QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Online Supporting Material Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paiva, S. A. R. Articles by Zornoff, L. A. M. Search for Related Content PubMed PubMed Citation Articles by Paiva, S. A. R. Articles by Zornoff, L. A. M.

---

Biochemical and Molecular Actions of Nutrients

ß-Carotene Attenuates the Paradoxical Effect of Tobacco Smoke on the Mortality of Rats after Experimental Myocardial Infarction^1,2

Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), Botucatu, Brazil

³To whom correspondence should be addressed. E-mail: Paiva{at}fmb.unesp.br.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The objective of this study was to investigate the effects of exposure to tobacco smoke (ETS) in rats that were or were not supplemented with dietary ß-carotene (BC), on ventricular remodeling and survival after myocardial infarction (MI). Rats (n = 189) were allocated to 4 groups: the control group, n = 45; group BC administered 500 mg/kg diet, n = 49, BC supplemented rats; group ETS, n = 55, rats exposed to tobacco smoke; and group BC+ETS, n = 40. Wistar rats weighing 100 g were administered one of the treatments until they weighed 200 to 250 g (5 wk). The ETS rats were exposed to cigarette smoke for 30 min 4 times/d, in a chamber connected to a smoking device. After reaching a weight of 200–250 g, rats were subjected to experimental MI (coronary artery occlusion) and mortality rates were determined over the next 105 d. In addition, echocardiographic, isolated heart, morphometrical, and biochemical studies were performed. Mortality data were tested using Kaplan-Meyer curves and other data by 2-way ANOVA. Survival rates were greater in the ETS group (58.2%) than in the control (33.3%) (P = 0.001) and BC+ETS rats (30.0%) (P = 0.007). The groups did not differ in the other comparisons. Left ventricular end-diastolic diameter normalized to body weight was greater and maximal systolic pressures were lower in the ETS groups than in non-ETS groups. Previous exposure to tobacco smoke induced a process of cardiac remodeling after MI. There is a paradoxical protector effect with tobacco smoke exposure, characterized by lower mortality, which is offset by BC supplementation.

KEY WORDS: • smoking • ventricular remodeling • ß-carotene • paradoxical effect • myocardial infarction

The association between smoking and coronary artery disease is universally accepted. Smoking influences the prevalence of myocardial infarction (MI)⁴ through several mechanisms, such as endothelial dysfunction, increased oxidation of LDL cholesterol, reduced HDL cholesterol concentration, higher levels of adhesion molecules and fibrinogen, increased platelet aggregation, and higher prevalence of vascular spasm (1). These mechanisms are related mainly to vascular disease itself.

Cigarette smoke contains high concentrations of 2 different populations of free radicals, one in the tar component and the other in the gas component phase of smoke (2,3). At least 4700 constituents of mainstream cigarette smoke have been identified (4); thus tobacco smoke poses a mixed oxidative challenge to the cells.

Free radicals, as reactive species of oxygen (ROS), induce the functional and structural damage of cardiac myocytes and may play an important role in diverse acute coronary syndromes and heart failure (5,6) in which an imbalance of oxidative stress status is present (7).

An increase in ROS during myocardial ischemia occurs both at an early phase, i.e., during reperfusion (8) and at a late phase, i.e., days or weeks after MI (9), contributing to stunning (10) and injury-reperfusion (11). In addition, experimental studies showed that ROS production at this later stage is associated with post-MI left ventricular remodeling and progression to heart failure (12,13). Thus, oxidative stress would cause myocyte injury independently of vascular disease.

Evidence suggests that the free radicals of cigarette smoke contribute to the adverse effects of smoking (3,14), which are clearly detrimental to health and particularly to the heart (15). In this view, antioxidant nutrients such as carotenoids (16) are attractive agents that could protect against cardiovascular injury, assuming that they are capable of preventing oxidative damage. Several observational and prospective epidemiologic studies have consistently shown an inverse relation between dietary intakes or blood levels of ß-carotene (BC) and cardiovascular diseases (17–20).

We hypothesized that previous exposure to tobacco smoke (ETS) would adversely affect remodeling after MI and that this effect would be prevented by BC. The objective of this study was to investigate the effects of the tobacco smoke exposure, isolated or in association with dietary BC, on ventricular remodeling and survival after MI in rats.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Groups and treatment.

