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Non-cholinergic mechanisms underlying the acute lethal effects of P = S type organophosphorus insecticides in rats
1Mitsukaido Laboratories, Institute of Environmental Toxicology, Ibaraki, Japan.
Abstract:
Intravenous administration of the lethal dose of diazinon or fenthion, P = S type organophosphates, to urethan anesthetized rats induced bradycardia and transient apnea followed by a decline of blood pressure, and death. We investigated the mechanisms of the lethal action of these organophosphates in rats through measurements of blood pressure, heart rate, and respiratory pattern. We compared their cardiorespiratory effects in the five different conditions under anesthesia; 1) normal (without treatment), 2) artificially ventilated, 3) vagotomized, 4) atropinized, 5) pithed, vagotomized and atropinized. It was found that the administration of 200 mg/kg of fenthion and 100 mg/kg of diazinon, caused sudden bradycardia, transient apnea and gradual decline of blood pressure in the anesthetized normal rat, and the rat died. The rats in other conditions also died except the artificially ventilated rats, in which 400 mg/kg of fenthion was administered to cause hypotension and subsequent death. Hypotension was observed consistently even after the cardiac effect such as bradycardia was eliminated by atropine treatment. In the pithed rats which were further vagotomized and atropinized, these organophosphates also caused hypotension. These results may indicate that hypotension is the main cause of death which resulted from intravenous administration of the P = S types. Hypotension may be caused by peripheral cardiovascular effect of the P = S types, which is unrelated to cholinergic mechanisms.
Insights
Organophosphates like diazinon and fenthion cause death in rats by inducing bradycardia and hypotension. Hypotension appears to be the primary lethal mechanism, potentially linked to peripheral cardiovascular effects unrelated to cholinergic pathways.
Area of Science:
- Toxicology
- Cardiovascular Physiology
- Neuropharmacology
Background:
- Organophosphates (OPs) are widely used pesticides.
- P=S type OPs, such as diazinon and fenthion, are known for their toxicity.
- The precise mechanisms underlying their lethal effects, particularly cardiorespiratory dysfunction, require further elucidation.
Purpose of the Study:
- To investigate the cardiorespiratory mechanisms responsible for the lethal effects of diazinon and fenthion in rats.
- To determine whether hypotension or cardiac dysfunction is the primary cause of death following P=S type OP administration.
- To explore the role of cholinergic pathways in the observed cardiorespiratory effects.
Main Methods:
- Intravenous administration of lethal doses of diazinon and fenthion to urethane-anesthetized rats.
- Monitoring of blood pressure, heart rate, and respiratory patterns under various physiological conditions: normal, artificial ventilation, vagotomy, atropinization, and pithing.
- Comparative analysis of cardiorespiratory parameters and survival rates across different experimental groups.
Main Results:
- Diazinon and fenthion induced bradycardia, transient apnea, and a decline in blood pressure, leading to death in normal anesthetized rats.
- Hypotension was a consistent finding, persisting even after eliminating bradycardia with atropine.
- Pithhed, vagotomized, and atropinized rats also developed hypotension after OP administration, suggesting a peripheral cardiovascular effect.
- Artificially ventilated rats survived higher doses, but eventually succumbed to hypotension.
Conclusions:
- Hypotension is identified as the principal cause of death following intravenous administration of P=S type organophosphates (diazinon and fenthion) in rats.
- The observed hypotension appears to result from peripheral cardiovascular effects of these OPs.
- These effects are likely independent of central cholinergic mechanisms, indicating a non-cholinergic pathway in OP-induced lethality.