CPO
Carboxypeptidase O precursor (EC 3.4.17.-) (CPO)
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Chlorpyrifos and diazinon are two commonly used organophosphorus insecticides (OPs), and their primary mechanism of action involves the inhibition of acetylcholinesterase by their metabolites chlorpyrifos-oxon (CPO) and diazinon-oxon (DZO), respectively. The study objectives were to assess the in vitro age-related inhibition kinetics of neonatal rat brain cholinesterase (ChE) for CPO and DZO by estimating the bimolecular inhibitory rate constant (k(i)) values. Brain ChE inhibition and k(i) values following CPO and DZO incubation with neonatal Sprague-Dawley rat brain homogenates were determined at postnatal day (PND) 5, 12, and 17 and compared with the corresponding inhibition and k(i) values obtained in the adult rat. A modified Ellman method was utilized for measuring the ChE activity. CPO caused a greater ChE inhibition than DZO as evidenced from the estimated k(i) values of both compounds. Neonatal brain ChE inhibition kinetics exhibited a marked age-related sensitivity to CPO, with the order of ChE inhibition being PND 5 > PND 7 > PND 17 with k(i) values of 0.95, 0.50, and 0.22 nM(-1)hr(-1), respectively. In contrast, DZO ChE inhibition was not age related in the neonatal brain, and the estimated k(i) value at all PND ages was 0.02 nM(-1)hr(-1). These results demonstrated an age- and OP-selective inhibition of rat brain ChE, which may be critically important in understanding the potential sensitivity of juveniles to specific OPs exposures.
MeSH Terms
- Acetylcholinesterase
- Age Factors
- Aging
- Animals
- Animals, Newborn
- Brain
- Chlorpyrifos
- Cholinesterase Inhibitors
- Diazinon
- Dose-Response Relationship, Drug
- In Vitro Techniques
- Kinetics
- Models, Biological
- Rats
- Rats, Sprague-Dawley
- Time Factors
The purpose of this study was to indicate the normal range for peak cardiac power output (CPO(peak)) in healthy adults and to explore age- and sex-related variations of this parameter. Using the non-invasive exponential CO(2) rebreathing technique [J.G. Defares, J Appl Physiol13 (1958) 159], cardiac output was measured at an exercise intensity determined to coincide with > or =95% of peak oxygen consumption in 102 healthy adults (mean /- SD, age 43 /- 13 years, body mass 74 /- 13 kg). Peak cardiac power was then computed from measurements of peak cardiac output (Q(Tpeak)) and peak mean arterial pressure (MAP(peak)) using the equation described by Cooke et al. [Heart79 (1998) 289]. Peak oxygen consumption in the study population was 2.42 ( /-0.74) l min(-1) and subjects achieved 101 /- 7% of this value during the measurement of . was 17.3 ( /-4) l min(-1), and CPO(peak) was computed as 4.5 ( /-1.2) W. CPO(peak) ranged from 3.11 to 7.94 W in men and 2.53 to 5.57 W in women. Additionally, ageing appears to be associated with a significant loss of peak cardiac power in men that is not apparent in women. Although the sample size remains moderate, the CPO values attained were normally distributed and these values provide a useful indication of the normal range for CPO(peak) in healthy adults.
MeSH Terms
- Adult
- Aging
- Blood Pressure
- Body Weight
- Cardiac Output
- Electrocardiography
- Exercise
- Exercise Test
- Female
- Heart
- Humans
- Male
- Middle Aged
- Oxygen Consumption
- Sex Characteristics
Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides, which elicit toxicity following biotransformation to the potent acetylcholinesterase inhibitors, paraoxon (PO) and chlorpyrifos oxon (CPO). Both oxons have also been shown to interact directly with muscarinic receptors coupled to inhibition of adenylyl cyclase. Immature animals are more sensitive than adults to the acute toxicity of PS and CPF but little is known regarding possible age-related differences in interactions between these toxicants and muscarinic receptors. We compared the inhibition of forskolin-stimulated cAMP formation by PO and CPO (1 nM-1 mM) in vitro in brain slices from 7-, 21-, and 90-day-old rats to the effects of well-known muscarinic agonists, carbachol and oxotremorine (100 microM). Both agonists inhibited cAMP formation in tissues from all age groups and both were more effective in adult and juvenile (20-26% inhibition) than in neonatal (12-13% inhibition) tissues. Atropine (10 microM) completely blocked agonist-induced inhibition in all cases. PO maximally inhibited (37-46%) cAMP formation similarly in tissues from all age groups, but atropine blocked those effects only partially and only in tissues from 7-day-old rats. CPO similarly inhibited cAMP formation across age groups (27-38%), but ATR was partially effective in tissues from all three age groups. Both oxons were markedly more potent in tissues from younger animals. We conclude that PO and CPO can directly inhibit cAMP formation through muscarinic receptor-dependent and independent mechanisms and that the developing nervous system may be more sensitive to these noncholinesterase actions.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Chlorpyrifos
- Colforsin
- Cyclic AMP
- Female
- In Vitro Techniques
- Male
- Paraoxon
- Pregnancy
- Rats
- Rats, Sprague-Dawley