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.     

Effect of cigarette smoke on pharmacokinetics of oral,intrarectal, or intravenous indomethacin in rats

Summary The effect of cigarette smoke exposure on the pharmacokinetics of indomethacin administered orally, intravenously or intrarectally was investigated in rats. When cirgarette smoke exposure was performed for 10 min using a Hamburg II smoking machine immediately after the oral administration of indomethacin (5 mg/kg), the plasma indomethacin concentration was significantly lowered during the first 2 h after administration. However, there was no significant difference in plasma indomethacin concentration between the cigarette smoke-exposed and nonexposed control rats thereafter. Cigarette smoke exposure caused a significant decrease in the area under the concentration-time curve from 0 to 4 h (AUC_0–4) and a prolongation of the time to reach the maximum concentration (t_max). The plasma level of O-desmethyl-indomethacin (a major metabolite) was not significantly changed by cigarette smoke. When indomethacin (5 mg/kg) was administered to rats intravenously or intrarectally, cigarette smoke exposure did not have any influence on the pharmacokinetics of indomethacin or 0-desmethyl-indomethacin. The pharmacokinetic effect of cigarette smoke on orally administered indomethacin was mimicked by the subcutaneous injection of nicotine at 0.3 mg/kg but not at 0.1 mg/kg. These results suggest that acute exposure to cigarette smoke decreases the plasma concentration of indomethacin when it is administered orally but not intrarectally or intravenously. Send offprint requests to R. Oishi at the above address     

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.     

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 exposure to standard- and nicotine-reduced-cigarette smoke on pharmacokinetics of theophylline and cimetidine in rats.

Influences of exposure to standard- (containing nicotine and tar) and nicotine-reduced-cigarette smoke on the pharmacokinetics of theophylline (20 mg/kg, per os) and cimetidine (50 mg/kg, per os) were investigated in rats. Animals were exposed to standard- or nicotine-reduced-cigarette smoke for 8 min with a "smoking machine". In control rats, theophylline concentrations in plasma increased rapidly, peaked 2 h later, and then decreased gradually. Concentrations of theophylline in plasma of rats exposed to standard- and nicotine-reduced-cigarette smoke were suppressed in comparison with that of control rats, and the suppressive effect of nicotine-reduced-cigarette smoke was weaker than that of standard-cigarette smoke. The suppression of theophylline concentrations in plasma induced by exposure to cigarette smoke may be due to nicotine and other constituents of the cigarette smoke, even if the effects are slight. For cimetidine, no difference was found between drug concentration in plasma of rats exposed to nicotine-reduced-cigarette smoke and that of control rats; however, the drug concentration in plasma of rats exposed to standard-cigarette smoke was markedly suppressed. These results suggest that the suppression of cimetidine concentrations in plasma may be due solely to nicotine in cigarette smoke.     

Effects of chronic smoke exposure on the cardiovascular responses to acute nicotine infusion in the rat

Rats were exposed daily to cigarette smoke for 17-22 weeks in order to characterize mean arterial pressure and regional hemodynamic effects of chronic smoke exposure and to determine if cardiovascular reactivity to acute nicotine infusions is altered by chronic smoke exposure. Urethane-anesthetized animals were instrumented with miniaturized pulsed-Doppler flow probes on the iliac and mesenteric vascular beds. Under resting conditions sham-smoked and smoke-exposed animals had similar levels of mean arterial pressure and mesenteric blood flow; however, resting heart rate was lower in the smoke-exposed group, while iliac blood flow was elevated in the smoke-exposed group. Acute nicotine infusion (6.25, 12.5 and 25 micrograms/kg per min) produced equivalent, dose-dependent pressor effects as well as increases in iliac and mesenteric resistance in sham and smoke-exposed groups. Thus, chronic cigarette smoke-exposure in rats may exert significant cardiovascular effects other than on arterial pressure such as lowered heart rate and elevated blood flow to skeletal muscle beds, while cardiovascular responses to nicotine are not altered by chronic smoke-exposure.     

