Actions of the lipid mediator thromboxane (Tx) A₂ acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA₂ in hypertension, we examined the consequences of deficiency of the TP receptor on the course of hypertension associated with endothelial dysfunction and salt sensitivity. To this end, the nitric oxide synthase inhibitor L-NAME was administered to TP-deficient (Tp^-/-) and wild-type (Tp^+/+) control mice in drinking water for 21 weeks along with a high salt (HS) (6% NaCl) diet. Administration of L-NAME increased urinary excretion of TxB2 to a similar extent in both Tp^+/+ and Tp^-/- animals. L-NAME also caused significant and sustained elevations in blood pressure that reached a maximum between weeks 3 and 6. However, the severity of hypertension was attenuated in the Tp^-/- mice throughout the study period (p<0.001). At the end of the study, the wild-type mice developed significant cardiac hypertrophy (23.6 +/- 2% increase in heart to body weight ratio). The severity of cardiac hypertrophy was attenuated in the TP-deficient group (11.1+/-2.6%; p<0.05). In contrast, kidney hypertrophy was exaggerated in the Tp^-/- mice compared to controls (37.1+/-5.4 vs. 12.3+/-2.3%; p<0.01). Moreover, the severity of glomerulosclerosis, tubule vacuolization and interstitial chronic inflammation was also enhanced in the Tp^-/- group (p<0.01). Thus, in L-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury.