ToxSci Advance Access originally published online on January 30, 2008
Toxicological Sciences 2008 103(1):207-214; doi:10.1093/toxsci/kfn018
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Perinatal Lead Exposure Affects Nitric Oxide and Cyclooxygenase Pathways in Aorta of Weaned Rats
Departamento de Farmacologia, Instituto de Biociências, São Paulo State University—UNESP, Distrito de Rubião Júnior s/n, 18618-000 Botucatu, SP, Brazil
1 To whom correspondence should be addressed at Departamento de Farmacologia, Instituto de Biociências, UNESP, 18618-000, Rubião Júnior s/n, Botucatu, São Paulo, Brazil. Fax: +55-14-3815-3744. E-mail cordelli{at}ibb.unesp.br.
Received September 6, 2007; accepted January 23, 2008
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ABSTRACT |
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Perinatal Pb exposure may modulate arterial tone through nitric oxide (NO) and cyclooxygenase products. To investigate this, Wistar dams received 1000 ppm of Pb or sodium acetate (control) in drinking water during pregnancy and lactation. Curves were constructed in phenylephrine-precontracted intact and/or denuded rings of thoracic aortas of weaned (23-day-old) male pups from their responses to N
-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor) and ACh in the absence or presence of indomethacin (10–5M, cyclooxygenase inhibitor) or L-NAME (3 x 10–7M and 3 x 10–4M). Blood lead concentration and systolic blood pressure (SBP) were higher in intoxicated than control pups (blood lead µg/dl: control < 3.0, Pb 58.7 ± 6.5*; SBP mmHg: control 111.4 ± 2.3, Pb 135.5 ± 2.4*). In L-NAME–treated rings maximal responses increased in Pb-exposed rats, and were higher in intact than in denuded aortas (contraction [% of phenylephrine] intact: control 184.3 ± 23.7, Pb 289.1 ± 18.3*; denuded: control 125.1 ± 4.5, Pb 154.8 ± 13.3*). ACh-induced relaxation in intact aortas from Pb-exposed rats presented rightward shift in L-NAME presence (EC50 x 10–7M: control 1.32 [0.33–5.18], Pb 4.88 [3.56–6.69]*) but moved left under indomethacin (EC50 x 10–7M: control 8.95 [3.47–23.07], Pb 0.97 [0.38–2.43]*). *p < 0.05 significant relative to the respective control; N = 7–9. Endothelium removal abolished ACh-induced relaxation. Perinatal Pb exposure caused hypertension associated with alterations in the production and/or release of basal and stimulated endothelium-derived relaxing factors–NO and constricting cyclooxygenase products. These findings may help explain the contribution of NO and cyclooxygenase products to the etiology and/or maintenance of Pb-induced hypertension and could ultimately lead to therapeutic advantages in plumbism. Key Words: metals; developmental toxicology; cardiovascular system; endothelial factors; perinatal intoxication; weaned rats.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIAL AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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Lead (Pb) acquires greater importance every year as both an industrial and environmental hazard. This has led to concern about the impact of increased Pb burden on blood pressure and cardiovascular diseases.
Some epidemiological data are compatible with the idea that Pb exposure plays a role in the development of the arterial hypertension in persons occupationally exposed to Pb (Cooper and Gaffey, 1975
) as well as in the general population (Bost et al., 1999). Nowack et al. (1993) reported a biphasic effect of Pb on blood pressure of rats.
In adult rats, the arterial hypertension induced by Pb exposure during postnatal life is characterized by an increase in vascular reactivity to catecholamines (Skoczynska et al., 1986), and an increase in plasma noradrenaline level as well as a decrease in beta-adrenergic receptors (Tsao et al., 2000). Contrarily, Purdy et al. (1997) reported no aorta reactivity alteration to either vasoconstrictors (noradrenaline and phenylephrine) or vasodilators (acetylcholine, ACh and sodium nitroprusside, SNP) associated with Pb-induced hypertension in rats.
Most studies have focused on the concept that this heavy metal interacts with and (1) regulatory processes involving calcium ion, cyclic guanosine monophosphate as second messengers, and protein kinase C (Khalil-Manesh et al., 1993; Watts et al., 1995); and (2) rennin–angiotensinn–aldosterone, kallikreinn–kinin, and other autacoidal (e.g., endothelin) and transductional systems (e.g., nitric oxide, NO) (Khalil-Manesh et al., 1993); and (3) endothelial cell and smooth muscle proliferation (Fujiwara et al., 1995; Kaji et al., 1995); and (4) oxidative stress (Ding et al., 2000).
