An examination of bedtime media and excessive screen time by Canadian preschoolers during the COVID-19 pandemic.

BACKGROUND: Risky media use in terms of accumulating too much time in front of screens and usage before bedtime in early childhood is linked to developmental delays, reduced sleep quality, and unhealthy media use in later childhood and adulthood. For this reason, we examine patterns of media use in pre-school children and the extent to which child and family characteristics contribute to media use during the COVID-19 pandemic. METHODS: A cross-sectional study of digital media use by Canadian preschool-aged children (mean age = 3.45, N = 316) was conducted at the start of the COVID-19 pandemic between April and August of 2020. Parents completed a questionnaire and 24-h recall diary in the context of an ongoing study of child digital media use. From these responses we estimated hours of average daily screen time, screen time in the past 24 h, average daily mobile device use, and media use before bedtime. Parents also answered questions about their child (i.e., age, sex, temperament), family characteristics (parental mediation style, parental screen time, education, income), and contextual features of the pandemic (ex., remote work, shared childcare). Daycare closures were directly assessed using a government website. RESULTS: Our results indicate that 64% of preschoolers used more than 2 h of digital media hours/day on average during the pandemic. A majority (56%) of children were also exposed to media within the hour before bedtime. Logistic and multinomial regressions revealed that child age and temperament, restrictive parental mediation, as well as parent digital media use, education, satisfaction with the division of childcare, remote work, and number of siblings and family income were all correlates of risky digital media use by preschoolers. CONCLUSIONS: Our results suggest widespread risky media use by preschoolers during the pandemic. Parenting practices that include using more restrictive mediation strategies may foster benefits in regulating young children's screen time.

Post-discharge follow-up using text messaging within an enhanced recovery program after colorectal surgery.

INTRODUCTION: Enhanced recovery after surgery programs (ERP) often lead to early discharge and return to home. In terms of risk management, extended surveillance is recommended. Surveillance using text messages (TM) has been validated for minor operations in ambulatory surgery. The goal of this study was to evaluate the feasibility of home surveillance by TM after colorectal surgery within an ERP. METHODS: This prospective multicenter study involved the University hospitals of Clermont-Ferrand, Grenoble, Marseille and Lyon Sud between November 2014 and September 2015. All patients underwent colorectal surgery within an ERP. Post-discharge, patients received TM (4 simple questions with regard to pain, bowel movements, temperature and phlebitis) on days 1, 3 and 5. If there was abnormal or lack of response, an automatic alert was sent to the attending physician via Internet and the patient was contacted immediately. RESULTS: One hundred and eleven patients were included. Responses were obtained within a median of 12 (1-422) minutes, and 90% of patients answered all TM. There were 48 alerts: 56% because of pain and 40% due to absence of response to the TM. Alerts led to in-hospital care for 4% of patients including three re-hospitalizations and two unplanned re-operations. The median satisfaction score (85% of patients responded) was 5 on a scale of 1 to 5. CONCLUSION: This study suggests the possibility, as for ambulatory surgery, to use test messaging for post-discharge home surveillance for patients undergoing colorectal surgery within an ERP.

Comparative proteomics reveals proteins impacted by nitrogen deprivation in wild-type and high lipid-accumulating mutant strains of Tisochrysis lutea.

