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.     

The effects of cigarette smoke compared to 3-methylcholanthrene and phenobarbitone on alkoxyresorufin metabolism by lung and liver microsomes from rats

The rates of metabolism of phenoxazone and a homologous series of its ethers (alkoxyresorufins) by liver and lung microsomes of rats exposed to cigarette smoke were compared with the metabolism in rats pretreated with 3-methylcholanthrene (3MC) or phenobarbitone (PB). The rate of resorufin production was dependent on the length of the ether side chain. Liver and lung microsomes from control rats differed in their activity profiles (rate of resorufin production plotted against side-chain length), showing highest activity with ethoxy- and benzyloxyresorufin respectively. 3MC and PB selectively induced hepatic microsomal resorufin production with only certain of the substrates and the two agents differed in their selectivity, inducing most greatly with ethoxy- and benzyloxyresorufin respectively. Pulmonary microsomal resorufin production was induced by 3MC with a substrate selectivity similar to that shown for liver, but PB suppressed pulmonary metabolism with all the substrates. A single, short exposure to cigarette smoke induced ethoxyresorufin O-deethylase activity transiently in liver and lung microsomes. Three consecutive daily short exposures to cigarette smoke caused a weak 3MC-like induction of liver microsomal alkoxyresorufin metabolism, but the effect on lung microsomes was like weak 3MC and PB inductions combined. It is concluded that cigarette smoke induces selected cytochrome P-450-linked alkoxyresorufin O-dealkylase activities to a similar extent in both lung and liver and that the effects of cigarette smoke are characteristic of both 3MC-type and non-3MC-type inducers.     

Mutagenic potential of anticonvulsant diphyenylhydantoin (DPH) on human lymphocytes in vitro

Diphenylhydantoin (DPH)-treated human peripheral blood cultures were examined for sister chromatid exchange (SCE) frequency and mitotic index. A significantly enhanced SCE frequency in DPH-treated cultures was observed at a 15 micrograms/ml concentration (10-20 micrograms/ml DPH therapeutic range) and above. These results suggest an enhanced SCE response of lymphocytes in the therapeutic blood level of DPH. A significant linear fall in mitotic index was observed with increasing DPH concentrations. It is postulated that even in therapeutic doses DPH possibly affects nucleic acid metabolism.     

Interactive effects of estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic cytochrome P-450 and mouse uterus

Weanling C57B/6 female mice treated with 6 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 3 times a week for one month (total dose 72 micrograms/kg) were observed to have greatly reduced relative uterine weights and histopathological changes in the uterus. Weanling CD-1 female mice were then treated with estradiol (E2) subcutaneously daily for 2 weeks. Half the mice also received 10 micrograms/kg TCDD in corn oil: acetone (9:1) by gavage 4 times during the second week. Control mice received either no E2 or no TCDD. Mice were killed on day 15 and autopsied. Relative uterine weights increased with increasing E2 doses; however, TCDD decreased this effect of E2 markedly. Liver microsomes from these animals showed that cytochrome P1-450 and P3-450 and, aryl hydrocarbon hydroxylase (AHH) induction by TCDD were independent of E2 dosage. Epoxide hydrolase was induced in TCDD treated animals. Gels showed an E2 dose dependent decrease in a protein migrating near epoxide hydrolase and 'P-450a' in animals receiving both E2 and TCDD. These results suggest that: E2 may act at the TCDD receptor; the TCDD receptor may be related to the estrogen receptor; the anti-estrogenic effects of TCDD are possibly independent of the Ah locus and AHH induction, and in TCDD-treated mice a protein migrating near epoxide hydrolase and 'P-450a' may be controlled by estrogen levels.     

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.     

Changes in thyroid hormones and thyroxine glucuronidation in hamsters compared with rats following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin

In rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, serum thyroxine (T4) is depressed. Since hamsters are relatively insensitive to TCDD-induced lethality, the effects of TCDD on several parameters of thyroid status were measured in hamsters as a comparison with the more sensitive rat. At 7 days after ip injection of TCDD, there was a dose-dependent increase in serum 3,5,3'-triiodothyronine (T3) and T4 in hamsters to a maximum level 200% of control; the ED50 was approximately 10 micrograms/kg. Hamsters receiving 100 micrograms/kg lost up to 4% of their body weight but began to recover after about 3 weeks. Serum T4 in these animals was elevated compared to pair-fed and ad libitum controls throughout the 53-day experiment, although it also began to recover after Day 21. This was in direct contrast to the marked reduction of T4 in rats exposed to lower doses of TCDD. T3 was significantly higher in TCDD-treated hamsters than in pair-fed controls on Days 2-7, and TSH was also elevated on Days 2-21. Reverse T3, like T4, was increased by TCDD in hamsters whereas it was decreased in rats. Hepatic microsomal UDP-glucuronosyltransferase (GT) activity was measured using T4 as substrate (T4-GT). On a whole liver basis, T4-GT was induced by TCDD by the same proportion in both rats and hamsters (170-180% of controls) although absolute activities in rats were 3- to 4-fold higher than in hamsters. This similarity in T4-GT inducibility by TCDD suggests that there are likely mechanisms in addition to T4-GT induction which account for the species-specific alterations in T4. Thus, while the response of thyroid hormones to TCDD differed qualitatively, effective doses in hamsters were higher than in rats, suggesting that these changes, although secondary, may correlate more directly with toxicity than does enzyme induction (whose ED50s are similar in both species). An understanding of the mechanism of this species difference may be helpful in unravelling the primary mechanisms of TCDD toxicity.     

Sister-chromatid exchanges in the lymphocytes of people exposed to environmental cadmium

Sister-chromatid exchanges (SCEs) were analyzed from peripheral lymphocyte cultures of 8 men and 16 women who had been exposed to environmental cadmium (Cd), and 6 controls. Average Cd concentrations in blood of the Cd-polluted group were 8.9 micrograms/l for men and 10.0 micrograms/l for women. These were no significant differences in SCE rates between the Cd-polluted and nonpolluted groups. There were no significant correlations between SCE rates and blood or urinary Cd concentrations. Cadmium alone may be an insignificant agent in producing chromosomal damage to peripheral blood lymphocytes.     

Induction of benzo[a]pyrene metabolism by 2,3,7,8-tetrachlorodibenzo-p-dioxin in primary cultures of adult rat hepatocytes

Primary hepatocyte cultures prepared from adult male Sprague-Dawley rats were extremely sensitive to induction of benzo[a]pyrene (BaP) metabolism by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), added to the cells in culture. A 48-hr exposure to 1 pmol TCDD/10⁶ cells resulted in a 4-fold induction of BaP metabolism. Significant induction was produced by a 48-hr exposure to a dose as low as 0.01 pmol (3 pg) TCDD/10⁶ cells. Cells exposed to TCDD from 7 to 55 hr in culture and then assayed for BaP metabolism responded to much lower doses of TCDD than did cells assayed at 36 hr in culture after being exposed to TCDD from 7 to 36 hr in culture. The doses of TCDD required for half-maximal induction of BaP metabolism were 24.8 and 164 fmol TCDD/10⁶ cells for cells assayed at 55 and 36 hr, respectively. Hepatocytes treated with TCDD starting at later times in culture showed a much more rapid time course of induction than did cells treated at earlier times in culture. A 2.6-fold induction occurred in cells treated from 49 to 55 hr in culture, compared to a 1.2-fold induction from 31 to 37 hr in culture. In contrast to cells exposed to TCDD from 7 to 55 hr in culture, cells exposed from 49 to 55 hr in culture were nearly as sensitive to inhibition of BaP metabolism by SKF 525-A as were uninduced control cells. An apparent derepression of the induction of BaP metabolism is occurring in primary hepatocyte cultures, resulting in an increase in the intitial rate of induction by TCDD and a decrease in the dose of TCDD required to obtain the half-maximum response.     

Promutagen activation of triazine herbicides metribuzin and ametryn through Vicia faba metabolism inducing sister chromatid exchanges in human lymphocytes in vitro and in V. faba root tip meristems.

The aim of our study was the induction of sister chromatid exchanges (SCE) in human lymphocytes in vitro and in root tip meristems of Vicia faba to evaluate the genotoxic effects of metribuzin and ametryn. Direct treatments of these herbicides on human lymphocytes in vitro applied 24 h after the beginning of culture did not induce SCE; however, they showed a cytotoxic effect in the cultures expressed as cellular death. On the contrary, when extracts of V. faba roots, treated for 4 h with metribuzin and ametryn (in vivo activation), were added to the lymphocyte cultures, SCEs were significantly induced with an asymptotic response. Negative responses appeared with the in vitro assays, in which metribuzin and ametryn were added directly to the 48 h lymphocyte cultures for 4 h. Nevertheless, in treatments in which the S10 metabolic mix was added, the SCE frequencies were significantly different to the control, although a concentration-response relationship was only observed with metribuzin. The results showed that both herbicides needed the V. faba metabolism to produce SCE in human lymphocyte cultures. Metribuzin and ametryn applied to V. faba root tip meristems for 4 h increased SCE frequency significantly, and a concentration-response relationship was observed with both herbicides.     

