There is an imbalance between contractile and relaxing endothelial factors in hypertension which induces vascular dysfunction. It involves cyclooxygenase (COX) due to production of vasoconstrictor agonists such as thromboxane A2 (TXA2). In this work we used the NO-NSAID vasodilator compound NCX2121 that has nitric oxide (NO) in its structure and the non-selective COX inhibitor indomethacin. This class of pro-drug has been demonstrated hypotensive effect in animal models of hypertension without alteration in the arterial pressure of normotensive rats. It has been pointed a direct vasodilator effect of NO-NSAIDS which mechanism remains unclear. This study aimed to evaluate the cellular mechanisms involved in the NCX2121-induced relaxation in renal hypertensive two kidney-one clip (2K-1C) rat aorta with intact endothelium and denuded aortas. Our data demonstrated that NO was directly released from the compound NCX2121 in the cytosol of the vascular smooth muscle cells. The relaxation induced by NCX2121 was similar in 2K-1C and normotensive two kidney (2K). It was impaired by the endothelium removal and NO-Synthase (NOS) inhibition in both rat aorta groups. The inhibition of the main NO target, soluble guanylyl-cyclase (sGC) with ODQ, abolished NCX2121-induced relaxation in denuded aorta. The expression of COX-1 and COX-2 as well the produced stable analog of Thromboxane A2 (TXA2) were higher in 2K-1C than in 2K. NCX2121 decreased the augmented production of TXA2 in 2K-1C rat aortas. In intact-endothelium aorta, ODQ impaired the relaxation induced by NCX2121 in 2K but it had no effect in 2K-1C rat aorta. Taken together, our results show that NCX2121-induced relaxation is due to the direct NO release inside the vascular smooth muscle cells and sGC activation in denuded aortas, whereas in intact endothelium aortas, NCX2121-induced relaxation could be due to eNOS activation and inhibition of prostanoids production. In addition, relaxation-induced by NCX2121 is not greater in normotensive than in hypertensive rat aortas because COX activity is higher in 2K-1C than in 2K rat aortas.