Several diseases developing during adulthood were probably determined during early stages of life, under the effect of exposure or preferential maternal diet during pregnancy. Although a great deal of progress has been made with regard to neurochemical, behavioral, and other alterations induced by perinatal exposure to Pb (Dearth et al., 2002; Lasley et al., 1992; Moreira et al., 2001), the effects of Pb exposure during pregnancy and lactation on cardiovascular system remain to be completely clarified.
Thus, the present study aimed to evaluate the impact of perinatal exposure to Pb on NO and cyclooxygenase pathways modulation of arterial tone. These studies advance understanding of the cardiovascular effects of Pb exposure during pregnancy and lactation and could aid in the development of proper therapies for cardiovascular diseases caused by plumbism.
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MATERIAL AND METHODS |
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Animals and treatment.
Wistar rats were obtained from University of São Paulo facilities and used as the parent generation. The animals were mated at the age of 90 days (two females and one male per cage). On pregnancy day 0 (determined by the presence of sperm in vaginal smears), the dams were divided into nonintoxicated or Pb-exposed groups and were housed singly. The drinking water of dams was altered with 1000 ppm Pb (as Pb acetate) or sodium acetate to equalize acetate exposure for the groups. The Pb exposure regimen was chosen based on previous studies (Berry et al., 2002
; Kitchen and Kelly, 1993; Ma et al., 1997; Reinholz et al., 1999). To prevent the formation of Pb precipitate, 0.5 ml of glacial acetic acid was added while stirring to prepare 1000 ml of both solutions (sodium acetate and Pb). The treatment lasted throughout pregnancy and lactation. At birth, the number of pups per litter was recorded and after which all litters were culled to eight pups. Whenever possible, only male rats were kept within the litter and females were kept just to maintain equal litter sizes. Pb-exposed rats were weaned at 21 days of age and evaluated at 23 days of age. Aged matched-controls received sodium acetate during the same periods of Pb exposure. Maternal body weights were measured on pregnancy day 0, the day before delivery, after delivery and at weaning. Pup weights were recorded at birth and at weaning. Lights in the animal room were set on 12:12-h cycle with temperature maintained at 22 ± 1°C. The animals were fed with regular lab chow. Animal procedures were in accordance with the principles and guidelines of the National Council for Control of Animal Experimentation.
Measurement of blood pressure.
Systolic blood pressure (SBP), in conscious rats, was determined using tail-cuff plethysmography (Narco Bio-Systems, Inc., Houston, TX), on postnatal day 22. The rats were prewarmed for 10–15 min and placed into a restrainer for blood pressure measurement. Three consecutive recordings (
1 min apart) were performed, and the mean of these three measurements was recorded.
Determination of lead in blood.
Whole blood was collected from the heart of anesthetized (urethane 1.25 g/kg) pups at 23 days of age.
Blood was prepared for Pb analysis by microwave dissolution procedure utilizing a DGT-100 plus microwave digestion apparatus (Provecto, Brazil). Nitric acid was added to the digestion vessels containing 1 ml of blood.
Lead content of whole blood was determined using an atomic absorption spectrophotometer GBC AA 932 (EEA-flame). The recovery of Pb that had been added externally to control samples was found to be consistently greater than 96%. A standard additional method was applied for the determination to eliminate possible matrix interference. Whole-blood lead values were expressed as micrograms per deciliter. The detection limit was 3 µg/dl.
Experimental protocols.
Immediately after the blood had been collected, the descending thoracic aorta was excised and trimmed free of adhering fat and connective tissue. Two transverse rings of the same artery, each about 4 mm in length, were cut and mounted at the optimal length for recording isometric tension in organ chambers. One ring served as control, whereas the endothelium was mechanically removed from the other by gently rubbing the luminal surface. The preparations were mounted in organ baths containing 7 ml of Krebs–Henseleit solution, with composition in mM: NaCl 113.0, KCl 4.7, CaCl2 2.5, NaHCO3 25.0, MgSO4 1.1, KH2PO4 1.2, and glucose 11.1. The bathing fluid, kept at 37°C, was saturated with a gas mixture of 95% O2 and 5% CO2. The preparations were allowed to equilibrate for at least 1 h under a resting tension of 1.5 g, which is optimal for inducing the maximum contraction. Tension was recorded by an F-60 microdisplacement myograph (Narco Bio-Systems), and displayed on a physiograph. Preparations with and without endothelium isolated from rats exposed or not to Pb were studied in parallel.