Understanding microalgal lipid accumulation under nitrogen starvation is of major interest for biomass feedstock, food and biofuel production. Using a domesticated oleaginous algae Tisochrysis lutea, we performed the first comparative proteomic analysis on the wild type strain and a selected lipid over-accumulating mutant. 2-DE analysis was made on these strains cultured in two metabolic conditions, with and without nitrogen deprivation, which revealed significant differences in proteomes according to both strain and nitrogen availability. Mass spectrometry allowed us to identify 37 proteins that were differentially expressed between the two strains, and 17 proteins regulated by nitrogen starvation concomitantly with lipid accumulation. The proteins identified are known to be involved in various metabolic pathways including lipid, carbohydrate, amino acid, energy and pigment metabolisms, photosynthesis, protein translation, stress response and cell division. Four candidates were selected for possible implication in the over-accumulation of lipids during nitrogen starvation. These include the plastid beta-ketoacyl-ACP reductase protein, the coccolith scale associated protein and two glycoside hydrolases involved in biosynthesis of fatty acids, carbon homeostasis and carbohydrate catabolism, respectively. This proteomic study confirms the impact of nitrogen starvation on overall metabolism and provides new perspectives to study the lipid over-accumulation in the prymnesiophyte haptophyte T. lutea. BIOLOGICAL SIGNIFICANCE: This paper study consists of the first proteomic analysis on Tisochrysis lutea, a non-model marine microalga of interest for aquaculture and lipids production. Comparative proteomics revealed proteins putatively involved in the up-accumulation of neutral lipids in a mutant strain during nitrogen starvation. The results are of great importance for future works to improve lipid accumulation in microalgae of biotechnological interest for biofuel production. This article is part of a Special Issue entitled: Proteomics of non-model organisms.

[Comparison of the urinary excretion of biomarkers of exposure to pyrethroids and pyrethrins between residents of urban and rural areas of the province of Quebec, Canada]. / Comparaison de l'excrétion urinaire de biomarqueurs d'exposition aux pyréthrinoïdes et aux pyréthrines chez les résidents de régions urbaine et rurale de la Province de Québec, Canada.

BACKGROUND: Residents of rural (agricultural) areas are often suspected of being exposed to higher levels of pesticides than residents of urban areas. However, only a limited number of studies have specifically evaluated the impact of the geographical area of residence on pyrethroid and pyrethrin exposure in the general population. This study aimed at comparing the levels of biomarkers of exposure between an urban and rural, adult and children, population of the Province of Quebec, Canada. METHODS: A total of 154 urban (Montreal) and 154 rural (Monteregie) participants provided a complete overnight timed-urine collection and filled a self-administered questionnaire. Urine samples were analyzed for pyrethroid and pyrethrin metabolites: cis- and trans-dichloro- and cis-dibromo- vinyldimethylcyclopropane carboxylic acids, phenoxy- and fluorophenoxy-benzoic acids and chrysanthemum dicarboxylic acid. Amounts of metabolites (pmol/12h par kilogram body weight) and their frequency of detection in the two populations were compared and interpreted with the help of the answers gathered by questionnaire. RESULTS: Adults and children from the rural area tended to excrete higher levels of the main urinary metabolites, the cis- and trans-dichlorovinyldimethylcyclopropane carboxylic acids and the phenoxybenzoic acid, than those living in the urban area. When the adults and children were combined, this difference was statistically significant for the phenoxybenzoic acid (p=0.020), marginally significant for the trans-dichlorovinyldimethylcyclopropane carboxylic acid (p=0.053) and nonsignificant for the cis-dichlorovinyldimethylcyclopropane carboxylic acid (p=0.158). The chrysanthemum dicarboxylic acid, the fluorophenoxybenzoic acid and the dibromovinyldimethylcyclopropane carboxylic acid were detected in much lower proportion but, in the case of the fluorophenoxybenzoic acid, the relative frequency of detection was statistically significantly higher (p<0.001) in the rural population. CONCLUSION: The presence of a baseline level of biomarkers in the urban and rural population confirms the ubiquity of pyrethroids and pyrethrins in the environment. However, in the rural adult and infantile population under study, other factors possibly contributed to slightly increase exposure compared to the urban population, namely the use of mosquito repellents and household insecticides as reported by questionnaire.

Peripheral muscle endurance and the oxidative profile of the quadriceps in patients with COPD.

