Administration of 100 ppm lead acetate daily for 3 months caused hypertension in Sprague-Dawley rats, with reversal by treatment with 2,3-dimercaptosuccinic acid (DMSA) (0.5% for 2 weeks). Animals from each group were infused sequentially in 30-min intervals with saline (S), L-arginine (Arg), Arg+ superoxide dismutase (SOD), S, and sodium nitroprusside (SNP). Baseline mean blood pressure (MBP) was elevated in lead-treated animals (Pb) compared to that in controls(C), returning toward normal after DMSA (105 +/- 2 mmHg, C, vs 149 +/- 2, Pb, and 124 +/- 1, DMSA, P < 0.001). Infusion of Arg caused a fall in MBP in all animals, normalizing the MBP in Pb-treated animals. SNP caused a greater fall in MBP in all groups of animals, normalizing the MBP in Pb. Measurement of urinary nitrite + nitrate (NOx) by chemiluminescence revealed at baseline a reduced level in Pb, restored to normal by DMSA (6.6 +/- 1.5 nmol/min/100 g BW, C, vs 3.3 +/- 1.7, Pb, P < 0.05, vs 5.8 +/- 2.6, DMSA, P = NS). Infusion of arginine increased urinary NOx in all groups, but to a lesser degree in Pb and DMSA. Assay of plasma malondialdehyde (MDA) by HPLC, as a measure of reactive oxygen species (ROS), was elevated at baseline in Pb, reduced by DMSA (3.6 +/- 0.4 mumol/L, Pb, vs 1.9 +/- 0.2, C, and 1.9 +/- 0.3, DMSA, P < 0.01). In the Pb group, SOD resulted in a significant fall in MDA (2.0 +/- 0.3 mumol/L, SOD, vs 3.1 +/- 0.1, Arg, P < 0.01), but no further fall in MBP or increase in urinary NOx. Thus, hypertension in lead-exposed animals is related to both diminished NO and increased ROS. The elevation in MBP can be ameliorated by additional NO through infusion of substrate arginine or by treatment with the ROS scavenger, DMSA. Lead-exposed animals show enhanced MBP sensitivity to the NO donors, Arg and SNP, but no further response to SOD, despite a reduction in MDA to normal. We speculate that lead-induced hypertension may be caused by one species of ROS which enhances vascular reactivity, and that provision of additional NO acts to scavenge the ROS and/or acts directly as a vasodilator.