Search PubMed⌕ Search

Biomedical subjects

N L Benowitz

Publications and source records attributed to N L Benowitz.

At least 55 records · Page 3Linked to original sources
PubMed1998

Nicotine metabolism and intake in black and white smokers.

CONTEXT: Racial differences in tobacco-related diseases are not fully explained by cigarette-smoking behavior. Despite smoking fewer cigarettes per day, blacks have higher levels of serum cotinine, the proximate metabolite of nicotine. OBJECTIVE: To compare the rates of metabolism and the daily intake of nicotine in black smokers and white smokers. DESIGN: Participants received simultaneous infusions of deuterium-labeled nicotine and cotinine. Urine was collected for determination of total clearance of nicotine and cotinine, fractional conversion of nicotine to cotinine, and cotinine elimination rate. Using cotinine levels during ad libitum smoking and clearance data, the daily intake of nicotine from smoking was estimated. SETTING: Metabolic ward of a university-affiliated public hospital. PARTICIPANTS: A total of 40 black and 39 white smokers, average consumption of 14 and 14.7 cigarettes per day, respectively, of similar age (mean, 32.5 and 32.3 years, respectively) and body weight (mean, 73.3 and 68.8 kg, respectively). MAIN OUTCOME MEASURES: Clearance (renal and nonrenal), half-life, and volume of distribution of nicotine and cotinine and the calculated daily intake of nicotine. RESULTS: The total and nonrenal clearances of nicotine were not significantly different, respectively, in blacks (17.7 and 17.2 mL x min(-1) x kg(-1)) compared with whites (19.6 and 18.9 mL x min(-1) x kg(-1)) (P=.11 and .20). However, the total and nonrenal clearances of cotinine were significantly lower, respectively, in blacks (0.56 and 0.47 mL x min(-1) x kg(-1)) than in whites (0.68 vs 0.61 mL x min(-1) x kg(-1); P=.009 for each comparison). The nicotine intake per cigarette was 30% greater in blacks compared with whites (1.41 vs 1.09 mg per cigarette, respectively; P=.02). Volume of distribution did not differ for the 2 groups, but cotinine half-life was higher in blacks than in whites (1064 vs 950 minutes, respectively; P = .07). CONCLUSIONS: Higher levels of cotinine per cigarette smoked by blacks compared with whites can be explained by both slower clearance of cotinine and higher intake of nicotine per cigarette in blacks. Greater nicotine and therefore greater tobacco smoke intake per cigarette could, in part, explain some of the ethnic differences in smoking-related disease risks.

Adult↗
PubMed1998

Rate of caffeine metabolism and risk of spontaneous abortion.

In a case-control study of 73 women with and 141 women without spontaneous abortion, the authors determined the activity of the three principal caffeine-metabolizing enzymes--cytochrome P-4501A2 (CYP1A2), xanthine oxidase, and N-acetyltransferase 2--by measuring levels of caffeine metabolites in urine. After examining the effect of enzyme activity and different levels of caffeine intake, they concluded that there was no evidence that an interaction between enzyme activity and caffeine intake during pregnancy resulted in risk of spontaneous abortion. In a subsample comparing 24 cases with recurrent (two or more) spontaneous abortions and 21 controls with two or more livebirths and no previous spontaneous abortions, the unadjusted odds ratio for low CYP1A2 enzyme activity (below the median) was 0.92 (95% confidence interval (CI) 0.28-3.04) compared with higher CYP1A2 activity. The odds ratio for risk of recurrent spontaneous abortion and low xanthine oxidase activity (below the median) versus higher activity was 0.37 (95% CI 0.10-1.29). Phenotypically slow acetylators (N-acetyltransferase 2 index <0.37) had an odds ratio of 1.58 (95% CI 0.48-5.13) for recurrent loss compared with rapid acetylators. Thus, some association of the latter two caffeine-metabolizing enzymes with recurrent spontaneous abortion is suggested but may also be due to chance.

