Effects of standard cigarette and nicotine-less cigarette smoke inhalings on nicorandil plasma levels in rats

The influence of cigarette smoke on nicorandil plasma levels at a dose of 10 mg/kg administered orally was investigated in rats. The animals were exposed to standard and nicotine-less cigarette smoke for 8 min using a 'smoking machine'. In nonsmoking control rats, nicorandil plasma levels increased rapidly and reached the maximum (approx. 7.6 micrograms/ml) after 1 h and then decreased gradually. On the other hand, nicorandil plasma levels in the rats inhaling standard cigarette and nicotine-less cigarette smoke reached the maximum (approx. 4.7 and 4.9 micrograms/ml, respectively) after 1-2 h. These results suggest that nicorandil plasma levels after oral administration are influenced not only by standard cigarette smoke but also by nicotine-less cigarette smoke.     

Tail-tremor induced by exposure to cigarette smoke in rats.

Tremors appearing only in the tail (tail-tremor) induced by cigarette smoke and subcutaneous nicotine were investigated using a smoking machine and Wistar rats. Daily exposure (twice a day) to smokes of two commercial cigarettes (Mild-Seven Select for the first 7 days and Long-Peace for the next 6 days) caused the tail-tremor to appear even if it was slight. A single subcutaneous nicotine (0.5 mg/kg) administration to rats exposed to the cigarette smokes for 13 days markedly caused the tail-tremor. On the other hand, daily subcutaneous injection of nicotine (0.5 mg/kg/day) also caused the tail-tremor to appear beginning on the 4th day and the incidence of tremor increased to 100% by the 12th day. These results indicate that tail-tremor can be caused not only by daily subcutaneous administration of nicotine but also by daily exposure to cigarette smoke.     

Influences of cigarette smoke inhalation on pharmacokinetics of cimetidine in rats.

The influences of cigarette smoke inhalation on the pharmacokinetics of cimetidine administered orally and parenterally were investigated in rats using a smoking machine. The animals were exposed to two kinds of cigarette smoke, low- or high-nicotine.tar, inhaled for 10 min immediately after oral (50 mg/kg), intraperitoneal (25 mg/kg) or intravenous (10 mg/kg) administration of cimetidine. The plasma level after cimetidine was administered orally was lower in the absorption phase in the two cigarette smoke inhaling groups than in the non-smoking control group, and was particularly marked in the high-nicotine.tar cigarette smoke inhaling group. In contrast, no significant difference was found in cimetidine plasma level between the cigarette smoke inhaling groups and the non-smoking control group when administered intraperitoneally or intravenously. These results suggest that cigarette smoke inhalation may cause a suppression or a delay in cimetidine absorption from the gastrointestinal tract, and that the degree of influence is dependent upon the content of nicotine.tar in the cigarette smoke.     

Effects of standard cigarette smoke and nicotine-reduced cigarette smoke on plasma concentrations of indomethacin administered orally to rats.

The influence of acute exposures to standard (ST) and nicotine-reduced (NR) cigarette smokes on the plasma concentration of orally administered indomethacin (IM, 5 mg/kg) was investigated in rats. IM plasma concentrations in the ST- and NR-groups were lower than those in the non-smoking control group, while the lowered effect in the NR-group was slightly weaker than in the ST-group. These results suggest that the plasma concentrations of IM administered orally are lowered by the acute exposure of cigarette smoke, and this influence may be attributed largely to constituents other than nicotine in the cigarette smoke as well as slightly attributable to nicotine.     

The effect of cigarette smoke on the plasma piroxicam concentrations in rats

The plasma concentration of unchanged piroxicam has been determined at 15, 30, 60 and 90 min after 10 mg kg-1 oral administration of the drug to rats exposed to cigarette smoke or pretreated with phenobarbitone, 3,4-benzpyrene or ethanol. Plasma piroxicam concentrations decreased in rats pretreated with phenobarbitone, 3,4-benzpyrene and ethanol and in rats 24 h after exposure to cigarette smoke.     

