Newton001 Temporal profiling of cardiac autonomic changes following organophosphorus poisoning

Organophosphorus (OP) compounds are the most widely used insecticides in many countries including Brazil, Egypt, India and USA. According to the latest reports, OP are responsible for the majority of poisonings, deaths and suicides attempts in Brazil. The latest Brazilian National System reporting on Toxico-Pharmacological Poisoning (SINITOX, 2009) indicated that the number of people poisoned by pesticides between 2001 and 2007 increased in 347% in a single State alone (Espirito Santo) compared to an equivalent period in previous years. This Brazilian State now has the second highest number of OP poisoning cases (5,512) within the south-east region of Brazil. OP compounds act by interfering with nerve cell communication by blocking an enzyme (acetyl cholinesterase). This leads to disruption of both the central and peripheral nervous systems. The effects on the heart, circulation and breathing by OP are likely to contribute in a major way to their lethality. Although clinical signs of OP poisoning are well described, our understanding of the precise mechanisms and their time course is highly limited and it this we wish to study. This is important because it would reveal the most effective therapeutic treatment relative to the time after OP poisoning. Following OP exposure, clinical symptoms are classified into 3 stages: (i) acute crisis syndrome within the first few hours; (ii) an intermediate stage between 12-96 hours and (iii) a delayed nervous system dysfunction stage. We wish to understand how the heart, circulation and respiratory symptoms occur within the first two stages of OP poisoning, and whether these are worsened in conditions of pre-existing heart failure. We propose that the deleterious effects of OP poisoning immediately affect the peripheral nervous system controlling the heart, circulation and respiration, worsen with time and are exaggerated if the subject has pre-existing heart failure.

Among the pesticides available for use, organophosphorus (OP) compounds are the most widely used insecticides in: Brazil, Egypt, India and USA. OP compounds are responsible for the majority of poisonings in Brazil. The latest Brazilian survey (SINITOX, 2009) indicated that OP poisoning increased between 2001 and 2007 by 347% compared to an equivalent previous period in a single state alone. OP compounds block acetyl cholinesterases in both central and peripheral cholinergic synapses. A major health threat is the effects on the autonomic nervous system including disruption to the cardiac function, vascular and bronchial tone. Myocardial infarction and sudden cardiac death, mediated by severe autonomic dysfunction, are common. Although clinical signs are well described, our mechanistic understanding is limited and this compromises effective therapeutic intervention. We found that exposure to OP impaired physiological reflexes that protect against myocardial ischaemia.
Hypothesis: OP exposure increases the hearts' vulnerability to cardiac arrest, lethal arrhythmias and is worsened with time after exposure, and exaggerated if pre-existing heart failure exists.
Plan: We will establish an in situ rat model in the Brazilian lab. Sub-lethal dose-responses of the effects of OP (10-50 mg/kg) on cardiac sympathetic, cardiac vagal, phrenic and recurrent (or superior) laryngeal nerve activities will be recorded acutely. We will also test the effects of OP on cardioprotective reflexes including the peripheral chemo- and laryngeal reflexes. Studies will be repeated in animals pre-treated with OP 24 hours beforehand. We will design a cocktail of medication to correct the autonomic nervous system imbalance.
These studies will guide the use of novel interventional treatment targeting cardiac sympathetic transmission, and/or modulating sino atrial nodal cell excitability (IIvabradine), which may in combination with an alpha-adrenoceptor blocker, enhance vagal tone to the heart.

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