Abortion, Spontaneous↗
PubMed1998

Effects of cotinine on information processing in nonsmokers.

Cotinine, the major proximate metabolite of nicotine, is present in smokers in higher concentrations and for a longer time than nicotine, yet its effects on information processing have not previously been reported. We studied the cognitive effects of cotinine in non-smokers. Sixteen subjects were tested on three doses of cotinine (0.5, 1.0, and 1.5 mg cotinine base/kg), and placebo, on a choice reaction time (RT) task and on a verbal recall task with short and long lists. Cotinine significantly impaired recall on the long list and displayed non-significant but generally consistent dose-related slowing of RT and N100 latency. The acute effects of cotinine were small, and probably do not account for the cognitive deficits observed in tobacco withdrawal, although the cognitive effects of chronic cotinine administration need to be investigated.

Adult↗
PubMed1998

Effects of stress on circulating nicotine and cotinine levels and in vitro nicotine metabolism in the rat.

The effects of physical and psychological stress on circulating nicotine levels and conversion of nicotine to cotinine were examined in the rat. Animals received one of three dosages of nicotine (0, 6, and 12 mg/kg) via miniosmotic pumps. On day 14 of drug infusion, animals from each drug condition were randomly assigned to one of three stress conditions (noise, rubber ligature, or no stress). After 2.5 h of stress exposure, animals were killed and plasma nicotine and cotinine were measured in vivo and hepatic conversion of nicotine to cotinine was determined in vitro. Stress lowered blood nicotine levels. However, this difference was statistically significant only among animals receiving 12 mg/kg per day nicotine. In contrast, stress had no consistent effect on either measure of conversion of nicotine to cotinine in rats. Taken together, these results suggest that stress lowers circulating nicotine levels. However, the mechanism by which this occurs remains unclear.

Animals↗
PubMed1998

Dose-related cardiovascular and endocrine effects of transdermal nicotine.

BACKGROUND: Transdermal nicotine in doses up to 21 mg/24 hr is used to facilitate smoking cessation. However, this dose does not achieve the nicotine plasma levels seen among heavy smokers, and underdosing may be one of the reasons for the limited efficacy of transdermal nicotine. There are some concerns about the adverse cardiovascular effects of nicotine, especially with concomitant smoking. Treatment with higher doses of transdermal nicotine has been proposed for highly dependent smokers, but the effects of such treatment on the cardiovascular system have not been determined. The objective of this study was to determine the cardiovascular effects of high-dose transdermal nicotine with concomitant smoking. METHODS: Twelve healthy male smokers received three doses of transdermal nicotine (21, 42, and 63 mg/24 hr) and placebo, each for 5 days, in a balanced order. The subjects smoked during the first 4 days of each treatment and abstained from smoking during the fifth day. Ambulatory 24-hour daytime and nighttime heart rate and blood pressure values were determined for each treatment; plasma nicotine, cotinine, and carboxyhemoglobin levels and urinary catecholamines with aldosterone were measured on days 4 and 5. The data were compared by means of repeated-measures ANOVA. RESULTS: There was no difference in heart rate or blood pressure and no changes in the pattern of circadian variations with various transdermal nicotine doses compared with smoking alone, consistent with the development of tolerance. Urinary epinephrine level was significantly higher (p < 0.05) with transdermal nicotine compared with no nicotine but was not higher with transdermal nicotine and smoking compared with smoking alone. No change was found in fibrinogen and lipid profiles with different nicotine doses. CONCLUSIONS: High-dose nicotine treatment, even with concomitant smoking, caused no short-term adverse effects on the cardiovascular system.

Administration, Cutaneous↗
PubMed1998

Relationship of blood pressure, heart rate and behavioral mood state to norepinephrine kinetics in younger and older men following caffeine ingestion.