Tone-related release of NO.
Before the initiation of experiments, intact and denuded aortic rings precontracted with phenylephrine (10–6M and 3 x 10–7M, respectively) were challenged with three concentrations of ACh (10–6–10–4M) to assess integrity or removal of endothelium and one concentration of SNP (10–4M) to assess integrity of smooth muscle. After a 45-min interval had elapsed, the aortic rings were precontracted with phenylephrine at concentrations that induced 60–80% of the maximum effect. After precontracting aortic rings, cumulative concentration effect curves were constructed from the response of the tissue to N-nitro-L-arginine methyl ester (L-NAME, inhibitor of NO synthase [NOS]; Cignarella et al., 2000; Rees et al., 1990).
Stimulated release of NO.
In another series of experiments, cumulative concentration effect curves for ACh, an endothelium-dependent relaxant agent, were examined in phenylephrine-precontracted intact aortic rings at concentration that induced 60–80% of the maximum effect in the absence and presence of two different concentrations of L-NAME (3 x 10–7M, more selective for endothelial NOS (eNOS) at this concentration, and 3 x 10–4M, unspecific for NOS subtypes) (Wu and Yen, 1999). Removal of endothelium abolished the response to ACh.
Response to exogenous NO donor.
Cumulative concentration effect curves for SNP, an endothelium-independent relaxant agent, were also examined in phenylephrine-precontracted intact and denuded aortic rings at concentrations that induced 60–80% of the maximum effect.
Cyclooxygenase pathway in aortic tissues.
Finally, the relaxant responses evoked by ACh were investigated in phenylephrine-precontracted intact aortic rings at concentration that induced 60–80% of the maximum effect in the absence and presence of indomethacin (10–5M, inhibitor of cyclooxygenase pathway) (Vane, 1971).
Both L-NAME and indomethacin were added in the last 30-min stabilization period and remained in contact with the preparations until the end of the experiment.
Concentration-effect curves for vasoactive agents were expressed as percentage of contraction induced by phenylephrine.
Drugs and solutions.
The following drugs were used: ACh bromide, indomethacin, lead acetate, L-NAME, phenylephrine hydrochloride, sodium acetate, SNP, urethane (all obtained from Sigma Chemical Co., St Louis, MO). The drugs were dissolved in Krebs–Henseleit solution and the concentrations were expressed in molarity. Lead and sodium acetate were dissolved in acidified tap water as described above.
Data analysis and statistics.
The litter was considered to be the experimental unit in all statistical analyses performed. The concentration of vasoactive agents producing a response that was 50% of the maximum (EC50) was calculated in each experiment. Mean EC50s are presented as geometric means with 95% confidence intervals. The maximal responses, expressed as mean ± SE, and the EC50 values were compared by one-way analysis of variance. A p value less than 0.05 was considered statistically significant. In order to test differences among means, Tukey–Kramer's multiple comparisons test was used. The other parameters (blood pressure, body weight, number of pups and lead determination) were compared by Mann–Whitney test.
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RESULTS |
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Body Weight, Number of Pups, Blood Lead Concentration, and Blood Pressure
The Pb regimen employed in the present report did not affect body weight of dams (Table 1). Similarly, the number of pups per litter was not altered by Pb exposure (control 11.0 ± 0.4, Pb 9.3 ± 0.8; p > 0.05; n = 7–10).
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The data also showed that the Pb regimen employed did not influence the weight of pups either at birth or at weaning (Table 1). Moreover, Pb-exposed pups presented increased Pb levels in the blood (µg/dl: control < 3.0, Pb 58.7 ± 6.5*; *p < 0.05, n = 7–10) as well as increased arterial blood pressure compared with the control group (mmHg: control 111.4 ± 2.3, Pb 135.5 ± 2.4*; *p < 0.05, n = 7–10). This result is comparable to those obtained under other dietetic regimens (Devoto et al., 2001
; Lasley, 1992; Widzowski et al., 1994).
Vascular Contractility Determinations
Tone-related release of NO.