All experiments and procedures were performed in accordance with NIH guidelines for the Care and Use of Laboratory Animals and were approved by the Animal Ethics Committee of our Institution.

Male Wistar rats (n = 189), weighing 100 g, were randomly allocated to 4 groups: 1) Control group, n = 45, control rats were fed a standard diet⁵ without ETS; 2) Group BC, n = 49, rats fed the same diet supplemented with 500 mg of ß-carotene/kg diet (Sigma) milled in the feed; 3) Group ETS, n = 55, rats exposed to tobacco smoke; 4) Group BC+ETS; n = 40, rats exposed to tobacco smoke plus BC supplementation. The BC supplementation and tobacco smoke exposure were performed simultaneously until the rats weighed 200 to 250 g (5 wk). The ETS rats were exposed to cigarette smoke in a chamber (dimensions 95 x 80 x 65 cm) connected to a smoking device based on a model published by Wang et al. (21) and adapted by Paiva et al. (22). The smoke was drawn out of filtered commercial cigarettes (composition per unit: 1.1 mg of nicotine; 14 mg of tar; and 15 mg of carbon monoxide) with a vacuum pump and was exhausted into the smoking chamber. During wk 1, the number of cigarettes was gradually increased from 5 to 10 over a 30-min period, twice in the afternoon. During the next 3–4 wk, until the rats reached the target weight, 10 cigarettes were used in each smoking trial, repeated 4 times/d, twice in the morning and twice in the afternoon. In a previous study, with similar tobacco exposure time, samples of arterial blood were collected from rats, and carboxy-hemoglobin was measured. The carboxy-hemoglobin levels in smoke-exposed rats were greater than in the control group (control rats: 0.9 ± 0.7% and ETS rats: 5.3 ± 2.8%, P = 0.008) (23).

After this period of BC supplementation and tobacco smoke exposure, rats were subjected to coronary artery occlusion. Rats in the 2 ETS groups were not exposed to tobacco smoke 12 h before the procedure. After this procedure, the surviving rats were fed the control diet and observed for 105 d. Then, the rats were anesthetized, subjected to an echocardiographic study, killed by excision of the heart, and utilized for isolated heart, morphometrical, and biochemical studies.

Coronary artery ligation.

All procedures were performed by the same person, who had no knowledge of the rats’ treatment. MI was produced as previously described (24). In brief, the rats were anesthetized with ether, and after a left thoracotomy, the heart was exteriorized. The left atrium was retracted to facilitate a permanent ligation of the left coronary artery with 5–0 mononylon between the pulmonary outflow tract and the left atrium. The heart was then replaced in the thorax, the lungs inflated by positive pressure, and the thoracotomy closed. After surgery, the rats were housed in a temperature-controlled room (24°C) with a 12-h light:dark cycle. Rats consumed food and water ad libitum.

Echocardiographic study.

After 105 d, before killing, all of the rats were weighed and evaluated by a transthoracic echocardiography exam. The exams were performed as described by Paiva et al. (25). End-systolic and end-diastolic cavity areas were calculated as the sum of the areas from both the short- and long-axis views in diastole (SumD) and systole (SumS), respectively. Fractional area change (FAC) was calculated from the composite cavity areas as: FAC = (SumD – SumS)/SumD x 100 (26).

Isolated heart study.

The rats were anesthetized with thiopental sodium (50 mg/kg, i.p.) and heparinized (2000 UI, i.p.). The chest was entered through a median sternotomy under artificial ventilation. The entire heart was quickly removed from the chest and transferred to a perfusion apparatus (model 830 Hugo Sachs Eletronik). The ascending aorta was isolated and cannulated for retrograde perfusion with filtered and oxygenated Krebs-Henseleit solution, which was maintained at a constant temperature and perfusion pressure (37°C, and 75 mm Hg, respectively). The Krebs Henseleit solution had the following composition (mmol/L): 115 NaCl; 5.4 KCl; 1.25 CaCl₂; 1.2 MgSO₄; 1.15 NaH₂PO₄; 25 NaHCO₃; 11 glucose; and 8 mannitol. All hearts were paced at 200 beats/min. The procedures and measurements were executed following a previously described method (27).

Morphometric analysis.