BACKGROUND: Based on previously reported changes in muscle metabolism that could increase susceptibility to fatigue, we speculated that patients with chronic obstructive pulmonary disease (COPD) have reduced quadriceps endurance and that this will be correlated with the proportion of type I muscle fibres and with the activity of oxidative enzymes. METHODS: The endurance of the quadriceps was evaluated during an isometric contraction in 29 patients with COPD (mean (SE) age 65 (1) years; forced expiratory volume in 1 second 37 (3)% predicted) and 18 healthy subjects of similar age. The electrical activity of the quadriceps was recorded during muscle contraction as an objective index of fatigue. The time at which the isometric contraction at 60% of maximal voluntary capacity could no longer be sustained was used to define time to fatigue (Tf). Needle biopsies of the quadriceps were performed in 16 subjects in both groups to evaluate possible relationships between Tf and markers of muscle oxidative metabolism (type I fibre proportion and citrate synthase activity). RESULTS: Tf was lower in patients with COPD than in controls (42 (3) v 80 (7) seconds; mean difference 38 seconds (95% CI 25 to 50), p<0.001). Subjects in both groups had evidence of electrical muscle fatigue at the end of the endurance test. In both groups significant correlations were found between Tf and the proportion of type I fibres and citrate synthase activity. CONCLUSION: Isometric endurance of the quadriceps muscle is reduced in patients with COPD and the muscle oxidative profile is significantly correlated with muscle endurance.

Effects of peak concentrations on the neurotoxicity of styrene in volunteers.

The manufacture of fibreglass reinforced plastic products may give rise to substantial peak exposures to styrene. Such exposure patterns need further consideration in terms of styrene neurotoxicity. The aim of this study was to evaluate the neurotoxic effects of short-term peak exposures in volunteers, at levels respecting the Quebec occupational exposure limits (8 hours time weighed average of 213 mg/m3 and 15 min average of 426 mg/ m3). The volunteers had not been previously exposed to styrene and they had no documented exposure to known neurotoxicants during the study. Twenty-four volunteers were exposed to five exposure scenarios during 6 hours: a, stable exposure to 106 mg/m3; b, variable exposure with a mean concentration of 106 mg/m3 with four 15 min peaks mounting up to 213 mg/m3; c, stable exposure to 213 mg/m3; d, variable exposure with a mean concentration of 213 mg/m3 and four peaks of 426 mg/m3 and e, two stable exposures to 5 mg/m3 (control). Before and after each exposure scenario, volunteers were submitted to a battery of sensory tests (visual and olfactory), neuropsychological tests (reaction time, attention, memory, psychomotor function), and self-evaluation questionnaires (mood and symptoms) in a test-retest design. The results show that the different exposure scenarios involving peak exposures did not influence either the performance to any test or subjective signs and symptoms. However, due caution must be exercised in extrapolation of the current results to occupational exposure since only acute exposures were tested and volunteers were at rest during exposure, which resulted in lower doses than those experienced by physically active workers.

Assessment of bioaccumulation and neurotoxicity in rats with portacaval anastomosis and exposed to manganese phosphate: a pilot study.

The use of the additive methylcyclopentadienyl manganese tricarbonyl in unleaded gasoline has resulted in increased attention to the potential toxic effects of manganese (Mn). Hypothetically, people with chronic liver disease may be more sensitive to the adverse neurotoxic effects of Mn. In this work, bioaccumulation of Mn, as well as histopathology and neurobehavioral damage, in end-to-side portacaval anastomosis (PCA) rats exposed to Mn phosphate via inhalation was investigated. During the week before the PCA operation, 4 wk after the PCA operation, and at the end of exposure, the rats were subjected to a locomotor evaluation (day-night activities) using a computerized autotrack system. Then a group of 6 PCA rats (EXP) was exposed to 3050 microg m(-3) (Mn phosphate) for 8 h/day, 5 days/wk for 4 consecutive weeks and compared to a control group (CON), 7 PCA rats exposed to 0.03 microg m(-3). After exposure, the rats were euthanized and Mn content in tissues and organs was determined by neutron activation analysis. The manganese concentrations in blood (0.05 microg/g vs. 0.02 microg/g), lung (1.32 microg/g vs. 0.24 microg/g), cerebellum (0.85 microg/g vs. 0.64 microg/g), frontal cortex (0.87 microg/g vs. 0.61 microg/g), and globus pallidus (3.56 microg/g vs. 1.33 microg/g) were significantly higher in the exposed group compared to the control group (p <.05). No difference was observed in liver, kidney, testes, and caudate putamen between the two groups. Neuronal cell loss was assessed by neuronal cell counts. The loss of cells in globus pallidus and caudate putamen as well as in frontal cortex was significantly higher (p <.05) for the EXP group. Assessment of the locomotor activities did not reveal any significant difference. This study constitutes a first step toward our understanding of the potential adverse effects of Mn in sensitive populations.