OBJECTIVE: To examine age-related differences in blood pressure, heart rate, behavioral mood state and norepinephrine kinetics after caffeine ingestion in younger and older men. DESIGN: Placebo-controlled, double-blind study. SETTING: General Clinical Research Center, University of Vermont. SUBJECTS: 10 older (O) (65-80 y) and 10 younger (Y) (19-26 y) healthy men who were moderate consumers of caffeine (Y= 126+/-30 mg/d; O = 160 44 mg/d:NS; mean +/- s.e.m.). INTERVENTION: All volunteers were characterized for fasting plasma glucose, insulin and caffeine levels, body composition, anthropometry, physical activity, and energy intake. Before and after placebo and caffeine ingestion (5 mg/kg fat-free mass) test days, the following variables were measured in all subjects: heart rate, blood pressure, mood state, and norepinephrine concentrations (NEconc), appearance (NEapp) and clearance (NEcl). MAIN OUTCOME MEASURES: Systolic and diastolic blood pressure, heart rate, mood state, and norepinephrine kinetic responses to placebo and caffeine ingestion. RESULTS: Following caffeine ingestion, plasma caffeine levels were similar in Y and O men. Systolic (SBP) and diastolic (DBP) blood pressure increased significantly (P < 0.01) from baseline by 9% (130+/-6 vs 142+/-6 mmHg) and 3% (75+/-3 vs 77+/-3 mmHg), respectively, in O men following caffeine ingestion, but remained unchanged in Y men. Self-reported feelings of tension (P < 0.05) and anger (P = 0.06) decreased in O men, while anger tended to increase in Y men (P < 0.06) following caffeine ingestion. Heart rates in both groups were unaltered following caffeine ingestion. No differences were noted at baseline between O and Y men for NEconc, NEapp and NEcl. After caffeine ingestion, NEconc were significantly greater in O than Y men, whereas NEapp and NEcl rates did not differ from baseline in either group. Blood pressure and subjective mood state effects of caffeine were not related to changes in norepinephrine kinetics. CONCLUSION: Age may play a role in augmenting blood pressure response and reducing subjective feelings of anger and tension following caffeine ingestion, suggesting that the elderly are more reactive to the pressor and less sensitive to the subjective effects of the drug. These effects do not appear to be mediated by changes in sympathetic nervous system activity.

Adult↗
PubMed1998

Caffeine withdrawal in normal school-age children.

OBJECTIVE: Caffeine is widely consumed by children around the world. The purpose of this study was to determine whether children manifest withdrawal effects after cessation of caffeine intake. METHOD: Thirty normal children completed the single-blind, within-subjects, repeated-measures study with weekly sessions. Subjects were tested four times: (1) baseline (on regular caffeine diet); (2) on caffeine (approximately 120 to 145 mg/day); (3) during withdrawal (24 hours after discontinuation of caffeine taken for 13 consecutive days); and (4) at return to baseline. Subjects were evaluated with self-report measures of symptoms and objective measures of attention, motor performance, processing speed, and memory. RESULTS: During caffeine withdrawal, there was a significant deterioration on response time of a visual continuous performance test of attention. This finding is consistent with caffeine withdrawal. The deterioration in response time appeared to persist for 1 week. CONCLUSIONS: Twenty-four hours after children discontinued caffeine, there was a decrease in performance on reaction time of a task requiring sustained attention. Further work is indicated to determine whether children manifest caffeine withdrawal effects after cessation of caffeine intake.

Analysis of Variance↗
PubMed1998

Evaluation of pharmacokinetic methods used to estimate caffeine clearance and comparison with a Bayesian forecasting method.