Histopathology,Urine Mutacenicity,and Bone Marrow Cytocenetics of Mice Exposed Nose-Only to Smoke from Cigarettes that Burn or Heat Tobacco

Abstract

Male and female B6C3F₁ mice were exposed nose-only to smoke from a test cigarette that heats tobacco, or from a reference cigarette that burns tobacco. Cigarette smoke was generated by a smoking machine, and the concentrations of wet total particulate matter (WTPM) were adjusted to 0, 0.16, 0.32, or 0.64 mg/l. Exposures were performed 1 h/day for 14 consecutive days. Urine mutagenicity was assessed by a modified Ames bacterial assay Clastogenesis (sister-chromatid exchanges, chromosome aberrations, and micronuclei) was evaluated in bone marrow cells. Respiratory rate was depressed significantly by exposure to smoke from the reference cigarette, but not the test. Blood carboxyhemoglobin, plasma nicotine, and plasma cotinine showed exposure-dependent increases in the smoke-exposed animals. Histopathological changes similar to those noted previously in smoke-exposed rats were noted, with fewer and less pronounced changes in the animals exposed to smoke from the test cigarette when compared with the reference. Positive urine mutagenicity and clastogenic responses were observed in the animals treated with positive control chemicals. However the urine mutagenicity and clastogenic responses of smoke-exposed animals (both cigarette types) were not different from those of sham-exposed animals, except for the micronucleus assay where animals exposed to high concentrations of reference cigarette smoke showed a significant increase over controls.     

In utero exposure to 1R4F reference cigarette smoke: evaluation of developmental toxicity.

The potential developmental effects of 1R4F reference cigarette smoke were examined using Sprague-Dawley rats exposed for 2 h/day, 7 days/week, by nose-only inhalation at target mainstream smoke concentrations of 150, 300, and 600 mg/m3 total particulate matter (TPM). Males were exposed 4 weeks prior to and during mating, with females exposed 2 weeks prior to mating and during mating, and through gestation day (GD) 20. Sham controls received filtered air to simulate nose-only exposure, while cage controls were maintained untreated. Smoke exposure was confirmed through biomarker evaluation (parental: carboxyhemoglobin, nicotine, and cotinine; fetal: nicotine and cotinine). Characteristic cigarette smoke-related histopathologic changes including nasal epithelial hyperplasia and squamous metaplasia and pigmented macrophages in the lung were observed in all exposed parental groups. Maternal toxicity during gestation was indicated at smoke concentrations of 300 and 600 mg TPM/m3, where corrected total body weight gain was significantly (p 相似文献   

Subchronic inhalation by rats of mainstream smoke from a cigarette that primarily heats tobacco compared to a cigarette that burns tobacco

A subchronic, nose-only inhalation study comparing the potential biological activity of mainstream smoke from a cigarette that primarily heats tobacco (Eclipse) to mainstream smoke from a 1R4F reference cigarette was conducted using Sprague-Dawley rats of each gender. Smoke exposures were for 1 h/day, 5 days/wk for 13 wk, at concentrations of 0, 0.16, 0.32, or 0.64 mg wet total particulate matter (WTPM)/L air. Smoke was generated at the Federal Trade Commission standard of a 2-s puff of 35 ml, taken once per minute. Clinical signs, body and organ weights, clinical chemistry, hematology, carboxyhemoglobin, serum nicotine, plethysmography, gross pathology, and histopathology were determined. Plethysmography indicated that respiratory rate was decreased at all concentrations of 1R4F smoke, but only at the high concentration of Eclipse smoke. Tidal volume was depressed and minute volume was lower for all smoke-exposed rats. Rats exposed to Eclipse smoke inhaled more smoke at the low and mid-concentration exposures than rats exposed to equivalent concentrations 1R4F smoke. Carboxyhemoglobin and serum nicotine were directly related to the exposure concentrations of carbon monoxide (CO) and nicotine in an exposure-dependent manner. Body weights were slightly lower in smoke-exposed rats, while no treatment-related effects were seen in clinical signs, clinical chemistry, hematology, or gross changes at necropsy. The only treatment-related effect seen in organ weights was an increase in heart weight in females in the Eclipse high-concentration exposure group, attributed to higher CO in the Eclipse exposure atmosphere. Higher CO resulted from the lower dilution of Eclipse smoke required to maintain WTPM concentrations equal to those of the 1R4F smoke, and not from a higher CO yield from Eclipse cigarettes. Nasal epithelial hyperplasia and ventral laryngeal squamous metaplasia were noted after exposure to either the 1R4F or Eclipse smoke. The degree of change was less in Eclipse smoke-exposed rats. Lung macrophages were increased to a similar extent in the Eclipse and 1R4F smoke-exposed groups. Brown/gold pigmented macrophages were detected in the lungs of rats exposed to 1R4F smoke, but not those exposed to Eclipse smoke. Subsets of rats from each group were maintained for an additional 13 wk without smoke exposures. Most of the changes noted at the end of the smoke exposures had disappeared, while those that remained were regressing toward normal. Evaluation of these findings indicated the overall biological activity of Eclipse smoke was less than 1R4F smoke at comparable exposure concentrations.     