First, the vascular responses mediated by the NO pathway were evaluated in phenylephrine-precontracted aortic rings. The responses to L-NAME (10–7–3 x 10–4M) were used to assess the tone-related release of NO. Perinatal Pb exposure increased the tone-related NO production in aortic tissues, that is, endothelium and smooth muscle, as observed from the higher contraction induced by increasing concentrations of L-NAME in intact and denuded aortas from Pb-exposed compared with control rats (Fig. 1 and Table 2). Moreover, the Pb-induced increase in tone-related NO production was higher in intact aortas, because the magnitude of the increase in the maximal response to L-NAME induced by Pb exposure was higher in intact than in denuded aortas (Fig. 1 and Table 2). Finally, Pb exposure did not alter the sensitivity to L-NAME of aortas with or without endothelium (Fig. 1 and Table 3).
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Stimulated release of NO.
Furthermore, the relaxant responses evoked by ACh (10–10–10–4M) that trigger the release of NO from endothelial cells were investigated in phenylephrine-precontracted intact aortic rings in the absence and presence of L-NAME.
In the absence of the inhibitor, ACh evoked a concentration-dependent relaxation in endothelium-intact rings that was similar between control and Pb-exposed rats (Fig. 2A and Tables 2 and 3).
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Inhibition of NO synthesis by the low concentration of L-NAME (i.e., 3 x 10–7M) had no effect on the maximum response of the aortic rings from both control and Pb-exposed rats, but significantly increased the EC50 value in aortic rings from Pb-exposed rats (Fig. 2B and Tables 2 and 3). Moreover, incubation with the high concentration of L-NAME (i.e., 3 x 10–4M) completely abolished the relaxant responses evoked by ACh in aortic rings of Pb-exposed rats, whereas about 10% of the ACh response remained in aortic rings of control rats (Fig. 2C and Tables 2 and 3).
Response to exogenous NO donor.
Endothelium-independent relaxant responses elicited by the exogenous NO donor SNP (10–13–10–4M) cumulatively added to phenylephrine-precontracted intact and denuded aortic rings were similar in control and Pb-exposed rats (Fig. 3 and Tables 2 and 3).
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Cyclooxygenase pathway in aortic tissues.
In a further set of experiments, alterations in cyclooxygenase metabolites of aortic tissues were evaluated through the relaxant responses elicited by ACh in phenylephrine-precontracted intact aortic rings incubated with indomethacin (10–5M) (Fig. 2D and Tables 2 and 3).
The presence of the cyclooxygenase inhibitor, indomethacin, had no significant effect on the EC50 and maximum response of the intact aortic rings of the control rats (Figs. 2A and 2D and Tables 2 and 3). But in the aortic rings of Pb-exposed rats, indomethacin incubation caused significant decrease in EC50 with no significant effect on maximum response (Figs. 2A and 2D and Tables 2 and 3). Also, there was a significant difference between the EC50 in the aortic rings of the Pb-exposed rats incubated with indomethacin, compared with respective controls (Fig. 2D and Table 3).
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DISCUSSION |
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Public health authorities use high levels to define blood lead levels of concerning in nonpregnant females (40 µg/dl, adult reference value in many countries).
In humans, the Center for Disease Control and Prevention's (CDC's) Adult Blood Lead Epidemiology and Surveillance program—United States, 2004 reported that 0.08 per 100,000 occupationally exposed females aged 16–44 years had blood lead levels 
40 µg/dl (CDC, 2007). If a policy of universal screening were employed, the number of reported cases would be substantially higher.
We must recognize that a significant proportion of nonpregnant females with blood lead levels 40 µg/dl will become pregnant and potentially expose their infants to a risk of adverse health effects from lead. Maternal and fetal blood lead levels are nearly identical because lead crosses the placenta unencumbered. This has provoked concern about elevated blood lead levels among all females of childbearing age because a great proportion of pregnancies are unplanned. Finally, pregnant women without symptoms frequently remain in contact with the source of exposure during pregnancy and lactation, especially in developing countries.
The severity of effects and the extent to which the cardiovascular system is affected by Pb appear to be influenced most directly by Pb concentration and the duration of Pb exposure in addition to factors including route of exposure, individual life phase, temperature, and dietary calcium intake level (Kopp et al., 1988). In the present work, we investigated the vascular alterations in pups exposed to Pb during pregnancy and lactation with blood levels 40 µg/dl. The Pb exposure regimen employed in the present study caused no effect on the weight of dams and pups at birth and weaning or on the number of pups per litter. All animals appeared healthy and none of them showed signs of toxicity.
