Antidotal efficacy of pyridinium oximes and cholineacetyltransferase inhibitors against organophosphorus intoxication in rodents.

In an attempt to develop effective antidote against organophosphorus intoxication, some new imidazole-pyridinium mono-oximes, long chain pyridinium mono-oximes and cholineacetyltransferase inhibitors were synthesised. These compounds were evaluated for their in vivo therapeutic protection and neuromuscular function studies in rodents. The results indicate that SPK-series oximes may be useful against sarin poisoning without any beneficial effect against VX (O-Ethyl S-2-NN-diisopropylaminoethyl methylphosphonofluoridate) intoxication. The cholineacetyltransferase (ChAT) inhibitors may not be of any help against any of the OP compounds studied in this study.

Dose response of sulphur mustard: behavioral and toxic signs in rats.

The present study elucidates the behavioral and toxic signs in rats following dermal application of sulphur mustard (SM). Graded doses of SM (0.10, 0.25, 0.50, 0.75 and 1.0 LD50) were topically applied to male Wister rats. The body weight as well as behavioral/toxic signs and symptoms were recorded at 1, 2, 3, and 4th day after application of SM. Sulphur mustard consistently decreased body weights of rats in a dose and time dependent manner with maximum decrease on 3rd day post treatment. Sedation and diarrhea were significant in response to doses of SM intoxication in rats. It is concluded that the body weight, sedation and diarrhea may be used as a reliable parameter in evaluating SM intoxication. It is also suggested that hydration and hypertonic saline must be used as a rescue agent within 1-3 days after exposure to SM.

Calcium modulatory properties of O,O-diphenyl O-N-cyclooctyl phosphoramidate [corrected] isolated from Ptychodiscus brevis in rat atria and smooth muscle.

Calcium modulatory activity of a marine toxin has been studied employing in vitro preparations. The toxin induced contracture in rat diaphragm was not modified by denervation, d-tubocurarine and tetrodotoxin (TTX). In contrast, varying concentrations of calcium, EGTA and ryanodine inhibited the contracture significantly. The toxin produced a series of repeating contractions in vas deferens. Experiments with TTX, adrenoceptor blockers and other agents exclude a release of neuromediators or direct stimulation of post synaptic receptors to account for the rhythmic effect in vas deferens. The dependence of rhythmicity on external Ca2+ concentration and inhibiting effect of Mn2+, ryanodine and nifedipine indicate a direct activation of voltage-sensitive calcium channel. The toxin also evoked a similar pattern of response in paced atria mediated through Ca2+ influx.

Mechanism of cardiotoxicity induced by a marine toxin isolated from Ptychodiscus brevis.

An organophosphate toxin of marine origin isolated from red tide dinoflagellate P. brevis produced a dose-dependent dual effect on rat atria, i.e. positive inotropic effect at low concentrations (2.8 x 10(-8) to 8.4 x 10(-7) M) and negative inotropic and chronotropic responses at an elevated dose (4.8 x 10(-6) to 7.2 x 10(-4) M). The negative chronotropic and inotropic responses of the toxin were potentiated with physostigmine and ouabain whereas antagonized by atropine and hemicholinium-3 pretreatments and those effects remained unaltered by isoproterenol, phenylephrine and ouabain pretreatments. The results indicate that the toxin induced negative inotropic and chronotropic effects are mediated through release of acetylcholine from the nerve endings and consequent activation of muscarinic receptor. In atria exposed to guanethidine, bretylium, propranolol and tyramine tachyphylaxis, the positive inotropic response of the toxin was not modified. However, the response was antagonized by EGTA, nifedipine, ryanodine, calcium-free ringer and potentiated with caffeine and amiloride pretreatments. The results suggest that the positive inotropic effect of the toxin is mediated through Ca2+ influx and impairment of Na+/Ca2+ exchange process.

Effect of foot-electroshock stress on cholinergic activity, tissue glycogen and blood sugar in albino rats.

The immediate or 24 hr delayed effects of 1-day (1-DS) or (7-DS) foot-electroshock stress in albino rats were studied on cardiac acetylcholine (ACh), blood and cardiac cholinesterase (ChE) activities, cardiac, hepatic and muscle glycogen contents and blood sugar concentrations. The effects of physostigmine (PHY), atropine, 6-hydroxydopamine (6-HD), vagotomy and adrenalectomy on 1-DS induced changes were also studied. 1-DS produced an increase in cardiac ACh content which lasted for 24 hr but repeated stress showed phenomenon of adaptation. There seems to be activation of autonomic cholinergic system in stress. 1-DS and 7-DS produced a short-lived inhibition of blood ChE activity and 7-DS also of cardiac ChE activity. Inhibition of ChE activity was probably related to release of adrenaline from adrenal medulla. 1-DS produced hepatic and muscle glycogenolysis with slight hypoglycaemia but without any effect on cardiac glycogen. Following repeated stress there was a phenomenon of adaptation. The hepatic and muscle glycogenolysis produced by stress is due to the release of adrenaline from adrenal medulla. Normally functioning cardiac cholinergic system seems to have a protective effect on heart against stress, in the absence of which cardiac glycogenolysis is induced by stress.