A biologically based dynamic model for predicting the disposition of methanol and its metabolites in animals and humans.

A multicompartment biologically based dynamic model was developed to describe the time evolution of methanol and its metabolites in the whole body and in accessible biological matrices of rats, monkeys, and humans following different exposure scenarios. The dynamic of intercompartment exchanges was described mathematically by a mass balance differential equation system. The model's conceptual and functional representation was the same for rats, monkeys, and humans, but relevant published data specific to the species of interest served to determine the critical parameters of the kinetics. Simulations provided a close approximation to kinetic data available in the published literature. The average pulmonary absorption fraction of methanol was estimated to be 0.60 in rats, 0.69 in monkeys, and 0.58-0.82 in human volunteers. The corresponding average elimination half-life of absorbed methanol through metabolism to formaldehyde was estimated to be 1.3, 0.7-3.2, and 1.7 h. Saturation of methanol metabolism appeared to occur at a lower exposure in rats than in monkeys and humans. Also, the main species difference in the kinetics was attributed to a metabolism rate constant of whole body formaldehyde to formate estimated to be twice as high in rats as in monkeys. Inversely, in monkeys and in humans, a larger fraction of body burden of formaldehyde is rapidly transferred to a long-term component. The latter represents the formaldehyde that (directly or after oxidation to formate) binds to various endogenous molecules or is taken up by the tetrahydrofolic-acid-dependent one-carbon pathway to become the building block of synthetic pathways. This model can be used to quantitatively relate methanol or its metabolites in biological matrices to the absorbed dose and tissue burden at any point in time in rats, monkeys, and humans for different exposures, thus reducing uncertainties in the dose-response relationship, and animal-to-human and exposure scenario comparisons. The model, adapted to kinetic data in human volunteers exposed acutely to methanol vapors, predicts that 8-h inhalation exposures ranging from 500 to 2000 ppm, without physical activities, are needed to increase concentrations of blood formate and urinary formic acid above mean background values reported by various authors (4.9-10.3 and 6.3-13 mg/liter, respectively). This leaves blood and urinary methanol concentrations as the most sensitive biomarkers of absorbed methanol.

Epoxyeicosatrienoic acid-induced relaxation is impaired in insulin resistance.

We assessed the effect of epoxyeicosatrienoic acids (EETs) in intact mesenteric arteries and Ca(2+)-activated K(+) (BK(Ca)) channels of isolated vascular smooth muscle cells from control and insulin-resistant (IR) rats. The response to 11,12-EET and 14,15-EET was assessed in small mesenteric arteries from control and IR rats in vitro. Mechanistic studies were performed in endothelium intact or denuded arteries and in the presence of pharmacological inhibitors. Moreover, EET-induced activation of the BK(Ca) channel was assessed in myocytes in both the cell-attached and the inside-out (I/O) patch-clamp configurations. In control arteries, both EET isomers induced relaxation. Relaxation was impaired by endothelium denudation, N(omega)-nitro-L-arginine, or iberiotoxin (IBTX), whereas it was abolished by IBTX + apamin or charybdotoxin + apamin. In contrast, the EETs did not relax IR arteries. In control myocytes, the EETs increased BK(Ca) activity in both configurations. Conversely, in the cell-attached mode, EETs had no effect on BK(Ca) channel activity in IR myocytes, whereas in the I/O configuration, BK(Ca) channel activity was enhanced. EETs induce relaxation in small mesenteric arteries from control rats through K(Ca) channels. In contrast, arteries from IR rats do not relax to the EETs. Patch-clamp studies suggest impaired relaxation is due to altered regulatory mechanisms of the BK(Ca) channel.