At the completion of the functional study, the right and left ventricles (including the interventricular septum) were dissected, separated, and weighed. The morphometric analysis (myocyte cross-sectional area and interstitial collagen volume fraction) of the myocardium was performed as described previously (28). The lengths of the infarcted and viable muscle for both the endocardial and epicardial circumferences were determined by planimetry. Infarct size was calculated by dividing the endocardial and epicardial circumference of the infarcted area by total epicardial and endocardial ventricular circumferences. Measurements were performed on mid-ventricular slices (5–6 mm from the apex), under the assumption that the left mid-ventricular slice had a close linear relation with the sum of the area measurements from all heart slices (29).

Biochemical study.

BC in blood and cardiac and liver tissue homogenates was assayed by an HPLC system that consisted of a separation module Alliance 2695 (Waters) and a 2996 programmable photodiode array detector (Waters) and C₁₈ column (pechosphere-3) according to the method of Tang et al. (30). Preparations of the homogenates of cardiac and liver tissues were changed according to Paiva et al. (31). The carotenoids were quantified by determining peak areas in HPLC chromatograms calibrated against known amounts of standards. Levels were corrected for extraction and handling losses by monitoring the recovery of internal standards (echinenone).

Statistical analysis.

Survival data were analyzed by the Kaplan-Meyer curve with the Cox regression model and the Wilcoxon test using GB-Stat for Windows. The value of was adjusted according to the Bonferroni method ( = 0.008). Other data that were normally distributed were tested by 2-way ANOVA. When data had a nonnormal distribution, the natural log transformation was performed. Data were expressed as means ± SEM. Differences were considered significant if P < 0.05. Statistical analyses were performed using SigmaStat for Windows v2.03 (SPSS).

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Survival study.

Survival rates were greater in the ETS group (58.2%) than in the control (33.3%) (P = 0.001) and BC+ETS groups (30.0%) (P = 0.007). The groups did not differ in the other comparisons (Fig. 1).

View larger version (13K): [in this window] [in a new window]   FIGURE 1 Mortality of rats that were or were not exposed to tobacco smoke and fed the control diet or that diet supplemented with 500 mg/kg BC. Control group (n = 45); BC group (n = 44); ETS group (n = 55) and BC+ ETS group (n = 40). Curves with different letters differ, P < 0.008.

Echocardiographic study.

Left ventricle end-diastolic dimension (LVEDD) was greater in ETS (11.0 ± 0.3 mm) than in non-ETS rats (10.3 ± 0.24 mm) and LVEDD/body weight (BW) was greater in ETS (25.9 ± 0.8 mm/kg) than in non-ETS rats (23.5 ± 0.5 mm/kg). The left ventricle posterior wall thickness (LVWT) was smaller in BC (1.30 ± 0.04 mm) than in non-BC rats (1.48 ± 0.03 mm) (supplemental Table 1).

Functional study in isolated heart.

Maximal systolic pressure was lower in ETS (118.9 ± 4.0 mm Hg) than in non-ETS rats (130.5 ± 4.1 mm Hg). Tobacco exposure and BC supplementation did not affect other functional variables measured in isolated heart (supplemental Table 2).

Morphometrical study.

The infarct size did not differ among the groups. The myocyte area was lower in BC (212.1 ± 2.6 µm²) than in non-BC rats (219.7 ± 2.5 µm²). The other variables tested did not differ among the groups (supplemental Table 3).

Biochemical study.

Serum and tissue BC concentrations were below the limit of detection in all rats studied 105 d after the MI.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The present study revealed interesting observations on ventricular remodeling, despite cessation of tobacco smoke exposure after MI. Ventricular remodeling is defined as alterations in ventricle architecture; clinically, these might be displayed as alterations in size, mass, geometry, and heart function (32,33). The process of ventricular remodeling is associated with a poorer prognosis because its presence is related to a greater incidence of aneurysms, cardiac rupture, fibrosis, functional worsening, arrhythmia, and death (34). Regardless of the complexity of the remodeling process, after MI, this term is frequently used as a synonym for ventricular dilatation (32–34). Therefore, in our experiment, tobacco smoke exposure intensified the ventricular remodeling process, characterized by an increase in the LVEDD/BW, which was associated with worsened ventricular dysfunction (lower maximal systolic pressure).