Pharmacodynamic effects of chronic cigarette smoke exposure in spontaneously hypertensive rats

In investigating the influence of chronic cigarette smoke exposure on hypertension, we compared the pharmacodynamic effects of enforced exposure to smoke on spontaneously hypertensive rats (SHR) with those on Wistar-Kyoto (WKY) rats. Chronic cigarette smoke exposure for 8 weeks decreased the elevated heart rate of mature male SHR to approximately the rate in WKY rats 24 h after smoke exposure. Both systolic and diastolic blood pressures also decreased slightly. However, WKY rats showed a marked rise in heart rate soon after exposure to cigarette smoke began, with no change in blood pressure, while the heart rate of SHR in the early stage remained similar to that of animals without exposure, although their blood pressure was clearly reduced. The body weight of both strains tended to decrease during smoke exposure, but the effect was more severe in SHR. Moreover, the effects of chronic smoke exposure were observed using retired, aged female SHR breeders. A decrease in body weight and heart rate, but not in blood pressure, was also recognized even in these mature animals. These effects gradually recovered after withdrawal from exposure. On the basis of these results, a profile of chronic cigarette smoke exposure under hypertension is discussed in this study.     

Chronic inhalation exposure to mainstream cigarette smoke increases lung and nasal tumor incidence in rats.

An animal model of lung carcinogenicity induced by chronic inhalation of mainstream cigarette smoke would be useful for research on carcinogenic mechanisms, smoke composition-response relationships, co-carcinogenicity, and chemoprevention. A study was conducted to determine if chronic whole-body exposures of rats would significantly increase lung tumor incidence. Male and female F344 rats (n = 81 to 178/gender) were exposed whole-body 6 h/day, 5 days/week for up to 30 months to smoke from 1R3 research cigarettes diluted to 100 (LS) or 250 (HS) mg total particulate matter/m(3), or sham-exposed to clean air (C). Gross respiratory tract lesions and standard lung and nasal sections were evaluated by light microscopy. A slight reduction of survival suggested that the HS level was at the maximum tolerated dose as commonly defined. Cigarette smoke exposure significantly increased the incidences of non-neoplastic and neoplastic proliferative lung lesions in females, while nonsignificant increases were observed in males. The combined incidence of bronchioloalveolar adenomas and carcinomas in females were: HS = 14%; LS = 6%; and C = 0%. These incidences represented minima because only standard lung sections and gross lesions were evaluated. Mutations in codon 12 of the K-ras gene occurred in 4 of 23 (17%) tumors. Three mutations were G to A transitions and one was a G to T transversion. The incidence of neoplasia of the nasal cavity was significantly increased at the HS, but not the LS level in both males and females (HS = 6%, LS = 0.3%, C = 0.4% for combined genders). These results demonstrate that chronic whole-body exposure of rats to cigarette smoke can induce lung cancer.     

Free lung cell response of mice and rats to mainstream cigarette smoke exposure

Male C57BL mice and F-344 rats were exposed through nose only to fresh mainstream smoke from one University of Kentucky Reference cigarette (2R1) daily under standardized conditions. At different exposure points, the lungs of room control (RM), sham control (SH), and smoke-exposed (SM) animals were lavaged and the number, composition, and properties of bronchoalveolar lavage (BAL) cells were studied. Significantly elevated levels of blood COHb and pulmonary aryl hydrocarbon hydroxylase activity indicated effective inhalation of smoke by animals. The BAL cell analysis showed that cigarette smoke induced a five- to sevenfold increase in the number of BAL cells in mice following 10- to 12-week exposure. The proportion of neutrophils (PMN) increased to about 18 +/- 3% in SM mice as compared to less than 1% in controls. Cessation of smoke treatments returned the PMN levels to those of controls within 5 weeks. Unlike mice, smoke exposure for up to 32 weeks failed to induce appreciable changes in the number and proportion of macrophages and neutrophils in rats. Large brown macrophages were observed in SM groups of both species. Functional analysis demonstrated that the BAL cells from SM mice but not rats released greater amounts of superoxides than controls under resting and phagocytically stimulated conditions. Enzymatic analysis of macrophages showed that the activity of N-acetylglucosaminidase was increased in SM groups of both species. The activity of 5'nucleotidase was significantly reduced in macrophages from SM mice but not rats. Activity of leucine aminopeptidase remained unaltered in both species. These results demonstrate distinct differences in the response of mice and rats to identically generated cigarette smoke.     

