Combination Therapy for the Cardiovascular Effects of Perinatal Lead Exposure in Young and Adult Rats

Abstract

Background: Combination therapy can play a significant role in the amelioration of several toxic effects of lead (Pb) and recovery from associated cardiovascular changes. Objective: To investigate the effects of combination therapy on the cardiovascular effects of perinatal lead exposure in young and adult rats Methods: Female Wistar rats received drinking water with or without 500 ppm of Pb during pregnancy and lactation. Twenty-two- and 70-day-old rat offspring who were or were not exposed to Pb in the perinatal period received meso-dimercaptosuccinic acid (DMSA), L-arginine, or enalapril and a combination of these compounds for 30 additional days. Noradrenaline response curves were plotted for intact and denuded aortas from 23-, 52-, 70-, and 100-day-old rats stratified by perinatal Pb exposure (exposed/unexposed) and treatment received (treated/untreated). Results: Systolic blood pressure was evaluated and shown to be higher in the 23-, 52-, 70-, and 100-day age groups with Pb exposure than in the corresponding control age groups: 117.8 ± 3.9*, 135.2 ± 1.3*, 139.6 ± 1.6*, and 131.7 ± 2.8*, respectively and 107.1 ± 1.8, 118.8 ± 2.1, 126.1 ± 1.1, and 120.5 ± 2.2, respectively (p < 0.05). Increased reactivity to noradrenaline was observed in intact, but not denuded, aortas from 52-, 70-, and 100-day-old exposed rats, and the maximum responses (g of tension) in the respective Pb-exposed and control age groups were as follows: 3.43 ± 0.16*, 4.32 ± 0.18*, and 4.21 ± 0.23*, respectively and 2.38 ± 0.33, 3.37 ± 0.13, and 3.22 ± 0.21, respectively (p < 0.05). Conclusions: All treatments reversed the changes in vascular reactivity to noradrenaline in rats perinatally exposed to Pb. The combination therapy resulted in an earlier restoration of blood pressure in Pb-exposed rats compared with the monotherapies, except for enalapril therapy in young rats. These findings represent a new approach to the development of therapeutic protocols for the treatment of Pb-induced hypertension.

Introdução: A terapia combinada parece desempenhar papel significativo em reduzir os efeitos cardiovasculares deletérios da exposição ao chumbo (Pb). Objetivo: Para investigar esta possibilidade, ratas Wistar receberam Pb (500 ppm na água de beber) ou água durante a prenhez e a lactação. Ratos com 22 e 70 dias, expostos perinatalmente ao Pb ou não, receberam DMSA, L- arginina, enalapril e a combinação destes por 30 dias adicionais. Métodos: Curvas concentração-efeito à noradrenalina foram obtidas em aortas intactas e desnudas, de ratos com 23, 52, 70 e 100 dias expostos ou não ao Pb, tratados ou não. Resultados: A pressão arterial sistólica caudal (mmHg) foi avaliada e mostrou-se aumentada em ratos expostos ao Pb [23, 52, 70 e 100 dias, respectivamente: controle 107,1±1,8, 118,8±2,1, 126,1±1,1, 120,5±2,2; Pb 117,8±3,9*, 135,2±1,3*, 139,6±1,6* e 131,7± 2,8*]. Observou-se aumento de reatividade à noradrenalina em aorta intacta, mas não desnudada, de ratos com 52, 70 e 100 dias expostos ao Pb [resposta máxima (g de tensão) 52 dias: Pb 3,43±0,16*, controle 2,38±0,33; 70 dias: Pb 4,32±0,18*, controle 3,37±0,13; 100 dias: Pb 4,21±0,23*, controle 3,22±0,21]. (*) p < 0,05 em relação ao respectivo controle. Conclusões: Todos os tratamentos restauraram as alterações de reatividade à noradrenalina em aortas de ratos expostos perinatalmente ao Pb. Exceto pelo enalapril em ratos jovens, a terapia combinada restaurou mais precocemente a pressão arterial de ratos expostos ao Pb em relação aos tratamentos isolados. Estes resultados representam uma nova abordagem no desenvolvimento de protocolos terapêuticos no tratamento da hipertensão induzida pela exposição ao Pb.