Name: VITOR SAMPAIO MINASSA
Publication date: 30/01/2026
Examining board:
Name |
Role |
|---|---|
| AGATA LAGES GAVA | Examinador Interno |
| JULIANA BARBOSA COITINHO GONCALVES | Examinador Interno |
| NAZARE SOUZA BISSOLI | Presidente |
| SÍLVIA MARGARIDA VILARES SANTOS CONDE | Examinador Externo |
| TADEU UGGERE DE ANDRADE | Examinador Externo |
Summary: Previous studies from our group showed that adult spontaneously hypertensive rats (SHR)
exhibit higher mortality following acute intoxication with chlorpyrifos (CPF), a widely used
organophosphate (OP) insecticide. However, whether this increased susceptibility was
associated with hypertension or with the genetic trait itself remains unclear. Furthermore,
although previous studies in young normotensive rats showed profound cardiorespiratory
alterations after acute CPF intoxication, it was unknown whether these changes were
accompanied by early alterations in the oxidative profile. Thus, in the present study, we
evaluated the effects of CPF intoxication, using in vivo and in situ models, on cardiorespiratory
function and oxidative profile in young Wistar and SHR rats. In Study 1 (in vivo), DMSO (n =
20) or CPF (30 mg/kg; n = 20) was administered intraperitoneally to young normotensive and
prehypertensive rats. Signs of acute toxicity were assessed, and after 24 hours, blood and
brainstem samples were collected for the analysis of cholinesterase (ChE) activities and
oxidative/nitrosative stress markers. In Study 2 (in situ), DMSO (n = 24) or the active
metabolite of chlorpyrifos, chlorpyrifos-oxon (CPO; 15 mg/kg; n = 24), was added to the
perfusion solution of the working heart–brainstem preparation (WHBP), and its effects on tonic
and reflex cardiorespiratory regulation were evaluated. At the end of the protocol, cardiac and
brain tissues were collected for ChE and oxidative profile analyses. Cardiorespiratory
recordings included phrenic (PN), recurrent laryngeal (RLN), and thoracic sympathetic nerve
(tSNA) activities, electrocardiographic (data of heart rate, HR), and perfusion pressure (PP).
Chemoreflex, baroreflex, and Bezold–Jarisch reflex (BJR) responses were assessed using
potassium cyanide, phenylephrine, and phenylbiguanide, respectively. Data were analyzed
using appropriate statistical methods. In Study 1, young SHR rats exhibited more intense signs
of acute toxicity compared with Wistar rats. In addition, erythrocyte acetylcholinesterase and
butyrylcholinesterase (BuChE) activities were inhibited 24 hours after intoxication in both
strains, with SHR rats presenting lower basal BuChE levels. In the brainstem, catalase (CAT)
protein expression increased in normotensive rats, whereas NADPH oxidase 2 (NOX-2)
expression increased in prehypertensive rats. In Study 2, CPO reduced HR only in SHR rats,
induced hypopnea in both strains, and caused greater bradypnea in Wistar rats, which also
showed increased susceptibility to apnea events and greater impairment of upper airway
respiratory control. SHR rats exhibited a greater increase in sympathetic drive after CPO,
whereas Wistar rats showed sympatho-respiratory uncoupling. Regarding cardiovascular
reflexes, CPO inhibited the tachypneic chemoreflex response in Wistar rats and potentiated it
in SHR rats, with similar potentiation of bradycardia and reduction of chemoreflex-induced
sympathoexcitation in both strains. CPO attenuated baroreflex bradycardic gain in
normotensive rats and increased it in SHR rats. Sympathoinhibition and the bradypneic
response of the BJR were attenuated after CPO administration, with a greater reduction in
sympathoinhibition in SHR rats and prolongation of expiratory time in Wistar rats. ChE activity
in the brainstem and atrium of both Wistar and SHR rats was inhibited after CPO. In
normotensive rats, oxidative/nitrosative stress markers reached levels similar to those observed
in prehypertensive rats after acute CPO intoxication. Moreover, no changes were observed in
CAT and NOX-2 protein expression. Our findings demonstrate that normotensive and
prehypertensive animals exhibit distinct patterns of cardiorespiratory, autonomic, and oxidative
impairment after acute CPF intoxication. These results highlight that OP toxicity constitutes a
dynamic and multifactorial process, in which the individual’s physiological phenotype may
influence functional outcomes following exposure.
