摘要:

Many chemical carcinogens target epithelial tissues, but the biological and biochemical bases of carcinogen specificity remain largely unknown. Focusing on the mammary gland, we discuss the concept that neutrophils metabolize carcinogens to reactive species that damage adjacent epithelial cells. This mechanism may help to explain why epithelial cells are sensitive targets for chemical carcinogenesis, despite their limited bioactivation capacity.Key words: carcinogenesis, neutrophil, bioactivation, peroxidase, epithelial tissue, inflammation.

ISSN:0008-4212    

DOI:10.1139/y98-083

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

Amantadine is a drug with a primary amino group, and consequently a likely candidate for metabolism by acetylation. This study assessed the possibility that a person's polymorphic (NAT2) acetylator phenotype could be used to predict the extent of amantadine acetylation. Thirty-eight normal, healthy volunteers were NAT2 acetylator phenotyped with sulfapyridine. Of the six fastest (75-86%) and six slowest (34-40%) sulfapyridine acetylators, two and three, respectively, had acetylamantadine present (18-338 µg) in the 8-h urine collection. There was no correlation between NAT2 acetylator phenotype and amantadine acetylation (p< 0.5), and no difference in the total urine amantadine excreted over 8 h between acetylators and nonacetylators (28.3 ± 9.7 vs. 30.4 ± 9.6 mg, respectively, mean ± SD). Acetylamantadine represented 0.1-1.5% (median 0.5%) of urinary drug content over 8 h. Our data confirm that amantadine is acetylated in humans and demonstrate for the first time that the extent is not correlated with NAT2 acetylator phenotype. Parallel in vitro enzyme studies indicate the possibility that neither NAT1 nor NAT2 is responsible for acetylation of amantadine.Key words: amantadine, acetylation, conjugation, drug metabolism.

ISSN:0008-4212    

DOI:10.1139/y98-086

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

We hypothesized that the respiratory baroreflex in conscious rats is either more transient, or has a higher pressure threshold than in other species. To characterize the effect of arterial pressure changes on respiration in conscious rats, ventilation (V) was measured by the plethysmographic technique during injections, or infusions, of pressor and depressor agents. Bolus injections of angiotensin II (Ang II) or arginine vasopressin (AVP), transiently increased mean arterial pressure (MAP; mean ± SE) 43 ± 6 and 28 ± 5 mmHg (1 mmHg = 133.3 Pa), respectively, and immediately reduced tidal volume (Vt) and, in the case of AVP,V. In contrast, by 10 min of a sustained elevation of MAP (40 ± 3 mmHg) with infusion of Ang II,Vt,f, andVwere not different from control levels. Bolus injection of sodium nitroprusside (SNP) to lower MAP (-28 ± 3 mmHg) immediately increased breathing frequency (f) andV, whereas sustained infusion of SNP to lower MAP (-21 ± 3 mmHg) did not changeforVat 10 and 20 min. In conscious rats, both injection and infusion of the pressor agent PE (+40 to 50 mmHg) stimulatedfandV; this contrasted with anesthetized rats where PE inhibitedfandV, as reported by others. In conscious rats, respiratory responses associated with baroreflexes adapt rapidly and, in the case of PE, can be overridden by some other mechanism.Key words: angiotensin II, arginine vasopressin, baroreceptor reflex, phenylephrine, sodium nitroprusside.

ISSN:0008-4212    

DOI:10.1139/y98-081

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

Sensitized guinea pigs were used to assess the effect of treatment with the compound U-83836E ((-)-2-[[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-h-6-ol, dihydrochloride) on the antigen-induced late-phase (16 h) airway hyperreactivity, increase in inflammatory cell number, edema, and release of inflammatory mediators in the bronchoalveolar lavage (BAL) fluid. After antigen challenge, an increase of the in vitro reactivity of the trachea and upper bronchi to acetylcholine and histamine and an increase in the number of leukocytes in the BAL fluid, mainly eosinophils and mononuclear cells, were observed. The concentrations of proteins, histamine, and PGE2in the BAL fluid were also significantly increased by 53, 57, and 216%, respectively, after antigen challenge. Treatment with U-83836E (10 mg/kg) given i.p. 17 and 3 h before and 6 h after antigen challenge inhibited by approximately 80% the total cell number in the airways and the BAL fluid protein content. Moreover, this treatment totally inhibited airway hyperreactivity. Histamine and PGE2levels in the BAL fluid were not significantly affected by U-83836E treatment. These results indicate that U-83836E is effective against some of the characteristic features of asthma in ovalbumin-sensitized guinea pigs.Key words: U-83836E, aminochroman, hyperreactivity, lung inflammation, edema.

