Mestrado em Ciências Farmacêuticas
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Navegando Mestrado em Ciências Farmacêuticas por Assunto "AChE"
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- ItemAvaliação in vitro e in vivo dos efeitos da intoxicação aguda com o inseticida organofosforado, clorpirifós, e da eficácia do tratamento farmacológico empregado na intoxicação sobre a modulação cardiorrespiratória tônica e reflexa(Universidade Federal do Espírito Santo, 2017-08-08) Felippe, Igor Simões Assunção; Harres, Vanessa Beijamini; Sampaio, Karla Nívea; Paton, Julian Francis Richmond; Silva, Valdo José Dias daIn Brazil, the usage of agrochemicals has grown significantly in recent years, making the country one of the world leaders in consumption. Organophosphates (OFs) have been associated with cardiovascular diseases and intoxication induced by these compounds has a high mortality rate. Previous studies from our laboratory have shown that acute exposure to an OP compound, chlorpyrifos (CPF), in rats impairs the cardiovascular responses of the baroreflex and chemoreflex. However, it was not possible to address in this study the effects induced by the exposure to this compound on the respiratory function, despite the important modulation that the cardiovascular reflexes, particularly the chemoreflex, exert on respiratory parameters. Considering that the cardiorespiratory function plays a major role in the survival of intoxicated individuals, it seems of pivotal importance the development of detailed studies, using in vitro and in vivo approaches, to investigate the effects of CPF exposure on the tonic and reflex cardiorespiratory modulation. Additionally, the present controversy surrounding the standard treatment adopted in OP intoxication and the absence of studies focusing on antidote treatment and restoration of OPinduced cardiovascular damage, further reinforces the importance of studies in the field. In the present study, in vitro and in vivo protocols were used to evaluate the effects of acute intoxication with CPF on tonic and reflex cardiorespiratory activity and to evaluate whether the pharmacological treatment with the antidotes atropine (ATR) and pralidoxime (2-PAM) was capable of reversing the damage on the chemoreflex function previously observed. Two groups (CPF and control) were submitted to the in vitro protocol involving the working heart-brain stem preparation (WHBP). In this preparation, basal activities of the phrenic (PNA), recurrent laryngeal (RLN) and thoracic sympathetic (tSNA) nerves, in addition to heart rate and perfusion pressure were recorded. Associated with these recordings, in situ activation of the chemoreflex and baroreflex was also performed, followed by procedures of bilateral vagotomy and blockade with atenolol and hexamethonium. In the in vivo model, animals were grouped according to different combinations of treatments with CPF, ATR and 2-PAM. Twenty-four hours after treatment, activation and records of the chemoreflex function were performed. The presence of intoxication signs, ataxia, tremor and sialorrhea, was evaluated along three hours after receiving injections of CPF or saline; and after the treatment with ATR and/or 2-PAM. For both in vitro and in vivo models, the activities of plasma butyrylcholinesterase (BuChE) and cerebral acetylcholinesterase (AChE) in the brainstem were quantified. Additionally, in the in vivo protocol, punchs of brain stem sections containing the nucleus ambiguous, rostral ventrolateral medulla (RVLM), the pre-Bötzinger complex (preBöTC) and the nucleus of the solitary tract (NTS) were collected for individualized quantification of cerebral AChE activity. Our data showed that acute exposure to CPF led to impairment of the chemoreflex responses either in the in vitro or in vivo models. Additionally in the in vitro study, an impairment of baroreflex function was also observed, indicated by the reduced reflex-induced inhibition of the sympathetic activity in poisoned animals. Concerning the respiratory function in the WHBP, a reduction in the amplitude of PNA and of the RLN post-inspiratory discharge was also observed in intoxicated animals when compared to the control group. CPF poisoned animals also presented a higher tachycardia following vagal section when compared to control group. Blockade with hexamethonium induced an increase in perfusion pressure of CPF intoxicated animals. In the in vivo model, treatment with the antidotes, ATR and 2-PAM, induced differentiated effects on chemoreflex responses in intoxicated animals. Treatment with 2-PAM restored the impairment of the chemoreflex-induced hypertension observed in CPF intoxicated animals. On the other hand, treatment with atropine attenuated the impairment of the bradycardic response of the chemoreflex observed in poisoned animals. Both treatments seemed to exert a protective effect on the tachypneic response of the chemoreflex. All CPF intoxicated animals showed a marked inhibition of the plasma butyrylcholinesterase and acetylcholinesterase activities either in the brainstem or in the isolated punchs. CPF animals also exhibited signs of acute intoxication, which were attenuated or abolished by the antidote treatments. Our data indicate that CPF intoxication induces an impairment of the chemo and baroreflex responses and that the antidote treatment seems to partially restore the damage observed in the cardiorespiratory function.