Effects of cigarette smoke on the immune response. II. Chronic exposure to cigarette smoke inhibits surface immunoglobulin-mediated responses in B cells.

We have previously reported that chronic exposure of rats to cigarette smoke inhibits the antibody-forming cell (AFC) response to both T-dependent and T-independent antigens and may reflect B cell dysfunction. In this communication we extend these studies to show that T cell functions are normal in chronically smoke-exposed rats (SM) as judged by their responses to mitogens and "nominal" or alloantigens. While B cells from SM respond significantly to the B cell mitogen lipopolysaccharide (LPS), they fail to proliferate in response to anti-IgM (anti-mu) or to produce significant AFC response to sheep red blood cells. On the basis of the number of rosettes formed with trinitrophenylated (TNP) horse red blood cells; the frequency of TNP-binding cells (TNP-ABC) in the spleens of SM is comparable to sham control rats. However, the proliferation of TNP-ABC to TNP-Brucella abortus is significantly decreased in SM. These differences in SM B cell responses, i.e., between LPS and anti-mu/antigen, may to be related to the ability of LPS to bypass a portion of the membrane signal transduction cascade. These results suggest that cigarette smoke affects an early step(s) in the antigen-dependent B cell signal transduction pathway.     

Effect of long-term cigarette smoke exposure on locomotor activity and brain monoamine levels in rats.

Rats were chronically exposed to cigarette smoke for 20 min twice daily using a smoking machine. On days 1, 4, and 14, locomotor activity and rearing were measured for 15 min in an open-field apparatus. On day 1, exposure to cigarette smoke increased locomotor activity and rearing in the latter half of the observation period. This effect became more pronounced on days 4 and 14. Chronic cigarette smoke exposures for 21 days significantly decreased the norepinephrine levels in the hypothalamus, thalamus, and pons-medulla, but not the levels of dopamine, 5-hydroxytryptamine, or their metabolites. These results suggest that repeated cigarette smoke exposure increasingly stimulates locomotor activity and rearing and affects norepinephrine metabolism, especially in the brainstem.     

Effect of subchronic administration of antioxidants against cigarette smoke exposure in rats

Effects of subchronic administration of antioxidants against pulmonary damage mediated by cigarette smoke were investigated in rats. Rats were continuously received ascorbic acid,N-acetylcysteine and ginseng extract together drinking water from day 25 after birth. After 30 days of antioxidant supplementation, rats were exposed to cigarette smoke generated from six cigarettes (11 mg tar) for 20 min per day throughout 30 days, and then several biochemical markers related to the redox status in vivo were analyzed in the respiratory system. The cigarette smoke induced mild histological changes in trachea and lungs. The activity of Superoxide dismutase (SOD) in the lung was significantly increased, and catalase and glutathione peroxidase activities were increased less than SOD, but total sulfhydryl compounds (Total-SH) content was decreased by cigarette smoking. In spite of the increase in activities of antioxidant enzymes, the inhibitory capacity of lung preparations on in vitro lipid peroxidation using ox brain homogenates was decreased and the change in the capacity was not related to the changes of these intracellular enzymes activities, but with the content of Total-SH. On the other hand, the content of thiobarbituric acid reactive substances and the ratio of elastase to anti-protease in the lung homogenates were significantly increased. Supplementation of antioxidants, however, effectively attenuated all of such alterations induced by cigarette smoke. These results indicate that although cigarette smoking induces antioxidant enzymes in the lung as a self defense mechanism, it seems to be not sufficient to protect the pulmonary system, and that chronic antioxidant feeding could be effective to reduce pulmonary damage induced by free radicals.     

