Evidence for adrenergic and tachykinin activity in venom of the stonefish (Synanceja trachynis).
The aim of the present study was to investigate previously suggested adrenergic and tachykinin activity, as well as the cardiovascular effects, of venom from the stonefish (Synanceja trachynis). Stonefish venom (60-120 micrograms/kg, i.v.) produced dose-dependent bronchoconstriction in anaesthetised guinea-pigs. This response (100 micrograms/kg, i.v.) was significantly reduced by the neurokinin 1 (NK1) receptor antagonist CP-99,994 (1 mg/kg, i.v.). Contractile responses to venom (4 micrograms/ml) of guinea-pig isolated ileum (GPI) were significantly inhibited by a combination of the sodium channel blocking drug tetrodotoxin (1 microM) and the ganglion blocking drug mecamylamine (10 microM). However, subsequent administration of CP-99,994 (0.1 microM) did not produce further inhibition. Endogenous tachykinin depletion with capsaicin (1 microM) also significantly attenuated responses to venom (4 micrograms/ml) in GPI. Venom (4 micrograms/ml) produced increases in rate and force of contraction of rat spontaneously beating isolated atria which were significantly inhibited by the beta-adrenoceptor antagonist propranolol (5 microM) but not by noradrenergic transmitter depletion with reserpine (4.5 mg/kg, i.p.). In the presence of the alpha 1-adrenoceptor antagonist prazosin (0.3 microM), venom (6 micrograms/ml) significantly inhibited electrically evoked twitches of prostatic segments of rat vas deferens. The inhibitory effect of venom was significantly reduced by the alpha 2-adrenoceptor antagonist idazoxan (1 microM) but not by propranolol (5 microM) or the neurokinin 2 (NK2) receptor antagonist SR-48,968 (0.1 microM). Venom (60-120 micrograms/kg, i.v.) produced dose-dependent increases in mean arterial blood pressure in anaesthetised rats. This pressor response (60 micrograms/kg, i.v.) was significantly reduced by prazosin (10-50 micrograms/kg, i.v.) and the leukotriene receptor antagonist SB205312 (1 mg/kg, i.v.), significantly increased by propranolol (2 mg/kg, i.v.), but not significantly affected by the cyclo-oxygenase inhibitor indomethacin (10 mg/kg, i.v.) or the thromboxane A2/prostaglandin H2 (TP) receptor antagonist GR32191B (1 mg/kg, i.v.). Pressor responses to venom (100 micrograms/kg, i.v.) were also observed in anaesthetised rabbits. These results suggest that stonefish venom contains a component capable of stimulating the release of endogenous tachykinins with subsequent activity at NK1 receptors. The venom also appears to act via stimulation of sodium channels on sensory nerves. The venom also has activity at alpha 2-adrenoceptors and a direct action at beta-adrenoceptors. The effect of venom on blood pressure of anaesthetised rats appears to include a pressor component that is mediated, in part,by alpha-adrenoceptors and leukotriene receptors, and a depressor component that is mediated by beta-adrenoceptors. However, the pressor response does not involve action at TP receptors, or require the production of cyclo-oxygenase metabolites.
Hopkins
B J
BJ
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Hodgson
W C
WC
Sutherland
S K
SK
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005397:Fish Venoms / Q000008:administration & dosage / Q000633:toxicity*; D005730:Ganglionic Blockers / Q000008:administration & dosage / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D008464:Mecamylamine / Q000008:administration & dosage / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D015320:Tachykinins / Q000378:metabolism; D013779:Tetrodotoxin / Q000008:administration & dosage / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D016861:Cyclooxygenase Inhibitors; D005397:Fish Venoms; D005730:Ganglionic Blockers; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013779:Tetrodotoxin; D008464:Mecamylamine; D002211:Capsaicin