Bioaccumulation and locomotor effect of manganese dust in rats.

The primary goal of this study is to determine the effects of Mn exposure via inhalation. The bioaccumulation of Mn in different organs and tissues, the alteration of biochemical parameters, and the locomotor activity were assessed. A group of 26 male Sprague-Dawley rats (E) were exposed to 3750 microg/m(3) of Mn dust for 6 h/day, 5 days/wk for 13 consecutive weeks and compared to a control group of 12 rats (C) exposed to 4 microg/m(3). After exposure, neurological evaluation was carried out for 36 h (a night-day-night cycle) using a computerized autotrack system. Rats were then sacrificed by exsanguination, and Mn content in organs and tissues was determined by neutron activation analysis. Mn concentrations in lung, putamen, and cerebellum were significantly higher in E than in C (0.30 vs. 0.17, 0.89 vs. 0.44, 0.63 vs. 0.48 ppm; p <.01), as well as in the kidney, frontal cortex, and globus pallidus (1.15 vs. 0.96, 0.84 vs. 0.47, 1.28 vs. 0.55 ppm; p <.05). Potassium concentration was significantly lower in E than in C (5.11 vs. 5.79 mmol/L; p <.05), as was alkaline phosphatase (106.9 vs. 129.6 U/L; p <.01). Locomotor activity indicated higher distance covered in the first 12-h period for E (45 383 vs. 36 098 cm; p <.05) and lower resting time in the last 12-h period for E (36 326 vs. 37 393 s; p <.05). This study is the first of several ongoing studies in our laboratory that address health concerns associated with inhalation exposure to different Mn species and to different levels of exposure.

Angiotensin II relaxes microvessels via the AT(2) receptor and Ca(2+)-activated K(+) (BK(Ca)) channels.

Angiotensin II (Ang II) is one of the most potent vasoconstrictor substances, yet paradoxically, Ang II may dilate certain vascular beds via an undefined mechanism. Ang II-induced vasoconstriction is mediated by the AT(1) receptor, whereas the relative expression and functional importance of the AT(2) receptor in regulating vascular resistance and blood pressure are unknown. We now report that Ang II induces relaxation of mesenteric microvessels and that this vasodilatory response was unaffected by losartan, an AT(1) receptor antagonist, but was inhibited by PD123,319, a selective antagonist of AT(2) receptors. In addition, reverse transcriptase-polymerase chain reaction studies revealed high amounts of AT(2) receptor mRNA in smooth muscle from these same microvessels. Ang II-induced relaxation was inhibited by either tetraethylammonium or iberiotoxin, suggesting involvement of the large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channel. Subsequent whole-cell and single-channel patch-clamp studies on single myocytes demonstrated that Ang II increases the activity of BK(Ca) channels. As in our tissue studies, the effect of Ang II on BK(Ca) channels was inhibited by PD123,319, but not by losartan. In light of these consistent findings from tissue physiology, molecular studies, and cellular/molecular physiology, we conclude that Ang II relaxes microvessels via stimulation of the AT(2) receptor with subsequent opening of BK(Ca) channels, leading to membrane repolarization and vasodilation. These findings provide evidence for a novel endothelium-independent vasodilatory effect of Ang II.

A toxicokinetic model for predicting the tissue distribution and elimination of organic and inorganic mercury following exposure to methyl mercury in animals and humans. II. Application and validation of the model in humans.