ISSN:0008-4212    

DOI:10.1139/y98-080

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

Treatment of cardiac dysrhythmias with the iodinated benzofuran derivative amiodarone (AM) is limited by pulmonary toxicity. The susceptibilities of different lung cell types of male Golden Syrian hamsters to AM-induced cytotoxicity were investigated in vitro. Bronchoalveolar lavage and protease digestion to release cells, followed by centrifugal elutriation and density gradient centrifugation, resulted in preparations enriched with alveolar macrophages (98%), alveolar type II cells (75-85%), and nonciliated bronchiolar epithelial (Clara) cells (35-50%). Alveolar type II cell and Clara cell preparations demonstrated decreased viability (by 0.5% trypan blue dye exclusion) when incubated with 50 µM AM for 36 h, and all AM-treated cell preparations demonstrated decreased viability when incubated with 100 or 200 µM AM. Based on a viability index ((viability of AM-treated cells ÷ viability of controls) × 100%), the Clara cell fraction was significantly (p< 0.05) more susceptible than all of the other cell types to 50 µM AM. However, AM cytotoxicity was greatest (p< 0.05) in alveolar macrophages following incubation with 100 or 200 µM AM. There was no difference between any of the enriched cell preparations in the amount of drug accumulated following 24 h of incubation with 50 µM AM, whereas alveolar macrophages accumulated the most drug during incubation with 100 µM AM. Thus, the most susceptible cell type was dependent on AM concentration. AM-induced cytotoxicity in specific cell types may initiate processes leading to inflammation and pulmonary fibrosis.Key words: amiodarone, susceptibility, alveolar macrophage, accumulatio

ISSN:0008-4212    

DOI:10.1139/y98-084

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

The aim of this study was to evaluate the effects of dietary pure eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the physiology of the heart in normoxic conditions and during postischemic reperfusion. These effects were compared with those of dietaryn-6 polyunsaturated fatty acids (PUFA). Rats were fed a diet containing either sunflower seed oil (75 g·kg-1, SSO group), or a mixture of EPA (20:5n-3) ethyl ester and SSO (10:90, EPA group), or a mixture of DHA (22:6n-3) ethyl ester and SSO (10:90, DHA group), or a mixture of EPA + DHA ethyl esters and SSO (4.2:5.8:90, e+D group) for 6 weeks. The hearts were then perfused according to the working mode. The perfusion was maintained either in normoxic conditions or stopped for 17 min (global zero-flow ischemia) and restored for 33 min (reperfusion). The aortic and coronary flows, aortic developed pressure, and electrocardiogram were continuously monitored. When rats were fed a diet containing either EPA and (or) DHA, then-6/n-3 PUFA ratio of cardiac phospholipids decreased. The proportion of arachidonic acid was reduced more with DHA than dietary EPA. In the EPA group, the percentage of DHA was lower than in the DHA group, but the percentage of EPA and docosapentaenoic acid (22:5n-3) was higher. These changes in membrane fatty acid composition altered the cardiac function. In normoxic conditions, the coronary flow was higher in the SSO group than in the DHA and EPA groups. The heart rate was lower in the DHA and e+D groups than in the EPA and SSO groups. The aortic flow, cardiac output, and aortic developed pressure were not affected. During postischemic reperfusion, the recovery of aortic flow, coronary flow, and aortic developed pressure was similar in the four groups. A slightly improved recovery of cardiac function was noticed in the EPA group, but the difference was not significant. Feeding rats 5% fish oil + 5% SSO instead of 10% SSO for 8 weeks increased the incorporation of EPA in cardiac phospholipids and favored the recovery (+120%) of aortic flow during postischemic reperfusion. In conclusion, the beneficial effect of dietary fish oil on the recovery of cardiac pump activity during reperfusion was not observed with DHA or EPA alone. It appears to be positively related to the accumulation of EPA in membrane phospholipids. The dietary conditions favouring EPA accumulation remain to be determined.Key words: dietary polyunsaturated fatty acids, myocardial ischemia, reperfusion.

ISSN:0008-4212    

DOI:10.1139/y98-079

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

Previous evidence has shown sympathetic nerve responses to insular cortical (IC) stimulation are mediated by synapses within the lateral hypothalamic area (LHA) and ventrolateral medulla (VLM). The present study was aimed at determining the neurotransmitter(s) and receptor(s) involved at the synapse in the VLM. Twenty male Wistar rats were instrumented for renal nerve, arterial pressure, and heart rate recording. The IC or the LHA was stimulated with a bipolar electrode (200-1000 µA; 2 ms; 0.8 Hz) to elicit sympathetic nerve responses. Antagonists were then pressure-injected into the VLM (300 nL). Bilateral and unilateral kynurenate (25 mM) resulted in 100% block of IC- and LHA-stimulated sympathetic nerve responses. Bilateral injection of the non-NMDA (N-methyl-D-aspartate) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 200 µM) also resulted in up to 100% block of IC and LHA sympathetic responses. In addition, unilateral injections of CNQX were made in two animals, resulting in 100 and 83% block of LHA sympathetic responses. Bilateral injection of the NMDA receptor antagonistDL-2-amino-5-phosphonopentanoic acid (AP5; 200µM) did not affect the response to IC or LHA stimulation. Kynurenate, CNQX, and AP5 all resulted in an elevation of baseline sympathetic nerve activity and a pressor response. Kynurenate resulted in a 263 ± 79% increase in baseline activity, while CNQX and AP5 resulted in 83 ± 19% and 91 ± 21% increases, respectively. Bilateral injections of antagonists for GABAA(bicuculline; 0.1 µM), acetylcholine (atropine; 0.1 µM) and catecholaminergic alpha and beta receptors (phentolamine and propranolol: 0.1 µM) had no effect on LHA sympathetic responses. Thus, sympathetic responses originating in the IC and LHA are mediated by a non-NMDA receptors in the VLM, which are likely AMPA receptors.Key words: insular cortex, ventrolateral medulla, glutamate, sympathetic activity.

