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.
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.