Simplified pharmacokinetic methods have been used to estimate caffeine clearance in subjects with liver disease. There is a need to have a reliable, easy to implement method for research and possible clinical use. This study evaluates the use of Bayesian pharmacokinetic forecasting techniques to estimate caffeine clearance and compares its performance to other published methods. Commonly used published methods include the two-concentration overnight salivary clearance method (Jost method) and a method that samples caffeine concentrations over a 4-hour time period (Nagel method). Both have been used in studies incorporating serial measurements of caffeine clearance to predict clinical outcomes in subjects with liver disease, but these approaches have not been proven useful. However, neither method has been formally evaluated for accuracy in estimating caffeine clearance in subjects with cirrhosis. The performance of the Jost, Nagel, and Bayesian methods was compared to a Gold Standard method that accurately measured caffeine clearance in healthy subjects and subjects with cirrhosis using an intravenous infusion of stable isotope-labeled caffeine. The Bayesian method, even when only one measured concentration of caffeine was used, was more accurate, better correlated to the Gold Standard method, and had less intraindividual variation than the two previously published methods. Before the idea of using serial measurements of caffeine clearance for clinical usefulness is rejected, a reevaluation using methods of estimating caffeine clearance that are more accurate than previous paradigms is needed.

Bayes Theorem↗
PubMed1998

Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American Medical Association.

OBJECTIVE: To assess the feasibility of reducing tobacco-caused disease by gradually removing nicotine from cigarettes until they would not be effective causes of nicotine addiction. DATA SOURCES: Issues posed by such an approach, and potential solutions, were identified from analysis of literature published by the US Food and Drug Administration (FDA) in its 1996 Tobacco Rule, comments of the tobacco industry and other institutions and individuals on the rule, review of the reference lists of relevant journal articles, other government publications, and presentations made at scientific conferences. DATA SYNTHESIS: The role of nicotine in causing and sustaining tobacco use was evaluated to project the impact of a nicotine reduction strategy on initiation and maintenance of, and relapse to, tobacco use. A range of potential concerns and barriers was addressed, including the technical feasibility of reducing cigarette nicotine content to non-addictive levels, the possibility that compensatory smoking would reduce potential health benefits, and whether such an approach would foster illicit ("black market") tobacco sales. Education, treatment, and research needs to enable a nicotine reduction strategy were also addressed. The Council on Scientific Affairs came to the following conclusions: (a) gradually eliminating nicotine from cigarettes is technically feasible; (b) a nicotine reduction strategy holds great promise in preventing adolescent tobacco addiction and assisting the millions of current cigarette smokers in their efforts to quit using tobacco products; (c) potential problems such as compensatory over-smoking of denicotinised cigarettes and black market sales could be minimised by providing alternate forms of nicotine delivery with less or little risk to health, as part of expanded access to treatment; and (d) such a strategy would need to be accompanied by relevant research and increased efforts to educate consumers and health professionals about tobacco and health. CONCLUSIONS: The council recommends the following: (a) that cessation of tobacco use should be the goal for all tobacco users; (b) that the American Medical Association continue to support FDA authority over tobacco products, and FDA classification of nicotine as a drug and tobacco products as drug-delivery devices; (c) that research be encouraged on cigarette modifications that may result in less addicting cigarettes; (d) that the FDA require that the addictiveness of cigarettes be reduced within 5-10 years; (e) expanded surveillance to monitor trends in the use of tobacco products and other nicotine-containing products; (f) expanded access to smoking cessation treatment, and strengthening of the treatment infrastructure; and (g) more accurate labelling of tobacco products, including a more meaningful and understandable indication of nicotine content.

Behavior, Addictive↗
PubMed1998

Suppression of nicotine intake during ad libitum cigarette smoking by high-dose transdermal nicotine.

Nicotine replacement therapy is believed to facilitate smoking cessation both by relieving withdrawal symptoms and by reducing the psychological reward from smoking. The latter might occur via down-regulation of nicotine receptors in the brain, which might require high levels of nicotine exposure. Our study examined the hypothesis that transdermal nicotine, dosed up to three times the doses currently recommended for smoking cessation, would suppress nicotine intake from ad libitum smoking in a dose-dependent manner. Eleven volunteers with no desire to quit smoking received placebo or 21, 42, and 63 mg/day transdermal nicotine, with and without cigarette smoking, in a blinded crossover study. Cigarette smoking was permitted as desired. Transdermal nicotine suppressed nicotine intake from cigarette smoking by 3%, 10% and 40% on average in the 21, 42 and 63 mg/day conditions. The number of cigarettes smoked per day declined from an average of 17.2 to 12.7 and the intake of nicotine per cigarette declined from 2.5 to 1.6 mg, comparing placebo and 63 mg nicotine conditions. Our study results suggest that high-dose transdermal nicotine has the potential to substantially suppress the intake of tobacco smoke and could be a useful strategy for smoking cessation therapy or for reducing the harm caused by smoking.