Perinatal sidestream cigarette smoke exposure and the developing pulmonary surfactant system in rats.

1. Epidemiological studies have strongly implicated passive smoking with increased incidence of various respiratory diseases in children. Our earlier studies have shown that chronic exposure to tobacco smoke significantly changes the composition and the surface activity of the pulmonary surfactant in adult rats. The aim of the present study was to determine if perinatal exposure to sidestream cigarette smoke influences the composition and function of pulmonary surfactant system in developing rat pups. 2. Pregnant Sprague Dawley rats were exposed to sidestream cigarette smoke in a whole body exposure chamber for a total of 6 h each day and the pups born to these dams were further exposed to sidestream smoke for 2 h/day during postnatal period. Exposure of animals to smoke was ascertained by measuring their plasma cotinine. Surfactant analysis was performed on bronchoalveolar lavage fluids (BALF) collected from pups on postnatal day 1, 3, 7, 14, 21 and 35. The phospholipid (PL) content, percentage disaturated phosphatidylcholine (DSPC) and surfactant proteins (SP-A and SP-B) in BALF surfactant preparations from sham and smoke-exposed pups were compared. 3. Significant differences between the two groups were observed at two exposure points: a reduced level of SP-A on day 1, and, a higher level of SP-A and PLs on day 21, in smoke-exposed pups. Surface activity analysis of the surfactant films by pulsating bubble surfactometer did not show any significant differences between the sham and smoke-exposed groups at any exposure point. 4. The results indicate that perinatal exposure to sidestream smoke is capable of producing biochemical changes in the composition of pulmonary surfactant at different stages of development but these changes do not influence surface tension reducing properties of the surfactant.     

Mimicking cigarette smoke exposure to assess cutaneous toxicity

Cigarette smoke stands among the most toxic environmental pollutants and is composed of thousands of chemicals including polycyclic aromatic hydrocarbons (PAHs). Despite restrict cigarette smoking ban in indoor or some outdoor locations, the risk of non-smokers to be exposed to environmental cigarette smoke is not yet eliminated. Beside the well-known effects of cigarette smoke to the respiratory and cardiovascular systems, a growing literature has shown during the last 3 decades its noxious effects also on cutaneous tissues. Being the largest organ as well as the interface between the outer environment and the body, human skin acts as a natural shield which is continuously exposed to harmful exogenous agents. Thus, a prolonged and/or repetitive exposure to significant levels of toxic smoke pollutants may have detrimental effects on the cutaneous tissue by disrupting the epidermal barrier function and by exacerbating inflammatory skin disorders (i.e. psoriasis, atopic dermatitis). With the development of very complex skin tissue models and sophisticated cigarette smoke exposure systems it has become important to better understand the toxicity pathways induced by smoke pollutants in more realistic laboratory conditions to find solutions for counteracting their effects. This review provides an update on the skin models currently available to study cigarette smoke exposure and the known pathways involved in cutaneous toxicity. In addition, the article will briefly cover the inflammatory skin pathologies potentially induced and/or exacerbated by cigarette smoke exposure.     

Influences of psychological stress produced by intraspecies emotional communication on nicorandil plasma levels in rats

Influences of emotional stress on nicorandil pharmacokinetics were studied in rats that received physical and psychological stimuli (referred to as 'sender' and 'responder' rats, respectively) using the communication box paradigm. Concerning pharmacokinetic, there was no marked difference in the Tmax, Ka, Kel, T1/2 and Vd between the sender rats and the nonstressed control rats when both of which were orally administered 10 mg/kg of nicorandil. But the Cmax and AUC were lower and clearance (Cl) was higher in the sender rats. In the responder rats, there was no difference in Tmax, Ka, Kel, and T1/2. But the Cmax and AUC were lower and the Vd was higher than those of the control rats. On the other hand, when nicorandil was administered in a dose of 5 mg/kg subcutaneously, Tmax and T1/2 in the sender rats did not differ from those of the controls, but the Cmax, Ka and AUC were lower, and the Kel, Vd and Cl were higher. Between the responder and control rats, significant differences were found in all parameters except for Vd, i.e., Cmax, Ka, T1/2 and AUC were lower than those of control rats, and the Tmax, Kel and Cl were higher than those of control rats. This indicates that pharmacokinetics of nicorandil when administered orally and subcutaneously were influenced not only by physical stress but also by psychological stress.     