Effect of cigarette smoking on theophylline pharmacokinetics in rats.

The effect of acute cigarette smoke inhalation on the plasma levels of theophylline administered orally and parenterally to rats has been studied. The animals were exposed to smoke containing low- or high-nicotine/tar concentration for 10 min immediately after oral, intraperitoneal (i.p.) or intravenous (i.v.) administration of theophylline. The plasma levels of theophylline when administered orally (20 mg kg-1) were lower in the two cigarette smoke-inhaling groups than in the non-smoking restrained control group, with the lowest values in the high-nicotine/tar group. The plasma levels (8 and 12 h after administration) in the high-nicotine/tar group when theophylline was administered i.p. (10 mg kg-1), were also slightly lower than in the non-smoking restrained control group but this was not significant. When theophylline was administered i.v. (5 mg kg-1), there was no difference between the high-nicotine/tar group and the non-smoking restrained control group. These data indicate that cigarette smoke inhalation causes suppression or delay of theophylline absorption from the gastrointestinal tract.     

SUBCHRONIC INHALATION BY RATS OF MAINSTREAM SMOKE FROM A CIGARETTE THAT PRIMARILY HEATS TOBACCO COMPARED TO A CIGARETTE THAT BURNS TOBACCO

A subchronic, nose-only inhalation study comparing the potential biological activity of mainstream smoke from a cigarette that primarily heats tobacco (Eclipse) to mainstream smoke from a 1R4F reference cigarette was conducted using Sprague-Dawley rats of each gender. Smoke exposures were for 1 h/day, 5 days/wk for 13 wk, at concentrations of 0, 0.16, 0.32, or 0.64 mg wet total particulate matter (WTPM)/L air. Smoke was generated at the Federal Trade Commission standard of a 2-s puff of 35 ml, taken once per minute. Clinical signs, body and organ weights, clinical chemistry, hematology, carboxyhemoglobin, serum nicotine, plethysmography, gross pathology, and histopathology were determined. Plethysmography indicated that respiratory rate was decreased at all concentrations of 1R4F smoke, but only at the high concentration of Eclipse smoke. Tidal volume was depressed and minute volume was lower for all smoke-exposed rats. Rats exposed to Eclipse smoke inhaled more smoke at the low and mid-concentration exposures than rats exposed to equivalent concentrations 1R4F smoke. Carboxyhemoglobin and serum nicotine were directly related to the exposure concentrations of carbon monoxide (CO) and nicotine in an exposure-dependent manner. Body weights were slightly lower in smokeexposed rats, while no treatment-related effects were seen in clinical signs, clinical chemistry, hematology, or gross changes at necropsy. The only treatment-related effect seen in organ weights was an increase in heart weight in females in the Eclipse high-concentration exposure group, attributed to higher CO in the Eclipse exposure atmosphere. Higher CO resulted from the lower dilution of Eclipse smoke required to maintain WTPM concentrations equal to those of the 1R4F smoke, and not from a higher CO yield from Eclipse cigarettes. Nasal epithelial hyperplasia and ventral laryngeal squamous metaplasia were noted after exposure to either the 1R4F or Eclipse smoke. The degree of change was less in Eclipse smoke-exposed rats. Lung macrophages were increased to a similar extent in the Eclipse and 1R4F smoke-exposed groups. Brown/gold pigmented macrophages were detected in the lungs of rats exposed to 1R4F smoke, but not those exposed to Eclipse smoke. Subsets of rats from each group were maintained for an additional 13 wk without smoke exposures. Most of the changes noted at the end of the smoke exposures had disappeared, while those that remained were regressing toward normal. Evaluation of these findings indicated the overall biological activity of Eclipse smoke was less than 1R4F smoke at comparable exposure concentrations.     

Nicotine dose-concentration relationship and pregnancy outcomes in rat: biologic plausibility and implications for future research

Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.     

Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure

The pharmacokinetics of nicotine and its major metabolites was evaluated in male rats after multiple-cigarette smoke exposure. A smoke-exposure apparatus was used to deliver cigarette smoke to the exposure chamber. The rats were exposed to smoke from a single cigarette every 8 hr for 14 days and to the smoke of a cigarette spiked with radiolabeled nicotine on the 15th day. Blood and urine samples were collected at timed intervals during the 10-min smoke-exposure period of the last cigarette and up to 48 hr thereafter. Nicotine, cotinine, and other polar metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. The data were analyzed by computer fitting, and the derived pharmacokinetic parameters were compared to those observed after a single iv injection of nicotine and after a single-cigarette smoke exposure. The results indicated that the amount of nicotine absorbed from multiple-cigarette smoke was approximately 10-fold greater than that absorbed from a single cigarette. Also, unlike the single-cigarette smoke exposure experiment, nicotine plasma levels did not decay monotonically but increased after the 5th hr, and high plasma concentrations persisted for 30 hr. The rate and extent of the formation of cotinine, the major metabolite of nicotine, were decreased as compared with their values following a single-cigarette smoke exposure. It was concluded that nicotine or a constituent of tobacco smoke inhibits the formation of cotinine and may affect the biotransformation of other metabolites. Urinary excretion tended to support the conclusions that the pharmacokinetic parameters of nicotine and its metabolites were altered upon multiple as compared to single dose exposure.     

Effects of caffeic acid phenethyl ester on the histopathological changes in the lungs of cigarette smoke-exposed rabbits

We aimed at evaluating the effects of caffeic acid phenethyl ester (CAPE) on the histopathological changes in the lungs of rabbits exposed to cigarette smoke exposure. Four groups with six rabbits each were as follows: cigarette smoke group, CAPE group, cigarette smoke + CAPE group and control group. The cigarette smoke group was exposed to cigarette smoke 1 hr daily for 1 month. The CAPE group was administered intraperitoneal CAPE. The CAPE + cigarette smoke group was both exposed to cigarette smoke and was administered intraperitoneal CAPE. The control group was exposed to clean air. After 1 month, the rabbits were killed and the lung tissues were examined histopathologically. Peribronchial and intraparenchymal inflammation, intraparenchymal vascular congestion and thrombosis, intraparenchymal haemorrhage, respiratory epithelial proliferation, number of macrophages in the bronchiolar and alveolar lumen, alveolar destruction, emphysematous changes and bronchoalveolar haemorrhage scores were significantly higher in the cigarette smoke group than in the control group. Administration of CAPE to cigarette smoke-exposed rabbits significantly prevented all these changes. CAPE seems to have significant preventive effects on the severe histopathological changes in the lungs associated with cigarette smoke exposure. However, in some instances, it may not alter the progression to fibrosis.     

Comparison of the behavioral effects of cigarette smoke and pure nicotine in rats

Animal models of tobacco dependence typically rely on parenteral administration of pure nicotine. Models using cigarette smoke inhalation might more accurately simulate nicotine exposure in smokers. The primary goal of this study was to validate methods for administering cigarette smoke to rats using exposure conditions that were clinically relevant and also produced brain nicotine levels similar to those produced by behaviorally active doses of pure nicotine. A secondary goal was to begin examining the behavioral effects of smoke. Nose-only exposure (NOE) to smoke for 10-45 min or whole-body exposure (WBE) to smoke for 1-4 h produced serum nicotine concentrations similar to those in smokers (14-55 ng/ml), without excessive carbon monoxide exposure. Daily nicotine (0.1 mg/kg, s.c.) induced locomotor sensitization whereas 45-min NOE producing brain nicotine levels within the same range did not. Nicotine 0.125 mg/kg s.c. reversed withdrawal from a chronic nicotine infusion as measured by elevations in intracranial self-stimulation thresholds whereas 4-h WBE producing similar brain nicotine levels did not. These data demonstrate the feasibility of delivering cigarette smoke to rats at clinically relevant doses, and provide preliminary evidence that the behavioral effects of nicotine delivered in smoke may differ from those of pure nicotine.     

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.     

Effects of nicorandil and verapamil, antianginal agents, on plasma digoxin concentrations in rats and dogs

The effects of equihypotensive doses of nicorandil and verapamil on plasma digoxin concentrations have been assessed in rats and dogs. In a single digoxin dose study, digoxin (1 mg kg-1) alone, or in combination with nicorandil (5 mg kg-1) or verapamil (25 mg kg-1) was given orally to rats. When given chronically to rats, a single dose of digoxin (1 mg kg-1) orally for 7 consecutive days was followed, on day 8, by digoxin alone, or together with nicorandil (5 mg kg-1) or verapamil (25 mg kg-1). In dogs, a loading dose of digoxin (50 micrograms kg-1) was given orally on day 1, then 25 micrograms kg-1 was administered for the following 6 days. On day 8, digoxin (50 micrograms kg-1) was given with nicorandil (5 mg kg-1) or verapamil (20 mg kg-1). In rats, the AUC0-24 and Cmax of plasma digoxin were enhanced significantly by coadministration of verapamil, but not by nicorandil. In dogs, verapamil significantly increased the Cmax of plasma digoxin, but not the AUC. Nicorandil had no effect on either parameter.     