In our study, BC supplementation attenuated the remodeling process induced by MI, as shown by lower values for myocyte area and LVWT in the BC-supplemented groups. Because the detrimental effects of MI on ventricular remodeling seem to depend on increased generation of ROS (12,35), the BC effect might occur through its biological activity as an antioxidant (16).

The major and surprising finding in this study was that exposure to cigarette smoke for 4–6 wk increased survival after MI. Although epidemiologic studies strongly support the assertion that cigarette smoking increases the risk of MI and fatal coronary artery disease, there is evidence that smokers with MI have lower mortality (36–38), a finding known as the paradoxical effect of smoking (37,39).

One possible mechanism for the paradoxical lower mortality observed in this study is a "preconditioning-like" effect induced by tobacco smoke. Ischemic preconditioning is a phenomenon whereby a brief period of ischemia renders the myocardium resistant to infarction from a subsequent ischemic insult (10,40). Preconditioning limits infarct size, reduces the incidence of fatal arrhythmias (41), and protects against postischemic contractile failure (stunning) (42). In our experiment, the MI size was similar among the experimental groups and the reduction of mortality induced by tobacco smoke exposure was typically observed within the initial 24 h after MI. In this model, 87% of early deaths were a consequence of ventricular arrhythmia, particularly ventricular fibrillation (43). Therefore, in our study, the percentage of early deaths after MI suggests that the preconditioning-like effect of smoke induced a reduction in lethal arrhythmias.

There is evidence for a possible role for oxygen free radicals in preconditioning (44,45). Short ischemic episodes might result in the generation of free radicals, insufficient to cause cell necrosis but sufficient to modify cellular activities (46). These continuous processes would cause an improved resistance to infarction, as seen in hearts affected by preconditioning. Enormous amounts of free radicals and ROS are produced during cigarette smoking (47). The oxidative stress can be translated into the induction of antioxidant enzymes (45), which would allow the heart to better withstand oxidative stress. In this way, the above observations might explain the preconditioning effect induced by smoke in our experiment.

Another important issue was that in this study, supplementation with BC abolished the protector effect induced by tobacco smoke on mortality after MI. Baines et al. (48) reported in situ and in vitro that N-2-mercaptopropionyl glycine (a free radical scavenger) could abort a single episode of preconditioning. Indeed, preconditioning does not occur in the presence of antioxidants (41,49). Intervention studies (50–52) raised the possibility that BC supplementation might not only fail to provide protective benefits, but could also have additional deleterious effects because it increased the risk of cardiovascular death. Considering these observations together with our findings, it would be reasonable to suggest that BC supplementation attenuates the preconditioning effect of tobacco smoke. Therefore, BC supplementation given to rats before the experimental MI, by its antioxidant properties, promoted 2 different responses, i.e., abolishing the ETS protection against mortality likely by decreasing ischemic preconditioning, and attenuating ventricular remodeling.

In the relations among ß-carotene, tobacco smoke, and cardiac disturbances, the serum concentration and/or the tissue levels of ß-carotene are relevant issues. Therefore, to find an association between ß-carotene and cardiac disturbances in our study, the experimental design should consider a diet supplemented with ß-carotene. However, in rats, most of the ingested ß-carotene is converted in the enterocytes, mainly to retinal, by the enzyme ß,ß-carotene 15,15'-monooxygenase (53), and only the remaining ß-carotene is absorbed intact. There is activity of this enzyme in the intestine of rats, a pattern that hinders accumulation of ß-carotene in the body; accordingly, rats are classified as "nonaccumulators" (54). However, it was observed that a high dose of ß-carotene [>20 mg/(kg BW · d) (55)] and a vitamin A–sufficient diet (56) can enhance ß-carotene accumulation in rat tissues. In our study, each rat ingested 40 mg of ß-carotene/(kg BW · d) and the standard diet contained 12,000 IU of vitamin A/kg of diet; therefore, it is likely that ß-carotene accumulation occurred in the body tissues of treated rats. However, carotenoids were not found in the rat myocardium and liver because samples of these tissues were collected after a period of 105 d, when rats were fed a standard diet, not supplemented with ß-carotene.

In conclusion, our findings indicate that previous tobacco smoke exposure intensifies and BC supplementation reduces ventricular remodeling induced by experimental MI in rats. Also, there is a paradoxical protector effect with ETS, characterized by lower mortality, which is offset by BC supplementation.