The objective of this study was to develop a biologically based dynamical model describing the disposition kinetics of methyl mercury and its inorganic mercury metabolites in humans following different methyl mercury exposure scenarios. The model conceptual and functional representation was similar to that used for rats but relevant data on humans served to determine the critical parameters of the kinetic behavior. It was found that the metabolic rate of methyl mercury was on average 3 to 3.5 times slower in humans than in rats. Also, excretion rates of organic mercury from the whole body into feces and hair were 100 and 40 times smaller in humans, respectively, and urinary excretion of organic mercury in humans was found to be negligible. The human transfer rate of inorganic mercury from blood to hair was found to be 5 times lower than that of rats. On the other hand, retention of inorganic mercury in the kidney appeared more important in humans than in rats: the transfer rate of inorganic mercury from blood to kidney was 19 times higher than in rats and that from kidney to blood 19 times smaller. The excretion rate of inorganic mercury from the kidney to urine in humans was found to be twice that of rats. With these model parameters, simulations accurately predicted human kinetic data available in the published literature for different exposure scenarios. The model relates quantitatively mercury species in biological matrices (blood, hair, and urine) to the absorbed dose and tissue burden at any point in time. Thus, accessible measurements on these matrices allow inferences of past, present, and future burdens. This could prove to be a useful tool in assessing the health risks associated with various circumstances of methyl mercury exposure.

A toxicokinetic model for predicting the tissue distribution and elimination of organic and inorganic mercury following exposure to methyl mercury in animals and humans. I. Development and validation of the model using experimental data in rats.

The objective of this study was to develop a biologically based dynamic model for predicting the distribution and elimination of methyl mercury and its metabolite, inorganic mercury, under a variety of exposure scenarios in rats. A model is proposed based on a multicompartment approach; each compartment represents an organ or a group of organs or an excreta. The model translates into a set of coupled differential equations taking into account interorgan rates of exchanges and excretion together with the biotransformation process. The free parameters of the model are determined from statistical fits to the experimental data of the Farris et al. (Toxicol. Appl. Pharmacol. 119, 74-90, 1993) study on the time profiles of blood and tissue concentrations and cumulative excretions. The vast range of time scales that govern tissue absorption, distribution, biotransformation, and excretion served to solve the model step by step. This interplay of time scales in the rates explains the buildups and slow attrition of inorganic mercury in certain key organs such as the brain and the kidney, which are also the sites of the more important toxic effects. The model was validated on additional experimental data provided by Norseth and Clarkson (Arch. Environ. Health 21, 717-727, 1970) and Thomas et al. (Environ. Res. 41, 219-234, 1986; Environ. Res. 43, 203-216, 1987). This approach, when adapted to humans, allows the reconstruction of the time course of blood and tissue concentrations, starting from easily accessible data on hair, urine, and feces.

cAMP-dependent vasodilators cross-activate the cGMP-dependent protein kinase to stimulate BK(Ca) channel activity in coronary artery smooth muscle cells.

cAMP-dependent vasodilators are used to treat a variety of cardiovascular disorders; however, the signal transduction pathways and effector mechanisms stimulated by these agents are not fully understood. In the present study we demonstrate that cAMP-stimulating agents enhance the activity of the large-conductance, calcium-activated potassium (BK(Ca)) channel in single myocytes from coronary arteries by "cross-activation" of the cGMP-dependent protein kinase (protein kinase G, PKG). Single-channel patch-clamp data revealed that 10 micromol/L isoproterenol, forskolin, or dopamine opens BK(Ca) channels in coronary myocytes and that this effect is attenuated by inhibitors of PKG (KT5823; Rp-8-pCPT-cGMPS), but not by inhibiting the cAMP-dependent protein kinase (protein kinase A, PKA). In addition, a membrane-permeable analog, CPT-cAMP, also opened BK(Ca) channels in these myocytes, and this effect was reversed by KT5823. Direct biochemical measurement confirmed that dopamine or forskolin stimulates PKG activity in coronary arteries but does not elevate cGMP. Finally, the stimulatory effect of cAMP on BK(Ca) channels was reconstituted in a cell-free, inside-out patch by addition of purified PKG activated by either cGMP or cAMP. In contrast, channel gating was unaffected by exposure to the purified catalytic subunit of PKA. In summary, findings from on-cell and cell-free patch-clamp experiments provide direct evidence that cAMP-dependent vasodilators open BK(Ca) channels in coronary myocytes by cross-activation of PKG (but not via PKA). Biochemical assay confirmed this cross-activation mechanism of cAMP action in these arteries. This signaling pathway is a novel mechanism for regulation of potassium channel activity in vascular smooth muscle and other cells.

