Patterns of cardio-respiratory motor outputs during acute and subacute exposure to chlorpyrifos in an ex-vivo in situ preparation in rats.

While a considerable body of literature has characterized the clinical features induced by organophosphate pesticides, the field lacks scrutiny into cardio-respiratory changes in different phases of poisoning. Herein, we evaluated the impact of chlorpyrifos (CPF) and its active metabolite chlorpyrifos-oxon (CPO) on the cardiorespiratory system during acute and subacute phases of poisoning using an in situ experimental rodent model. CPF (30 mg/kg) was injected intraperitoneally to rats beforehand (24 h) whereas CPO (15 mg/kg) was added into the perfusate reservoir to evaluate the effects on the motor outputs throughout the three phases of the respiratory cycle: inspiration, post-inspiration and late expiration. Phrenic, recurrent laryngeal (RLN) and thoracic sympathetic nerve activity (tSNA) were recorded. Heart rate was derived from the electrocardiogram (ECG) and the baro- and chemo-reflexes tested. CPF and CPO led to a time-dependent change in cardiorespiratory motor outputs. In the acute phase, the CPO induced bradypnea, transiently reduced the inspiratory time (TI), and increased the amplitude of phrenic. Post-inspiratory (PI) discharge recorded from the RLN was progressively reduced while tSNA was increased. CPO significantly depressed the chemoreflex but had no effect on baroreflex. During subacute phase, CPF prolongated TI with no effect on respiratory rate. Both the RLN PI discharge, the chemoreflex and the baroreflex sympathetic gain were reduced. In addition, both CPF and CPO shifted the cardiac sympatho-vagal balance towards sympathetic dominance. Our data show that different phases of poisoning are associated with specific changes in the cardio-respiratory system and might therefore demand distinct approaches by health care providers.

Involvement of the purinergic system in central cardiovascular modulation at the level of the nucleus ambiguus of anaesthetized rats.

Anatomical studies have demonstrated the existence of purinergic P2 receptors in the nucleus ambiguus (NA), a site containing cardiac vagal motoneurons. However, very little is known about the functional role of these receptors in central cardiac vagal regulation. The aims of our study were to evaluate the following: (1) the blood pressure and heart rate responses following purinoceptor activation within the NA; (2) the role of purinoceptors and excitatory amino acid (EAA) receptors in mediating the cardiovascular responses evoked by ATP and L-glutamate stimulation of NA; and (3) the role of NA purinoceptors in mediating the cardiovascular responses of the Bezold-Jarisch reflex. In anaesthetized rats, microinjection of L-glutamate (5.0 nmol/50 nl) into the NA induced a marked and immediate onset bradycardia with minimal change in arterial pressure. Microinjection of ATP into the NA induced a dose-dependent (0.31-6.0 nmol/50 nl) bradycardia and pressor responses. It is noteworthy that the bradycardia occurred either before or simultaneously with a pressor response (when present), indicating that it was not a baroreceptor reflex mediated response due to the rise in arterial pressure. The pressor response was prevented by α(1)-adrenergic blockade with prazosin, whereas muscarinic blockade with methyl-atropine abolished the evoked bradycardia. Ipsilateral microinjection of PPADS (a P2 receptor antagonist; 500 pmol/100 nl) into the NA significantly attenuated the ATP-induced bradycardia but spared the pressor response. In contrast, PPADS in the NA had no effect on the L-glutamate-evoked bradycardic response. Ipsilateral injection of kynurenic acid (a non-selective EAA receptor antagonist; 10 nmol/50 nl) into the NA totally blocked the bradycardia induced by l-glutamate and partly attenuated the ATP induced bradycardia. Finally, both the depressor and the bradycardic responses of the Bezold-Jarisch reflex were attenuated significantly (P < 0.01 and P < 0.05, respectively) following bilateral microinjection of PPADS into the NA. These results identify ATP and purinergic P2 receptors within the ventrolateral medulla as excitatory to cardiovagal neurons. Additionally, our data show that P2 receptors within the ventrolateral medulla are integral to the cardiovascular responses of the Bezold-Jarisch reflex.