Administration, Cutaneous↗
PubMed1997

Determinants of plasma concentrations of nicotine and cotinine during cigarette smoking and transdermal nicotine treatment.

OBJECTIVE: Interindividual variability in plasma concentrations of nicotine and its proximate metabolite, cotinine, is considerable during smoking and transdermal nicotine treatment, even among individuals taking in nominally similar doses of nicotine. This report explores the determinants of this variability and the utility of baseline (smoking) plasma concentrations to predict concentrations during transdermal nicotine treatment. METHODS: Data were analysed from a smoking cessation study (n = 466), and from a pharmacokinetic study (n = 12). Multiple regression models examined the relationships of plasma concentrations to individual characteristics such as smoking pattern, absorbed dose of nicotine, and pharmacokinetic parameters. RESULTS: Plasma concentrations of nicotine and cotinine were highly variable in both studies. Indirect estimates of plasma clearance (baseline plasma concentration divided by cigarettes per day) together with other factors could account for 18 to 33% of the variability during transdermal nicotine treatment in the smoking cessation study. In contrast, 75 to 99% was accounted for by direct measurements of plasma clearances and systemic dose of nicotine in the pharmacokinetic study. CONCLUSION: Plasma concentrations of nicotine and cotinine during transdermal nicotine treatment are poorly predicted by clinical history or baseline plasma concentrations. This is a result of inadequate characterisation of highly variable individual pharmacokinetic parameters and absorbed dose of nicotine. Considering the interindividual variability of plasma nicotine and cotinine concentrations together with the lack of clinical end-points for transdermal nicotine dosing, it seems logical to investigate the utility of a therapeutic drug monitoring approach for transdermal nicotine treatment-particularly for high dose regimens (> 22 mg per 24 hours).

Administration, Cutaneous↗
PubMed1997

Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotine nasal spray, and intravenous nicotine.

BACKGROUND AND OBJECTIVES: Delivery of a high concentration bolus of nicotine through the arterial circulation is believed to be an important determinant of the addictive, behavioral, and physiologic effects of nicotine. To better understand the pharmacologic features of nicotine with different routes of administration, we measured arterial and venous plasma concentrations of nicotine, cotinine, epinephrine, and norepinephrine after tobacco smoking, intravenous nicotine infusion, and use of a nicotine nasal spray. SUBJECTS AND METHODS: Arterial and venous blood samples were drawn simultaneously from 12 male smokers. Six subjects received a single dose of 1 mg nicotine nasal spray, and six subjects smoked cigarettes, one puff per minute for 10 minutes. All 12 subjects were administered nicotine as a 30-minute infusion beginning 70 minutes after administration of the nicotine nasal spray or commencement of smoking. RESULTS: The mean peak arterial plasma concentrations of nicotine (Cmax) after smoking or administration of nicotine nasal spray, or intravenous nicotine averaged twofold those of venous plasma. For nicotine nasal spray, the time to Cmax was much faster for arterial than for venous plasma (median, 5 versus 18 minutes, p < 0.01). Intravenous nicotine produced the greatest increase in plasma epinephrine concentration, although smoking had a greater chronotropic effect. Acute tolerance to the chronotropic effects of nicotine was suggested at pharmacodynamic analysis with venous nicotine concentrations, whereas analysis of arterial concentrations found the opposite--a time lag between plasma concentration and effect. CONCLUSION: Nicotine is rapidly absorbed from nicotine nasal spray. The Cmax of nicotine after smoking or administration of nicotine nasal spray, or intravenous nicotine is substantially higher in arterial than venous plasma. Acute tolerance to the chronotropic effects of nicotine is not apparent if arterial plasma concentrations are measured.

Administration, Intranasal↗
PubMed1997

Absorption kinetics of misoprostol with oral or vaginal administration.

OBJECTIVE: To compare the pharmacokinetics of vaginal and oral administration of the prostaglandin E1 analogue, misoprostol. METHODS: Twenty women received 400-micrograms doses of misoprostol either orally or as tablets placed in the vagina. Serum levels of principal metabolite, misoprostol acid, were measured at 7.5, 15, 30, 45, 60, 90, 120, and 240 minutes. The first ten women were pregnant and undergoing first-trimester abortions, and the last ten were not pregnant and had additional blood sampling at 360 minutes. We compared the pharmacokinetics of misoprostol acid after oral and vaginal administration. RESULTS: All 20 subjects completed the study. The maximum mean (+/- standard deviation [SD]) of misoprostol acid differed significantly between the oral and vaginal groups (277 +/- 124 compared with 165 +/d- 86 pg/mL, respectively; P = .03, analysis of variance), as did the mean +/- SD time to peak levels (34 +/- 17 compared with 80 +/- 27 minutes, respectively; P < .001) and areas under the misoprostol concentration versus time curve (mean +/- SD) up to 4 hours (n = 20,273.3 +/- 110.0 compared with 503.3 +/- 296.7 pg.hour/mL, respectively; P = .033) and up to 6 hours (n = 10, 300.0 +/- 103.3 compared with 956.7 +/- 541.7 pg.hour/mL, respectively; P = .029). The extent of absorption was highly variable among subjects in each group. CONCLUSION: There are significant differences in the pharmacokinetics of misoprostol administered by vaginal and oral routes that may explain the difference observed in clinical efficacy. Assuming that the pharmacologic effect of misoprostol is related to its concentration in the plasma, our observation of the prolonged serum concentrations in the vaginal group suggests that vaginal administration could be dosed at longer intervals than oral.

Abortifacient Agents, Nonsteroidal↗
PubMed1997

Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy.

This review discusses the known cardiovascular effects of smoking and the effects of nicotine without tobacco smoke and interprets the available data on cardiovascular risk during nicotine replacement therapy (NRT). Nicotine gum and patches are now approved for over the counter sale in the United States. Smokers with cardiovascular disease are advised to seek physician counseling before using nicotine products, but information regarding the safety of these products in such patients is not readily available to most physicians. Nicotine may contribute to cardiovascular disease, presumably by hemodynamic consequences of sympathetic neural stimulation and systemic catecholamine release. However, there are many potential cardiovascular toxins in cigarette smoke other than nicotine. The doses of nicotine obtained by regular cigarette smoking generally exceed those delivered by NRTs, and the cardiovascular effects of nicotine are, in general, more intense when delivered rapidly by cigarette smoking than the slower delivery by transdermal nicotine or nicotine gum. Because the dose-cardiovascular response relation for nicotine is flat, the effects of cigarette smoking in conjunction with NRT are similar to those of cigarette smoking alone. Cigarette smoking increases blood coagulability, a major risk factor for acute cardiovascular events, whereas transdermal nicotine does not appear to do so. Clinical trials of NRT in patients with underlying, stable coronary disease suggest that nicotine does not increase cardiovascular risk. At worst, the risks of NRT are no more than those of cigarette smoking. The risks of NRT for smokers, even for those with underlying cardiovascular disease, are small and are substantially outweighed by the potential benefits of smoking cessation.

Administration, Cutaneous↗
PubMed1997

Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia.