	FOOTNOTES

 
¹ This study was supported in part by a grant from Fundação de Amparo à Pesquisa do Estado de São Paulo.

² Supplemental Tables 1–3 are available as Online Supporting Material with the online posting of this paper at www.nutrition.org.

⁴ Abbreviations used: BC, ß-carotene; BW, body weight; ETS, exposure to tobacco smoke; FAC, fractional area change; LVEDD, left ventricle end-diastolic dimension; LVWT, left ventricle posterior wall thickness; MI, myocardial infarction; ROS, reactive species of oxygen; SumD, sum of the areas from both the short- and long-axis views in diastole; SumS, sum of the areas from both the short- and long-axis views in systole.

⁵ Cereal-based diet (Nuvilab CR1) with the proximate composition (/kg mixture): protein, 220 g; fat, 40 g; mineral, 100 g, fiber, 80 g.

Manuscript received 8 March 2005. Initial review completed 14 April 2005. Revision accepted 29 June 2005.

	LITERATURE CITED

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

1. Ridker, P. M., Genest, J. & Libby, P. (2001) Risk factors for atherosclerotic disease. Braunwald, E. Zipes, D. P. Libby, P. eds. Heart Disease: A Textbook of Cardiovascular Medicine 6th ed. :1010-1039 W.B. Saunders Philadelphia, PA.

2. Pryor, W. A. & Stone, K. (1993) Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann. N.Y. Acad. Sci. 686:12-7; discussion 27–28.[Medline]

3. Church, D. F. & Pryor, W. A. (1985) Free-radical chemistry of cigarette smoke and its toxicological implications. Environ. Health Perspect. 64:111-126.[Medline]

4. Green, C. R. & Rogman, A. (1996) The Tobacco Chemist’s Research Conference: a half century forum for advances in analytical methodology of tobacco and its products. Recent Adv. Tobacco Sci. 22:131-304.

5. Ide, T., Tsutsui, H., Kinugawa, S., Utsumi, H., Kang, D., Hattori, N., Uchida, K., Arimura, K., Egashira, K. & Takeshita, A. (1999) Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ. Res. 85:357-363.[Abstract/Free Full Text]

6. Siwik, D. A., Tzortzis, J. D., Pimental, D. R., Chang, D. L., Pagano, P. J., Singh, K., Sawyer, D. B. & Colucci, W. S. (1999) Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro. Circ. Res. 85:147-153.[Abstract/Free Full Text]

7. Li, D., Williams, V., Liu, L., Chen, H., Sawamura, T., Romeo, F. & Mehta, J. L. (2003) Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction. J. Am. Coll. Cardiol. 41:1048-1055.[Abstract/Free Full Text]

8. Ferrari, R., Ceconi, C., Curello, S., Percoco, G., Toselli, T. & Antonioli, G. (1999) Ischemic preconditioning, myocardial stunning, and hibernation: basic aspects. Am. Heart J. 138:S61-S68.[Medline]

9. McMurray, J., McLay, J., Chopra, M., Bridges, A. & Belch, J. J. (1990) Evidence for enhanced free radical activity in chronic congestive heart failure secondary to coronary artery disease. Am. J. Cardiol. 65:1261-1262.[Medline]

10. Bolli, R., Zughaib, M., Li, X. Y., Tang, X. L., Sun, J. Z., Triana, J. F. & McCay, P. B. (1995) Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning.". J. Clin. Investig. 96:1066-1084.

11. Ferrari, R., Alfieri, O., Curello, S., Ceconi, C., Cargnoni, A., Marzollo, P., Pardini, A., Caradonna, E. & Visioli, O. (1990) Occurrence of oxidative stress during reperfusion of the human heart. Circulation 81:201-211.[Abstract/Free Full Text]

12. Dhalla, A. K., Hill, M. F. & Singal, P. K. (1996) Role of oxidative stress in transition of hypertrophy to heart failure. J. Am. Coll. Cardiol. 28:506-514.[Abstract]

13. Nakamura, R., Egashira, K., Machida, Y., Hayashidani, S., Takeya, M., Utsumi, H., Tsutsui, H. & Takeshita, A. (2002) Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation. Circulation 106:362-367.[Abstract/Free Full Text]