However, an increase in SBP was observed confirming previous reports showing a positive association between blood lead levels and arterial hypertension (Malvezzi et al., 2001). Behavioral and neurochemical alterations have also been reported in rats presenting similar blood lead levels (Deng and Poretz, 2001; Devoto et al., 2001).
Arterial hypertension can be associated with impaired response to ACh that is frequently related to an alteration in the NO pathway (Gao et al., 2007; Kagota et al., 2007). However, the present study indicates that ACh-induced endothelium-dependent relaxations in the aorta were unaffected by perinatal exposure to Pb. Despite this absence of effect, additional experiments were performed to determine whether the NO component of the endothelium-dependent relaxation was altered.
There is agreement in the literature that the contraction and inhibition of endothelium-dependent relaxation effects of the arginine analogs reflect inhibition of "basal" or "stimulated" activities of constitutive NOS. In order to investigate the hypothesis that plumbism could be associated with abnormality in the NO pathway, the vasoconstrictor response to L-NAME was first used to assess the tone-related release of NO. Furthermore, the relaxation evoked by ACh, which triggers the release of NO from the endothelial cell, was investigated in the presence of two different concentrations of L-NAME, 3 x 10–7 and 3 x 10–4M. The same strategies were used to investigate tone-related as well as stimulated release of NO after gonadectomy in rats (Cignarella et al., 2000).
The procedure reported herein showed a basal-related release of NO in both endothelium and smooth muscle of weaned rats exposed or not to Pb during pregnancy and lactation because, independently of endothelial integrity, L-NAME induced contraction in aortas from control and Pb-exposed rats. Moreover, perinatal exposure to Pb increased the tone-related release of NO and affected the NO pathway to a greater extent in endothelium than vascular smooth muscle. These conclusions could be inferred from the higher magnitude of the increase in maximal responses to L-NAME in Pb-exposed rats compared with controls and the greater effect of Pb exposure in intact aortas compared with denuded ones. At this point, it can be hypothesized that the vascular increase of the basal NO release in intoxicated weaned rats is an adaptive mechanism to counterbalance the hypertensive state developed as a consequence of Pb exposure during perinatal life.
NOS is present in several isoforms in a large variety of cells besides endothelial cells, such as the constitutive eNOS (e for endothelial) and nNOS (n for neuronal) under physiological conditions, and iNOS (i for inducible), which is induced by cytokines under pathophysiological conditions. In vascular tissues, only eNOS and iNOS have been identified and studied so far and the constitutive form of NOS is generally thought to be absent in vascular smooth muscle. The NOS inhibitor L-NAME, at a lower concentration (< 3 x 10–5M), is more selective for eNOS or nNOS, whereas at higher concentrations (> 3 x 10–4M), it also inhibits iNOS (Wu and Yen, 1999). Thus, the constrictor responses observed in intact and denuded aortas to L-NAME at concentrations lower than 3 x 10–5M suggest the basal expression of a constitutive NOS in both endothelium and vascular smooth muscle. These findings enlarge upon a previous report from the literature that has identified a neuronal-like constitutive form of NOS in vascular smooth muscle also using a functional contractility approach (Cheah et al., 2002; Trovati et al., 1999).
As reported above, perinatal Pb exposure did not alter the endothelium-dependent vasodilation due to ACh. However, after incubation with a low concentration of L-NAME, a specific inhibitor of NO from L-arginine, Pb-exposed rats demonstrate more depression of relaxation responses to ACh than aortic rings from control rats. Similar results were reported in aortic rings from Wistar-Kyoto and stroke-prone spontaneously hypertensive rats (Lee and Webb, 1992). These data suggest that Pb-exposed rats have altered metabolism or mobilization, or both, of L-arginine and therefore altered production of NO compared with nonintoxicated rats. The data also support the possibility that the control rats may present an alternative pathway for NO production that is not present in the intoxicated rats, because a very high concentration of L-NAME failed to completely inhibit ACh-induced relaxation in control aortic rings in contrast to those of Pb-exposed rats in which relaxation to ACh was completely inhibited.