OBJECTIVES: We sought to determine the effects of nicotine patch therapy, when used to promote smoking cessation, on myocardial ischemia in patients with coronary artery disease. BACKGROUND: Nicotine patches substantially increase quit rates among cigarette smokers, but their safety in patients with myocardial ischemia who are attempting to quit smoking is unknown. METHODS: This is a prospective study using exercise thallium-201 single-photon emission computed tomography (SPECT) to assess serial changes in the total and ischemic myocardial perfusion defect size at baseline while patients were smoking and during treatment with 14- and 21-mg nicotine patches. Entry criteria required that patients 1) smoked > or = 1 pack of cigarettes per day; 2) had known coronary artery disease; and 3) had myocardial ischemia (i.e., > or = 5% reversible perfusion defect) on SPECT. All patients performed symptom-limited treadmill exercise, and the baseline SPECT study served as its own control. We interpreted and computer quantified the SPECT images with no knowledge of the testing sequence. RESULTS: Thirty-six of the 40 enrolled patients had exercise SPECT at baseline and during treatment with at least 14-mg nicotine patches. These patients had an initial perfusion defect size of 17.5 +/- 10.6% while smoking an average of 31 +/- 11 cigarettes per day for 40 +/- 12 years. A significant reduction in the total perfusion defect size (p < 0.001) was observed from baseline (17.5 +/- 10.6%) to treatment with 14-mg (12.6 +/- 10.1%) and 21-mg (11.8 +/- 9.9%) nicotine patches. This reduction occurred despite an increase in treadmill exercise duration (p < 0.05) and higher serum nicotine levels (p < 0.001). There was a significant correlation between the reduction in defect size and exhaled carbon monoxide levels (p < 0.001) because patients reduced their smoking by approximately 74% during the trial. CONCLUSIONS: Nicotine patches, when used to promote smoking cessation, significantly reduce the extent of exercise-induced myocardial ischemia as assessed by exercise thallium-201 SPECT.

Administration, Cutaneous↗
PubMed1997

Contribution of adrenal hormones to nicotine-induced inhibition of synovial plasma extravasation in the rat.

1. In this study, we examined the mechanism(s) by which s.c. nicotine inhibits synovial plasma extravasation. We found that nicotine dose-dependently inhibited bradykinin (BK)- and platelet activating factor (PAF)-induced plasma extravasation. 2. The effect of nicotine on both BK- and PAF-induced plasma extravasation was attenuated by adrenal medullectomy. ICI-118,551 (a selective beta 2-adrenoceptor blocker) (30 micrograms ml-1, intra-articularly) significantly attenuated the inhibitory action of high-dose (1 mg kg-1) nicotine on BK-induced plasma extravasation without affecting the inhibition by low- (0.01 microgram kg-1) dose nicotine or that on PAF-induced plasma extravasation by nicotine at any dose. This suggested that beta 2-adrenoceptors mediate the inhibitory actions of high-dose, but not low-dose, nicotine. We also found that systemic naloxone (an opioid receptor antagonist) (two hourly injections of 1 mg kg-1, i.p.) attenuated the inhibitory action produced by all doses of nicotine on BK- or PAF-induced plasma extravasation, suggesting the contribution of endogenous opioids. 3. RU-38,486 (a glucocorticoid receptor antagonist) (30 mg kg-1, s.c.), and metyrapone (a glucocorticoid synthesis inhibitor) (two hourly injections of 100 mg kg-1, i.p.) both attenuated the action of high-dose nicotine without affecting that of low-dose nicotine. 4. Spinal mecamylamine (a nicotinic receptor antagonist) (0.025 mg kg-1, intrathecally, i.t.) attenuated the action of high-dose, but not low-dose, nicotine, suggesting that part of the action of high-dose nicotine is mediated by spinal nicotinic receptors. 5. Combined treatment with ICI-118,551, naloxone and RU-38,486 attenuated the action of low-dose nicotine by an amount similar to that produced by naloxone alone but produced significantly greater attenuation of the effect of high-dose nicotine when compared to the action of any of the three antagonists alone.

Adrenal Glands↗