Plasma nicotine and cotinine in tobacco smoke exposed beagle dogs

Nicotine and cotinine have been determined in plasma samples from 87 beagle dogs chronically exposed to cigarette smoke with three different levels of nicotine. An additional 18 sham-exposed animals were included in the study as controls. Smoke was administered to the animals through permanent tracheostomas via cuffed tracheostomy tubes and was generated from reference cigarettes under standard puffing parameters by ADL-II smoking machines. The dogs were exposed for an average of 2 years prior to sample collection. The results from blood samples collected at specific intervals in the daily exposure schedules indicate that nicotine may be useful as a relative index of smoke exposure. At elevated exposure levels, average blood concentrations were related to the number of cigarettes smoked as well as the nitocine delivery of the cigarette. Cotinine was found to increase more slowly than nicotine and was also metabolized more rapidly than in humans. Overall, the study affords an examination of the relationship of plasma nicotine and cotinine with estimated nicotine exposure.     

Mecamylamine increases nicotine preference and attenuates nicotine discrimination

Eight subjects evaluated various qualities of cigarette smoke after being given a range of doses (0, 2.5, 10 and 20 mg) of the nicotinic receptor blocker mecamylamine. In one test condition, subjects were given either high or low nicotine tobacco smoke to determine the effects of mecamylamine on their subjective responses. In another test condition, subjects were allowed to adjust the nicotine dose level of the smoke to determine the effects of mecamylamine on dose preference. When the subjects evaluated puffs of smoke with high and low nicotine content, mecamylamine caused a dose-related decrease in the self-rated strength and harshness of the high nicotine dose level smoke. In contrast, there was little effect on the low dose smoke. At the highest mecamylamine dose (20 mg) there was no significant difference in the ratings of high and low nicotine cigarettes. Low doses of mecamylamine decreased the reported desire for a cigarette, and also attenuated the reduction in desire for a cigarette caused by smoking. When the subjects were allowed to select their preferred level of nicotine intake using a smoke mixing device, the 10 and 20 mg doses of mecamylamine caused a significant increase in self-administered nicotine dose level. Despite this compensatory increase in nicotine self-administration, the reduction in desire for a cigarette after smoking was still less than after placebo.     

Enhanced chemotaxis and superoxide anion production by polymorphonuclear leukocytes from nicotine-treated and smoke-exposed rats

Although previous studies have shown that polymorphonuclear leukocytes (PMNs) exposed to nicotine in vitro exhibit enhanced superoxide anion generation and chemotactic responses, it is not known whether in vivo exposure to the alkaloid causes the same alterations in PMN function. Accordingly, this study evaluated superoxide anion generation evoked by phorbol myristate acetate (PMA) and chemotactic responses to formylmethionylleucylphenylalanine (fMLP) in PMNs isolated from rats treated acutely or subchronically with nicotine and from rats chronically exposed to cigarette smoke. Acute or subchronic (twice daily for 7 days) i.p. injection of 0.2 or 0.02 mg/kg nicotine potentiated PMA-induced superoxide anion generation by PMNs. Similarly, acute i.p. injection of 0.2 mg/kg nicotine or subchronic treatment with 0.02 mg/kg nicotine potentiated fMLP-induced chemotaxis. Subchronic treatment with 0.2 mg/kg of the alkaloid blunted fMLP-induced chemotaxis, in contrast to the potentiating actions of the lower dose. Treatment with nicotine mimicked the effects of tobacco smoke exposure. A 15-week exposure regimen to either sidestream and mainstream smoke from University of Kentucky 2R1 reference cigarettes potentiated PMA-induced superoxide anion generation. Mainstream but not sidestream smoke also enhanced chemotactic responses to fMLP. Viewed collectively, these observations indicate that in vivo exposure to nicotine or to tobacco smoke augment PMN superoxide anion generation and chemotactic responses to selected stimuli and thus implicate such adverse actions of smoking on PMN function in certain pathologies associated with excessive tobacco smoke exposure.