From our data, we cannot exclude the possibility that L-NAME might have greater access to NOS in aortic rings of Pb-exposed rats than those of control rats. However, similar EC50 values for L-NAME–induced contraction in aortas from intoxicated and nonintoxicated rats suggest that the access is probably the same. Finally, similar responses to SNP, which induces relaxation independently from the endothelial NO release, would suggest that NO-mediated signal transduction in the vascular smooth muscle is equal between animal groups. Differences in responses to ACh-mediated relaxations, however, may be secondary to differences in receptor-mediated signal transduction and the increased basal release of NO in aortic tissues of intoxicated rats strongly supports this hypothesis. Differences in the L-arginine: NO pathway between intoxicated and control rats may be an important factor contributing to altered vascular reactivity in plumbism-induced hypertension.
Several studies have also shown that endothelial cell function alterations are involved in a variety of hypertensive states, a phenomenon which is probably not related to the decreased release and/or production of endothelium-derived relaxing factors (EDRFs) but to a simultaneous release of endothelium-derived constricting factors (EDCFs), for example, products of the cyclooxygenase pathway (Cordellini, 1999).
Although the production ratio of cyclooxygenase metabolites by normal cells appears to favor vasodilator substances, it is possible that this ratio may differ in response to pathological states, for example, hypertensive states (Cordellini et al., 1990). There is agreement in the literature that the use of specific inhibitors of cyclooxygenase products can clarify the involvement of cyclooxygenase-dependent dilating and/or constricting substances released from endothelial cells. In order to investigate the hypothesis that plumbism could be associated with abnormality in the synthesis of endothelium-dependent vasodilator and/or vasoconstrictor products of the cyclooxygenase pathway, the reactivity to ACh of intact aorta pretreated with indomethacin was studied. The presence of indomethacin determined an increase in the sensitivity to ACh in aortas from intoxicated rats without changing the vasodilation responses to this agent in control rats. These data suggest that ACh-induced vasodilatation in Pb-exposed rats, but not in control rats, is partially modulated by vasoconstrictor cyclooxygenase products whose chemical identity needs further investigation. Despite the release of cyclooxygenase metabolites, ACh-induced aorta vasodilatation in the absence of indomethacin was similar between control and intoxicated rats. In this circumstance, the increased basal NO release after Pb exposure seems to blunt the probable contribution of vasoconstrictor cyclooxygenase products in limiting ACh-induced vasodilatation in plumbism. These data corroborate previous findings from the literature showing EDCF release, sensitive to cyclooxygenase inhibitor, in macro- and microvessels of hypertensive rats (Cordellini, 1999; Cordellini et al., 1988).
Altogether, the data reported herein suggest a simultaneous release of EDRF-NO and EDCF, probably a product of arachidonic acid metabolism through the cyclooxygenase pathway, in aorta of weaned rats exposed to Pb during pregnancy and lactation. Besides the difference in sensitivity, between intoxicated and control rats in response to the inhibitory effects of L-NAME, to ACh-induced relaxation in aortic rings—the release of this constricting substance may be viewed as a mechanism involved in the etiology and/or maintenance of the hypertensive state after Pb intoxication. Moreover, the increased basal release of NO might be considered a mechanism to counteract the vasoconstrictor production and the hypertensive state developed as a consequence of perinatal Pb exposure. This raises concern about the higher cardiovascular vulnerability of Pb-exposed individuals in the presence of associated pathologies that impair NO-system activity.
These findings may aid in understanding of the contribution of NO and cyclooxygenase products to the etiology and/or maintenance of the hypertensive state in Pb intoxication and could ultimately lead to therapeutic advantages against cardiovascular diseases in plumbism.
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FUNDING |
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TOPABSTRACTINTRODUCTIONMATERIAL AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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Fundação de Amparo à Pesquisa do Estado de São Paulo (process numbers: 03/06760-5 and 04/00640-0).
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NOTES |
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Part of a thesis submitted by Larissa Tercilia Grizzo to the Department of Pharmacology, Institute of Biosciences, University Estadual Paulista, Botucatu, São Paulo, Brazil in partial fulfillment of the requirements for the Bachelor's Degree.
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ACKNOWLEDGMENTS |
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We are very grateful to Dr Alaor Aparecido Almeida for his technical assistance in blood lead determination. We also acknowledge the technical assistance of Miss Ana Maria Seraphim.
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