The effect of a single treatment with cigarette smoke on the blood levels and hemodynamic effects of propranolol in rats

The effect of a single treatment with cigarette smoke on the blood levels and hemodynamic effects of propranolol in rats was studied. Pentobarbital sleep time was not affected whereas zoxazolamine paralysis time was shortened 72% in rats, 24 h after the cigarette smoke exposure. The beta-adrenoceptor blocking effect of propranolol observed at 10 and 20 min time intervals was abolished in rats exposed to cigarette smoke 24 h after the exposure. The blood propranolol concentrations were decreased in rats pretreated with phenobarbital, 3,4-benzpyrene and ethanol as well as in cigarette smoke exposed rats. Among several factors that could influence propranolol metabolism, in this study, enzyme induction is suggested to be dominant.     

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 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment on mechanical function of the rat heart

Mechanical responses of isolated atria to (-)-isoproterenol and activities of myocardial pyruvate kinase and citrate synthase, enzymes involved in energy metabolism, were assessed in rats 7 days after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment. Basal tension development by electrically paced left atria was significantly elevated by all doses of TCDD (6.25, 25, or 100 micrograms/kg) when compared to that of vehicle-treated rats with unlimited access to feed. The basal rate of spontaneously beating right atria was significantly depressed in rats receiving 100 micrograms/kg TCDD. In left atria from rats treated with 100 micrograms/kg TCDD, maximal inotropic responses to (-)-isoproterenol and 1-methyl-3-isobutylxanthine were enhanced to the same degree. Right and left atria from rats receiving 100 micrograms/kg TCDD had an increased sensitivity to the chronotropic and inotropic effects of (-)-isoproterenol, respectively. The augmented atrial effects caused by TCDD were not secondary to loss of body weight because pair-fed animals that lost the same amount of weight did not display the responses. The ratio of heart ventricular mass to body weight and the activities of pyruvate kinase and citrate synthase in homogenates of heart ventricular muscle were not affected by TCDD treatment. Thus, overtly toxic doses of TCDD in the rat did not depress mechanical function of the heart.     

Influence of chlordecone and mirex exposure on benzo[a]pyrene metabolism of rat-liver microsomes

The metabolism of benzo[a]pyrene (BP) in hepatic microsomes isolated from rats exposed to chlordecone or mirex was compared to that of untreated rats and rats treated with 3-methylcholanthrene (3-MC) or phenobarbital (PB). Treatment with chlordecone resulted in a two- to three-fold increase in cytochrome P-450 content but the BP-hydroxylase activity per mg microsomal protein was unaffected. Addition of alpha-naphthoflavone (alpha-NF) or chlordecone caused changes in BP-hydroxylase activity indicating that chlordecone-induced cytochromes P-450 were similar to control. H.p.l.c. analyses of BP metabolites confirmed this similarity. Treatment with mirex caused a two-fold induction of cytochrome P-450, and BP-hydroxylase activity expressed per mg microsomal protein was increased 1.3-fold. Addition of chlordecone or alpha-NF caused changes in BP-hydroxylase activity, indicating differences between control and mirex-induced cytochromes P-450. H.p.l.c. analyses of BP metabolites confirmed this difference. Treatment with chlordecone or mirex increased microsomal epoxide hydrolase activity three-fold. Chlordecone accumulated in hepatic nuclei.     