A novel transduction mechanism mediating dopamine-induced vascular relaxation: opening of BKCa channels by cyclic AMP-induced stimulation of the cyclic GMP-dependent protein kinase.

Dopamine dilates the coronary, renal and other vascular beds; however, the signaling pathway underlying this effect is unclear. In this study the signal-transduction process mediating dopamine-induced relaxation of porcine coronary arteries was investigated in isolated vessels and single arterial myocytes. Dopamine-induced relaxation of arteries was mediated through the DA- receptor and involved K+ efflux, and subsequent patch-clamp studies demonstrated that either dopamine or fenoldopam, a selective DA-1 agonist, increased the opening probability of the large-conductance, calcium- and voltage-activated K+ (BKCa) channel in coronary myocytes. Moreover, blockade of this channel by iberiotoxin prevented dopamine-induced coronary relaxation. Dopamine stimulation of BKCa channels was completely prevented by a DA-1-receptor antagonist, but was unaffected by propranolol. Furthermore, inhibiting adenylyl cyclase activity prevented stimulation of BKCa channel activity, whereas chlorophenylthio (CPT)-cyclic adenosine monophosphate (AMP), a membrane-permeable analog of cyclic AMP, mimicked the effects of dopamine. Interestingly, inhibiting the cyclic AMP-dependent protein kinase (PKA) did not affect the response to dopamine, whereas dopamine-induced channel activity was completely blocked by inhibiting the activity of the cyclic guanosine monophosphate (GMP)-dependent protein kinase (PKG). These findings demonstrate that activation of DA-1 receptors causes stimulation of BKCa channel activity by a mechanism involving cyclic AMP-dependent stimulation of PKG, but not PKA, and further suggest that this cross-reactivity mediates dopamine-induced coronary vasodilation.

The toxicokinetics of pyrene and its metabolites in rats.

Five experiments were conducted in male Sprague-Dawley rats regarding the kinetic of urinary excretion of 1-hydroxypyrene (1-OHP) following i.v., oral and dermal exposure to 0.5-50 micromol/kg pyrene either as a single substance or as mixture of various polycyclic aromatic hydrocarbons (PAH). Frequent urine collections over 48 h after exposure and a tissue versus time distribution experiment using [14C]pyrene allowed to define the kinetic profile of both pyrene and 1-OHP. For all exposure routes, there is a linear relationship over two orders of magnitude between the dose of pyrene and the urinary excretion of 1-OHP. Differences in biliary/urinary 1-OHP excretion ratio in canulated rats (3) versus faecal/urinary 1-OHP excretion ratio in non-canulated rats (0.6) indicate major enterohepatic recirculation of the metabolite. Half-lives of both pyrene and 1-OHP in all measured tissues were all comprised between 3.1 and 5.4 h, and 5.2-6.7 h, respectively, so that no long term accumulation would be predicted from these values for any tissue. Binary and ternary mixtures involving naphthalene and benzo(a)pyrene in addition to pyrene has no influence on the urinary excretion profile of 1-OHP. All these observations led to the proposal of a dynamic compartment model of pyrene and metabolite flows indicating that following rapid initial distribution to fatty tissues, pyrene is rapidly biotransformed into various metabolites and undergoes major enterohepatic recycling. Part of the initially formed and part of the recirculated 1-OHP eventually undergoes urinary excretion such that close to 60% of pyrene is eliminated as metabolites in urine by 24 h after injection while 20% is excreted in the faeces over the same period.