ISSN:0008-4212    

DOI:10.1139/y98-082

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

The influence of sleep on ventilation, metabolic rate, cardiovascular function, and regional distribution of blood flow during hypoxemia (PaO2of 45-50 mmHg (1 mmHg = 133.3 Pa)) was studied in piglets at 6 ± 1 and 34 ± 5 days (mean ± SD). Measurement of ventilation and metabolic rate was done in a metabolic chamber, and blood flow was measured using the microsphere technique. A subgroup of animals was instrumented for cardiac output measurement (dye-dilution technique) and continuous monitoring of the hemoglobin saturation in oxygen (SaO2) We found that although sleep did not influence the metabolic and cardiac output response to hypoxemia, it affected the ventilatory response as well as the brain and the respiratory muscle blood flows. During active sleep in the older animals, the ventilatory response to hypoxemia was smaller than in the other two states; marked drops inSaO2occurred with changes in the breathing pattern; and that state was associated with the highest rate of brain blood flow. As well, age affected the ventilatory and metabolic response, but not the cardiovascular response to hypoxemia. The age-dependent ventilatory changes with hypoxemia (smaller ventilatory response in the young than in the older animals) were related to the different levels of oxygen consumption. In summary, active sleep was responsible for all the sleep-dependent changes in the response to a moderate degree of hypoxemia.Key words: breathing pattern, metabolic rate, blood flow, microspheres, maturation.

ISSN:0008-4212    

DOI:10.1139/y98-088

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

The objective of this study was to measure the rate of demethylation of nitrosodimethylamine in vivo in the rat and determine its value to assess CYP2E1 activity in intact animals. Nitrosodimethylamine labeled with14C on both methyl groups was administered to rats and exhaled14CO2was collected during 2-3 h. The nitrosodimethylamine breath test was increased by inducers of CYP2E1, such as ethanol (+139%) and 4-methylpyrazole (+115%), and decreased by the inhibitor diallyl sulfide (-53%). In addition, the nitrosodimethylamine breath test was not changed significantly by inducers specific for other cytochrome P450 such as beta-naphthoflavone, dexamethasone, and phenobarbital. The specificity of the induction by 4-methylpyrazole and of the inhibition by diallyl sulfide for CYP2E1 was determined using the [14C]caffeine (CYP1A2), [14C]aminopyrine (CYP2C11), and [14C]erythromycin (CYP3A2) breath tests. 4-Methylpyrazole treatment caused a small increase of the caffeine (+33%) and aminopyrine (+9%) breath tests and no change of the erythromycin breath test. Diallyl sulfide treatment led to a small decrease of the caffeine breath test (-33%) and of the aminopyrine breath test (-13%) but a 23% increase of the erythromycin breath test. It is concluded that the [14C]nitrosodimethylamine breath test is useful to assess CYP2E1 activity in vivo in the rat.Key words: breath test, CYP2E1, nitrosodimethylamine.

ISSN:0008-4212    

DOI:10.1139/y98-087

出版商:NRC Research Press    

年代:1998

数据来源: NRC

摘要:

Previous studies have shown that the attenuated hypoxic pulmonary vasoconstriction (HPV) of young newborn lamb lungs was enhanced by cyclooxygenase inhibition. We sought to determine whether this reflected greater synthesis of and (or) responsiveness to dilator prostaglandins (PG). Protocol 1 measured responses to graded hypoxia and perfusate concentrations of 6-keto-PGF1alpha(the stable metabolite of PGI2) and PGE2in isolated lungs from 1-day- and 1-month-old lambs. Protocol 2 compared dose responses and segmental vascular resistances during infusion of PGI2and PGE2in hypoxic, cyclooxygenase-inhibited, lungs from 1- to 2-day-old and 1- to 3-month-old lambs. Lungs of 1-day-old lambs with attenuated responses to 4% O2had significantly higher perfusate concentrations of 6-keto-PGF1alphaand PGE2, but responses to both PGE2and the more potent vasodilator, PGI2did not differ with age. These data support the hypothesis that attenuated HPV in young newborn lamb lungs is due to increased synthesis of dilator PG, particularly PGI2.Key words: hypoxic pulmonary vasoconstriction, pulmonary vascular development, cyclooxygenase inhibition, segmental vascular resistances.

ISSN:0008-4212    

DOI:10.1139/y98-092

出版商:NRC Research Press    

年代:1998

数据来源: NRC