attenuated the response to subsequent administration of higher (lethal) venom doses. In this study, we investigated the possible mechanisms mediating this protective effect . Papuan taipan venom (5mug/kg, i.v.) produced a small transient hypotension in anaesthetized rats, while 10mug/kg resulted in a 73+/-30 decrease in arterial pressure. Venom (20mug/kg or 50mug/kg) produced cardiovascular collapse in all animals tested (n=12). Cardiovascular collapse by 50mug/kg venom was prevented by prior administration of priming doses of venom (5, 10 and 20mug/kg). Also, prior administration of indomethacin (30mg/kg, i.v.) or heparin (300units/kg, i.v.) prevented sudden collapse induced by venom (20mug/kg). Venom was without effect in isolated hearts indicating that a direct cardiac effect was unlikely to be responsible for sudden collapse . Venom induced endothelium-dependent and -independent relaxation in pre-contracted rat mesenteric artery rings which was inhibited by indomethacin, IbTx and Rp-8-CPT-cAMPs. This relaxation was markedly reduced (i.e. by 40+/-11 ) upon second exposure. Our results indicate that cardiovascular collapse induced by O. scutellatus venom may be due to a combination of release of dilator autacoids and to a direct relaxing effect on vascular smooth muscle involving the cAMP/protein kinase A cascade. Further work will involve identification of the venom component(s) responsible for this action and may provide insight into the management of envenomed patients.