14. Cross, C. E., O’Neill, C. A., Reznick, A. Z., Hu, M. L., Marcocci, L., Packer, L. & Frei, B. (1993) Cigarette smoke oxidation of human plasma constituents. Ann. N.Y. Acad. Sci. 686:72-89; discussion 89–90.[Abstract]

15. White, H. D. (1995) Lifting the smoke-screen: the enigma of better outcome in smokers after myocardial infarction. Am. J. Cardiol. 75:278-279.[Medline]

16. Paiva, S.A.R. & Russell, R. M. (1999) Beta-carotene and other carotenoids as antioxidants. J. Am. Coll. Nutr. 18:426-433.[Abstract/Free Full Text]

17. Gey, K. F., Moser, U. K., Jordan, P., Stahelin, H. B., Eichholzer, M. & Ludin, E. (1993) Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C. Am. J. Clin. Nutr. 57:787S-797S.[Abstract/Free Full Text]

18. Knekt, P., Reunanen, A., Jarvinen, R., Seppanen, R., Heliovaara, M. & Aromaa, A. (1994) Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am. J. Epidemiol. 139:1180-1189.[Abstract/Free Full Text]

19. Morris, D. L., Kritchevsky, S. B. & Davis, C. E. (1994) Serum carotenoids and coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial and Follow-up Study. J. Am. Med. Assoc. 272:1439-1441.[Abstract]

20. van Poppel, G. (1996) Epidemiological evidence for beta-carotene in prevention of cancer and cardiovascular disease. Eur. J. Clin. Nutr. 50:S57-S61.

21. Wang, X. D., Liu, C., Bronson, R. T., Smith, D. E., Krinsky, N. I. & Russell, M. (1999) Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke. J. Natl. Cancer Inst. 91:60-66.[Abstract/Free Full Text]

22. Paiva, S.A.R., Zornoff, L.A.M., Okoshi, M. P., Okoshi, K., Cicogna, A. C. & Campana, A. O. (2003) Behavior of cardiac variables in animals exposed to cigarette smoke. Arq. Bras. Cardiol. 81:221-228.[Medline]

23. Castardeli, E., Paiva, S.A.R., Matsubara, B. B., Matsubara, L. S., Minicucci, M. F., Azevedo, P. S., Campana, A. O. & Zornoff, L.A.M. (2005) Chronic cigarette smoke exposure results in cardiac remodeling and impaired ventricular function in rats. Arq. Bras. Cardiol. 84:320-324.[Medline]

24. Zornoff, L. A., Matsubara, B. B., Matsubara, L. S., Paiva, S. A. & Spadaro, J. (2000) Early rather than delayed administration of lisinopril protects the heart after myocardial infarction in rats. Basic Res. Cardiol. 95:208-214.[Medline]

25. Paiva, S.A.R., Zornoff, L. A., Okoshi, M. P., Okoshi, K., Matsubara, L. S., Matsubara, B. B., Cicogna, A. C. & Campana, A. O. (2003) Ventricular remodeling induced by retinoic acid supplementation in adult rats. Am. J. Physiol. 284:H2242-H2246.

26. Solomon, S. D., Greaves, S. C., Rayan, M., Finn, P., Pfeffer, M. A. & Pfeffer, J. M. (1999) Temporal dissociation of left ventricular function and remodeling following experimental myocardial infarction in rats. J. Card. Fail. 5:213-223.[Medline]

27. Zornoff, L. A., Paiva, S. A., Matsubara, B. B., Matsubara, L. S. & Spadaro, J. (2000) Combination therapy with angiotensin converting enzyme inhibition and AT1 receptor inhibitor on ventricular remodeling after myocardial infarction in rats. J. Cardiovasc. Pharmacol. Ther. 5:203-209.

28. Matsubara, L. S., Matsubara, B. B., Okoshi, M. P., Cicogna, A. C. & Janicki, J. S. (2000) Alterations in myocardial collagen content affect rat papillary muscle function. Am. J. Physiol. 279:H1534-H1539.