Perinatal exposure to aged and diluted sidestream cigarette smoke produces airway hyperresponsiveness in older rats

Exposing rats to aged and diluted sidestream cigarette smoke (ADSS) throughout in utero and postnatal life results in airway hyperresponsiveness and an increase in pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) in 7- to 10-week-old rats. Since human epidemiologic studies suggest that perinatal exposure to environmental tobacco smoke (ETS) may be detrimental to the lung function of older children, this study was designed to determine if perinatal exposure alone results in airway hyperresponsiveness and increased PNECs/NEBs later in life in rats. Pregnant Sprague-Dawley rats were exposed to filtered air (FA, n = 7) or ADSS (1 mg/m3 total suspended particulates, n = 7) for 4 to 6 h/day starting on Day 3 of gestation. Their pups continued to receive the same exposure regimen postnatally until 21 days of age. Thereafter all pups were exposed to FA until about 8 weeks of age. The airway responsiveness of one female pup from each litter was then assessed using an isolated perfused lung system whereby increasing doses of methacholine (-9.25 to -7.50 log mol) were administered into the pulmonary artery and lung resistance (Rl), dynamic compliance (Cdyn), and pulmonary pressure (Ppa) were measured. The number of PNECs/NEBs and mast cells per millimeter basal lamina were determined using immunocytochemical and histological staining and morphometric analysis. Statistics were performed using an unpaired Student's t test and repeated measures analysis of variance. Perinatal ADSS exposure enhanced methacholine-induced changes in Rl (p = 0.02), Cdyn (p = 0.004), and Ppa (p = 0.007). At the highest dose of methacholine, Rl in the ADSS-exposed lungs was threefold that in FA-exposed lungs. Although total PNEC number increased approximately twofold in the ADSS-exposed animals, this change was not found to be statistically significant. Mast cell number also was not different between groups. These data suggest that exposure to ADSS during the perinatal period followed by 5 weeks exposure to FA induces airway hyperresponsiveness in the absence of a significant change in PNECs, NEBs, or mast cells.     

Inhalation toxicity studies on cigarette smoke. V. Deposition of smoke particles in the respiratory system of rats under various exposure conditions

This paper describes a dosimetry experiment on rats which was designed to make a contribution towards the optimisation of exposure conditions for inhalation toxicology studies with smoke aerosols. The main conclusions drawn from the work are: (i) Under continuous exposure conditions the deposition of total particulate matter (TPM) in the respiratory system and carboxyhaemoglobin (COHb) levels in blood were linearly dependent on the concentration of smoke in the exposure chamber. (ii) Intermittent exposure gave relatively lower TPM deposition compared to continuous exposure, even after allowing for differences in actual exposure times. (iii) For arithmetically equivalent exposure levels, short exposure to high concentration gave greater TPM deposition than long exposures to low smoke concentrations. (iv) There was a good correlation between lower respiratory system (LRS) and lung deposition of TPM and blood COHb level for both continuous and intermittent exposure conditions. These findings are discussed in relation to the conduct of inhalation studies with tobacco smoke.     