- ItemEfeitos da exposição crônica ao organofosforado clorpirifós sobre a função cardiorespiratória(Universidade Federal do Espírito Santo, 2018-08-31) Batista, Thatiany Jardim; Sampaio, Karla Nívea; Silva, Valdo José Dias da; Bissoli, Nazare Souza; Santos, Leonardo dosPrevious studies of our group showed that acute exposure to high doses of organophosphorus compound (OP), chlorpyrifos (CPF), impaired cardiorespiratory reflexes in rats. In addition, some studies indicate that prolonged exposure to OP compounds impairs cardiovascular function, producing cardiac hypertrophy and altering the mechanical properties of the aorta. If prolonged CPF exposure also affects tonic and reflex cardiorespiratory function remained to be explored. Wistar rats were injected with CPF intraperitoneally (i.p.) for 4 weeks (three times a week) or 12 weeks (once a week) at the following doses: 7 mg/kg (CPF 7; 4 weeks, n=14; 12 weeks, n=14) and 10 mg/kg (CPF 10; 4 weeks, n=9; 12 weeks, n=12). The control group received saline (NaCl, 0.9%) for the same period (SAL, 4 weeks, n=9, 12 weeks, n=13). At the end of the treatment, the femoral artery and vein were catheterized under anesthesia with tribromoethanol (250 mg/kg, i.p.), to allow pressure recordings and drugs administration, respectively. After 24 hours of recovery from surgery, pulsatile arterial pressure (PAP) was recorded, from which diastolic blood pressure (DBP), systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were derived. Respiratory rate (fR), tidal volume (VT) and minute volume (VE) were obtained by whole-body plethysmography. The chemorreflex responses were evaluated by intravenous injections of KCN (10, 20, 40 and 80 μg) while the spontaneous baroreflex was evaluated from the PAS and pulse interval (PI) recordings using the sequence method. These recordings were also used to evaluate heart rate variability (HRV) in time and frequency domain (spectral analysis). Finally, the activities of plasma acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were also quantified. The results showed that the enzymatic activity of the CPF intoxicated animals was significantly lower than the control. In addition, CPF 10 group treated for 4 weeks presented a lower weight gain. No differences were observed in the baseline values of DBP, SBP, MAP, HR and fR, as well as in the HRV time-domain indices, either after 4 or 12 weeks of treatment. In the spectral analysis an increase was only observed for the very low frequency band (VLF). Animals treated with CPF presented an impairment of the baroreflex gain, for ascending ramps, and of the baroreflex effectiveness index (BEI). The chemoreflex bradycardic response was significantly reduced in the CPF treated rats for both treatment periods when compared to the control groups. No difference among groups was observed for the chemoreflex pressor response nor the tachypneic response for the two treatment periods. On the other hand, CPF 10 group had an increase in VT, for both treatment periods, and an increase in the VE, only after 1 month treatment. Similar to what was previously demonstrated after acute exposure to CPF, low doses chronic exposure also impairs cardiorespiratory function in rats. These results may have important clinical implications for workers, such as farmers, who are frequently exposed to these compounds.