29. Spadaro, J., Fishbein, M. C., Hare, C., Pfeffer, M. A. & Maroko, P. R. (1980) Characterization of myocardial infarcts in the rat. Arch. Pathol. Lab. Med. 104:179-183.[Medline]

30. Tang, G., Dolnikowski, G. G., Blanco, M. C., Fox, J. G. & Russell, R. M. (1993) Serum carotenoids and retinoids in ferrets fed canthaxanthin. J. Nutr. Biochem. 4:58-63.

31. Paiva, S.A.R., Yeum, K.-J., Lee, K. S., Park, I. S., Lee-Kim, Y. C. & Russell, R. M. (1999) Endogenous carotenoid concentrations in cancerous and non-cancerous tissues of gastric cancer patients in Korea. Asia Pacific J. Clin. Nutr. 8:160-166.

32. Pfeffer, J. M., Pfeffer, M. A. & Braunwald, E. (1985) Influence of chronic captopril therapy on the infarcted left-ventricle of the rat. Circ. Res. 57:84-95.[Abstract/Free Full Text]

33. Cohn, J. N., Ferrari, R. & Sharpe, N., International Forum on Cardiac Remodeling (2000) Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J. Am. Coll. Cardiol. 35:569-582.[Abstract/Free Full Text]

34. Pfeffer, M. A. & Braunwald, E. (1991) Ventricular enlargement following infarction is a modifiable process. Am. J. Cardiol. 68:127D-131D.[Medline]

35. Engberding, N., Spiekermann, S., Schaefer, A., Heineke, A., Wiencke, A., Muller, M., Fuchs, M., Hilfiker-Kleiner, D., Hornig, B., Drexler, H. & Landmesser, U. (2004) Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction: a new action for an old drug?. Circulation 110:2175-2179.[Abstract/Free Full Text]

36. Zornoff, L. A., Paiva, S. A., Assalin, V. M., Pola, P. M., Becker, L. E., Okoshi, M. P., Matsubara, L. S., Inoue, R. M. & Spadaro, J. (2002) Clinical profile, predictors of mortality, and treatment of patients after myocardial infarction, in an academic medical center hospital. Arq. Bras. Cardiol. 78:396-405.[Medline]

37. Ferreira, R. (1998) The paradox of tobacco. Smokers have a better post-infarct prognosis. Rev. Port. Cardiol. 17:855-856.[Medline]

38. Ottesen, M. M., Jorgensen, S., Kjoller, E., Videbaek, J., Kober, L. & Torp-Pedersen, C. (1999) Age-distribution, risk factors and mortality in smokers and non-smokers with acute myocardial infarction: a review. TRACE study group. Danish Trandolapril Cardiac Evaluation. J. Cardiovasc. Risk 6:307-309.[Medline]

39. Ruiz-Bailen, M., de Hoyos, E. A., Reina-Toral, A., Torres-Ruiz, J. M., Alvarez-Bueno, M. & Gomez Jimenez, F. J. (2004) Paradoxical effect of smoking in the Spanish population with acute myocardial infarction or unstable angina: results of the ARIAM Register. Chest 125:831-840.[Abstract/Free Full Text]

40. Goto, M., Cohen, M. V. & Downey, J. M. (1996) The role of protein kinase C in ischemic preconditioning. Ann. N.Y. Acad. Sci. 793:177-190.[Medline]

41. Chen, W., Gabel, S., Steenbergen, C. & Murphy, E. (1995) A redox-based mechanism for cardioprotection induced by ischemic preconditioning in perfused rat heart. Circ. Res. 77:424-429.[Abstract/Free Full Text]

42. Yellon, D. M., Baxter, G. F., Garcia-Dorado, D., Heusch, G. & Sumeray, M. S. (1998) Ischaemic preconditioning: present position and future directions. Cardiovasc. Res. 37:21-33.[Abstract/Free Full Text]

43. Opitz, C. F., Mitchell, G. F., Pfeffer, M. A. & Pfeffer, J. M. (1995) Arrhythmias and death after coronary artery occlusion in the rat. Continuous telemetric ECG monitoring in conscious, untethered rats. Circulation 92:253-261.[Abstract/Free Full Text]

44. Toufektsian, M. C., Morel, S., Tanguy, S., Jeunet, A., de Leiris, J. & Boucher, F. (2003) Involvement of reactive oxygen species in cardiac preconditioning in rats. Antioxid. Redox Signal. 5:115-122.[Medline]