香烟烟雾染毒对雄性大鼠睾丸组织 ATP 酶活性的影响

目的 探讨香烟烟雾染毒对大鼠睾丸结构及睾丸组织 ATP 酶活性的影响。方法 清洁级成年雄性 SD 大 鼠 70 只, 随机分为对照组 （10 只） 和低、 中、 高剂量染毒组 （每组 20 只, 分别给予 10 支、 20 支、 30 支香烟烟雾暴露）。 染毒组采用呼吸道静式染毒, 每日 1 次, 每次 30 min, 各剂量染毒组分别染毒 6 周和 12 周（每个时段 10 只大鼠）。 实验期间记录各组大鼠体质量变化。实验结束后, 摘取睾丸, HE 染色观察睾丸组织结构, 酶联免疫吸附试验检测睾 丸组织 Na＋-K＋-ATP 酶、 Ca２＋-ATP 酶活性。结果 随染毒剂量增加, 各组大鼠体质量逐渐降低 （P < 0.05）。染毒组 大鼠睾丸病理切片观察到不同程度损伤, 且随着染毒时间的延长和染毒剂量的增加, 损伤逐渐加重。染毒 6 周后, 高剂量组大鼠睾丸组织 Na+-K+-ATP 酶活性低于其他 3 组 （P < 0.05）, Ca2+-ATP 酶活性低于对照组 （P＜0.05）。染毒 12 周后, 低、 中、 高剂量组大鼠睾丸组织 Na+-K+-ATP 酶、 Ca2+-ATP 酶活性均较对照组显著降低（P < 0.05）。结论 香烟烟雾染毒可减缓雄性大鼠生长, 导致睾丸组织损伤, Na+-K+-ATP 酶和 Ca2+-ATP 酶活性降低。     

Changes of ghrelin and leptin levels in plasma by cigarette smoke in rats

Cigarettes smoke (CS) limits food intake and body weight increase. Ghrelin and leptin are hormones regulating appetite and energy balance. While ghrelin increases food intake and causes a positive energy balance, leptin decreases food intake and enhances a negative energy balance. To investigate the possible role of ghrelin and leptin regarding the negative energy balance caused by CS, 10-week old male Wistar rats (n = 10) were exposed to CS from 30 cigarettes twice a day for 5 days a week for four weeks. In the smoking group, food intake and body weight gain were less than those in the non-smoking group (n = 10) during the entire CS exposure. In the smoking group, the plasma levels of acyl ghrelin were significantly higher (75.9 ± 5.1 fmol/ml versus 46.5 ± 3.3 fmol/ml, p < 0.01), while those of leptin were significantly lower than those in the non-smoking group (434.9 ± 41.1 ng/ml versus 744.0 ± 45.4 ng/ml, p < 0.01) after the final CS exposure. However, the plasma des-acyl ghrelin levels were not affected by CS exposure. These results suggested that acyl ghrelin and leptin levels in plasma may change to compensate for the negative energy balance by CS.     

Inhalation bioassay of cigarette smoke in rats

Groups of 80 female rats were exposed to cigarette smoke from three types (code 13 = high tar, low nicotine; code 27 = low tar, medium nicotine; code 32 = high tar, high nicotine) of cigarettes in Maddox-ORNL smoking machines, eight cigarettes per day, 7 days per week, for up to 24 months. An additional group received sham exposures and a fifth group served as untreated controls. The sham-exposed animals had significantly lower body weights than the untreated controls. The smoke-exposed animals had significantly lower weights than the sham-exposed controls; the weights were lower for the code 27 and code 32 animals than for the code 13 animals during the second year of exposure. The survival of the code 13 animals was similar to that for the sham-exposed and untreated control group; survival times of the code 27 and code 32 animals were shorter. Body weight and survival reflected the high- and low-nicotine dose groups indicated by in vivo dosimetry measurements. Smoke-induced histopathologic lesions consisted primarily of pulmonary smoke granulomas; the smoke granulomas were less severe in the code 27 exposure group than in the groups exposed to smoke from code 13 or code 32 cigarettes. Additional changes included pulmonary alveolar epithelial hyperplasia, and squamous metaplasia and basal cell hyperplasia of laryngeal and tracheal epithelium. One primary epidermoid carcinoma was found in the lung of a code 27 rat. The rats tolerated the chronic exposures relatively well and certain of the smoke-induced lesions allowed differentiation between the different types of cigarettes.