Studies on the role of lipid peroxidation in the acute toxicity of TCDD in rats

Lipid peroxidation has been shown to be enhanced following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but its role in TCDD toxicity is unclear. The present study was undertaken to further elucidate the relations between lipid peroxidation and TCDD lethality. A time course and dose-response experiment in Long-Evans (L-E; LD50 ca. 10 micrograms/kg) and Han/Wistar (H/W; LD50 greater than 3000 micrograms/kg) rats showed that hepatic lipid peroxidation, measured as the amount of thiobarbituric acid-reactive substances (TBA-RS), was induced by TCDD dose-dependently in L-E, but not in H/W rats. Hepatic glutathione peroxidase activity was suppressed in much the same manner in both strains. Lipid peroxidation correlated with body weight loss in L-E rats alone. When 500 micrograms/kg of TCDD was given to L-E rats, lipid peroxidation increased about 3-fold on Day 11 in the liver, while no change was seen in cardiac or renal TBA-RS. The pair-fed controls did not survive the 11-day test period and exhibited gastrointestinal hemorrhages. At 6 days, liver atrophy and elevated (over 2-fold) TBA-RS values were recorded in pair-fed controls but not in their TCDD-treated counterparts. TCDD decreased hepatic glutathione peroxidase activity by almost 50% at 6 days, while pair-feeding was without effect. Liver morphology was different between TCDD-treated and pair-fed rats. Moreover, the livers of TCDD-treated L-E rats contained much higher concentrations of probably peripheral fat-derived fatty acids than did the livers of pair-fed or ad libitum control rats. Restricted feeding over 6 days induced hepatic lipid peroxidation more in H/W than in L-E rats. Endotoxin increased liver TBA levels similarly in both strains having an additive effect with high doses of TCDD in H/W rats. Added as a 0.5% concentration in chow, butylated hydroxyanisole (BHA), but not ethoxyquin, tended to increase survival rate and time in L-E rats exposed to 20 micrograms/kg of TCDD; at 50 micrograms/kg the only survivor was again in the BHA group. However, neither antioxidant had any effect on initial body weight loss. It is concluded that lipid peroxidation mainly arises as a secondary phenomenon in TCDD toxicity, is not the cause of the typical histopathological liver lesion, but may contribute to lethality.     

Cardioprotective effects of Sesbania grandiflora in cigarette smoke-exposed rats

Cigarette smoke is a major risk factor of coronary heart disease, myocardial infarction, and cardiac death. It has been reported to contain large amounts of oxidants. This study was undertaken to evaluate the cardioprotective effects of Sesbania grandiflora (S. grandiflora) against cigarette smoke-induced oxidative damage in rats. Adult male Wistar-Kyoto rats were exposed to cigarette smoke for a period of 90 days and consecutively treated with S. grandiflora aqueous suspension (SGAS, 1000 mg/kg body weight per day orally) for a period of 3 weeks. Lactate dehydrogenase activity in serum and cardiac lipid peroxidation product level were significantly increased while the activities of cardiac superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase then the levels of reduced glutathione, vitamin C, and vitamin E were significantly decreased in rats exposed to cigarette smoke. Besides, copper level was elevated, whereas zinc, manganese, and selenium levels were significantly diminished in the heart of rats exposed to cigarette smoke. Treatment with SGAS restored the antioxidant status and retained the levels of micronutrients. These results suggest that chronic cigarette smoke exposure increases the oxidative stress, thereby disquieting the cardiac defense system and S. grandiflora protects the heart from the oxidative damage through its antioxidant potential.     

Qualitative and quantitative differences in the induction and inhibition of hepatic benzo[a]pyrene metabolism in the rat and hamster

The present study compared the induction and inhibition of the metabolism of the prototype polycyclic aromatic hydrocarbon, benzo[a]pyrene (BaP), in rat and hamster liver microsomes. The production of total polar metabolites was quantitated by separating 3H-metabolites from [3H]-BaP using reverse-phase thin-layer chromatography. The rate of hepatic microsomal BaP metabolism was similar in the rat and hamster (0.81 vs 0.72 nmol/min/nmol cytochrome P-450 respectively). In the rat, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 5 micrograms/kg, i.p.) and 3-methylcholanthrene (3-MC; 50 mg/kg, i.p., X 3 days) pretreatments doubled the rate of BaP metabolism, whereas phenobarbital pretreatment (PB; 80 mg/kg, i.p., X 3 days) had no effect. In contrast, hamster hepatic microsomal BaP metabolism was elevated 2.3-fold by PB pretreatment, whereas TCDD and 3-MC pretreatments had no effect. Isosafrole pretreatment (ISO; 150 mg/kg, i.p., X 3 days) elevated the rate by almost 2-fold in each species. Another cytochrome P-448-mediated activity, 7-ethoxyresorufin O-deethylase (EROD), was induced by the same compounds that induced BaP metabolism in the rat. In hamster liver microsomes, in contrast to BaP metabolism, EROD was induced by TCDD and 3-MC but not PB or ISO pretreatments. The results suggest differences in the substrate specificity of the cytochromes P-448-450 induced by TCDD, 3-MC and PB in these species. This was supported by the different selectivity of the in vitro inhibitors, metyrapone and 7,8-benzoflavone, towards BaP metabolism and EROD in hepatic microsomes from TCDD- or PB-pretreated rats and hamsters. Reverse-phase HPLC analysis indicated that, while 3-hydroxy-BaP was the major metabolite formed by the untreated rat, untreated hamster liver microsomes formed predominantly BaP-4,5-diol. Microsomes from TCDD-treated rats generated elevated levels of all BaP-diols, diones and 3-hydroxy-BaP, with the major metabolites being BaP-9,10- and BaP-7,8-diols. In contrast, the metabolite profile from TCDD-pretreated hamsters was unchanged from the control. PB-treated hamster microsomes produced elevated levels of BaP-diones and 3-hydroxy-BaP. However, the major hepatic metabolite formed by PB-pretreated hamsters was BaP-4,5-diol, while BaP-9,10- and BaP-7,8-diols were not detected. The results of the study indicate differences in the induced cytochrome P-450s and the generation of toxic BaP metabolites in the liver of the rat and hamster.     