45. Das, D. K. & Maulik, N. (2003) Preconditioning potentiates redox signaling and converts death signal into survival signal. Arch. Biochem. Biophys. 420:305-311.[Medline]

46. Lecour, S., Rochette, L. & Opie, L. (2005) Free radicals trigger TNF alpha-induced cardioprotection. Cardiovasc. Res. 65:239-243.[Abstract/Free Full Text]

47. Pryor, W. A., Church, D. F., Evans, M. D., Rice, W. Y., Jr & Hayes, J. R. (1990) A comparison of the free radical chemistry of tobacco-burning cigarettes and cigarettes that only heat tobacco. Free Radic. Biol. Med. 8:275-279.[Medline]

48. Baines, C. P., Goto, M. & Downey, J. M. (1997) Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. J. Mol. Cell Cardiol. 29:207-216.[Medline]

49. Tanaka, M., Fujiwara, H., Yamasaki, K. & Sasayama, S. (1994) Superoxide dismutase and N-2-mercaptopropionyl glycine attenuate infarct size limitation effect of ischaemic preconditioning in the rabbit. Cardiovasc. Res. 28:980-986.[Abstract/Free Full Text]

50. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330:1029-1035.[Abstract/Free Full Text]

51. Hennekens, C. H., Buring, J. E., Manson, J. E., Stampfer, M., Rosner, B., Cook, N. R., Belanger, C., LaMotte, F., Gaziano, J. M., Ridker, P. M., Willett, W. & Peto, R. (1996) Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N. Engl. J. Med. 334:1145-1149.[Abstract/Free Full Text]

52. Omenn, G. S., Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Glass, A., Keogh, J. P., Meyskens, F. L., Valanis, B., Williams, J. H., Barnhart, S. & Hammar, S. (1996) Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334:1150-1155.[Abstract/Free Full Text]

53. Wyss, A. (2004) Carotene oxygenases: a new family of double bond cleavage enzymes. J. Nutr. 134:246S-250S.[Abstract/Free Full Text]

54. Krinsky, N. I., Mathews-Roth, M. M., Welankiwar, S., Sehgal, P. K., Lausen, N. C. & Russett, M. (1990) The metabolism of [¹⁴C]ß-carotene and the presence of other carotenoids in rats and monkeys. J. Nutr. 120:81-87.

55. Russell, R. M. (2004) The enigma of ß-carotene in carcinogenesis: what can be learned from animal studies. J. Nutr. 134:262S-268S.[Abstract/Free Full Text]

56. van Vliet, T., van Vlissingen, M. F., van Schaik, F. & van den Berg, H. (1996) ß-Carotene absorption and cleavage in rats is affected by the vitamin A concentration of the diet. J. Nutr. 126:499-508.

This article has been cited by other articles:

				A. Hozawa, D. R. Jacobs Jr., M. W. Steffes, M. D. Gross, L. M. Steffen, and D.-H. Lee Relationships of Circulating Carotenoid Concentrations with Several Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction: The Coronary Artery Risk Development in Young Adults (CARDIA)/Young Adult Longitudinal Trends in Antioxidants (YALTA) Study Clin. Chem., March 1, 2007; 53(3): 447 - 455. [Abstract] [Full Text] [PDF]

				L. A. M. Zornoff, L. S. Matsubara, B. B. Matsubara, M. P. Okoshi, K. Okoshi, M. Dal Pai-Silva, R. F. Carvalho, A. C. Cicogna, C. R. Padovani, E. L. Novelli, et al. Beta-Carotene Supplementation Attenuates Cardiac Remodeling Induced by One-Month Tobacco-Smoke Exposure in Rats Toxicol. Sci., March 1, 2006; 90(1): 259 - 266. [Abstract] [Full Text] [PDF]

				S. A. R. Paiva, L. S. Matsubara, B. B. Matsubara, M. F. Minicucci, P. S. Azevedo, A. O. Campana, and L. A. M. Zornoff Retinoic Acid Supplementation Attenuates Ventricular Remodeling after Myocardial Infarction in Rats J. Nutr., October 1, 2005; 135(10): 2326 - 2328. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Online Supporting Material Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paiva, S. A. R. Articles by Zornoff, L. A. M. Search for Related Content PubMed PubMed Citation Articles by Paiva, S. A. R. Articles by Zornoff, L. A. M.