2,4,6-Trinitrotoluene inhibits endothelial nitric oxide synthase activity and elevates blood pressure in rats

2,4,6-Trinitrotoluene (TNT), which is widely used in explosives, is an important occupational and environmental pollutant. Human exposure to TNT has been reported to be associated with cardiovascular dysfunction, but the mechanism is not well understood. In this study, we examine the endothelial nitric oxide synthase (eNOS) activity and blood pressure value following TNT exposure. With a crude enzyme preparation, we found that TNT inhibited the enzyme activity of eNOS in a concentration-dependent manner (IC50 value = 49.4 microM). With an intraperitoneal administration of TNT (10 and 30 mg/kg) to rats, systolic blood pressure was significantly elevated 1 h after TNT exposure (1.2- and 1.3-fold of that of the control, respectively). Under the conditions, however, experiments with the inducible NOS inhibitor aminoguanidine revealed that an adaptive response against hypertension caused by TNT occurs. These results suggest that TNT is an environmental chemical that acts as an uncoupler of constitutive NOS isozymes, resulting in decreased nitric oxide formation associated with hypertension in rats.