Corticosterone decreases toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in hypophysectomized rats

Male Sprague-Dawley rats were hypophysectomized by an established surgical technique. Hypophysectomy aggravated the toxicity (mortality and mean time to death) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 125 micrograms/kg ip) when compared to sham-operated rats (100% mortality with 9 +/- 1 d mean time to death vs. 90% mortality with 32 +/- 6 d mean time to death, respectively). However, administration of corticosterone (25 micrograms/ml in drinking water) to hypophysectomized rats resulted in an attenuation of the toxicity (40-60% mortality with 40-90 d mean time to death) to a range of TCDD doses (125, 250, 500 micrograms/kg) much higher than the LD50 (about 60 micrograms/kg TCDD) in nonhypophysectomized rats (about 30 d mean time to death). Furthermore, thyroid hormone supplementation in hypophysectomized rats dosed with 125 micrograms/kg TCDD restored the toxicity of TCDD to approximately "normal." Based on these data it is concluded that one or more as yet unknown key factors that are important in the modulation of the toxicity of TCDD reside in the pituitary.     

Effect of thyroid hormones on liver microsomal enzyme induction in rats exposed to 2,3,7,8,-tetrachlorodibenzo-p-dioxin

The effect of thyroidectomy and thyroid hormone replacement therapy on liver microsomal enzyme induction was studied in 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats (100 micrograms/kg). Treatment of non-thyroidectomized rats with TCDD had no effect on the concentration of liver microsomal cytochrome b5. In contrast, cytochrome b5 content was increased by TCDD treatment of thyroidectomized rats, regardless of replacement therapy with either T3 or T4. TCDD treatment increased the concentration of cytochrome P-450 (2-3-fold) and the activities of benzo[a]pyrene hydroxylase (4-7-fold), ethoxyresorufin O-de-ethylase (50-70-fold) and UDP-glucuronosyltransferase (5-7-fold) in non-thyroidectomized and thyroidectomized as well as thyroidectomized thyroid hormone treated rats; indicating the induction of these liver microsomal enzyme activities is independent of thyroid status. Because thyroid status alters the toxicity of TCDD but does not alter the ability of TCDD to induce microsomal enzymes, it appears that TCDD toxicity may not be directly related to microsomal enzyme induction.     

Lack of sensitivity of sister-chromatid exchange for lymphocyte chromosomal damage detection caused by antichagasic treatment

No studies exist on sister-chromatid exchange (SCE) formation in chagasic patients therapeutically exposed to nifurtimox (NFX) or benznidazol (BZ). In the present study SCE was analyzed in cultures of peripheral lymphocytes of patients aged 11 months to 11 years treated with NFX 12-15 mg/kg/d for 60 days or with BZ 5 mg/kg/d for 30 days. Chagasic patients before treatment constituted a control group. A mean of 30 metaphases were examined for each individual. All treated patients compared with untreated controls did not show a significant increase in SCE frequency. Compared with the percentage of chromosomal aberrations in these patients and others belonging to the same epidemic protocol, SCE seems to be less sensitive in the detection of lymphocyte chromosomal damage caused by NFX or BZ.     

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.