It was suggested that in hypertension, increased vascular ROS may reduce NO bioavailability resulting in the loss of its vasoprotective effect, and ROS scavengers could attenuate the norepinephrine- induced contraction of rat aorta. In this study, plasma nitrite and nitrate concentrations were measured for PI-103 systemic NO production. DM, either alone or as combination treatment, improved the attenuated endothelial dependent vasodilation of the aorta in SHR by increasing systemic antioxidant capacity and by upregulating NO bioavailability. Furthermore, DM, either alone or in combination treatment, also improved endothelial-independent vasorelaxation of aortas in response to SNP, suggesting its direct effects on vascular smooth muscle cells. On the other hand, in this study, though significantly reducing BP, AM either in 1 mg or in 5 mg did not alter endothelial-dependent aortic dilatation induced by acetylcholine, suggesting that the effects of AM on BP reduction may be not necessarily associated with the improvement of vascular endothelial function. However, DM, either in 1 mg or in 5 mg, could not only significantly reduce BP but also enhance Ponatinib acetylcholine-induced endothelial-dependent vasodilatation. The endothelial-dependent vasodilatation could be also enhanced while AM was combined with DM. Accordingly, though BP lowering effects may theoretically contribute to vascular protection, it seems more likely that DM could improve endothelialdependent and -independent vasodilatation and prevent aortic hypertrophy mainly by its direct anti-oxidant effects. Indeed, our in vitro findings showed that DM could inhibit the activity/ activation of NADPH oxidase and ROS production induced by angiotensin II in HAECs, suggesting the direct effects of DM on vascular endothelium. Another novel finding of this study is that DM, even in low dose, could significantly decrease BP and further enhance the BPlowering effects of AM in SHRs. Combination therapy is one of the main strategies in current management of hypertension. Given the fewer side effects, low-dose combination therapy might be more preferred clinically. Current guideline suggests that combination therapy could be anticipated with thiazide, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, CCB or adrenergic b �Cblocker in various combinations. Our findings show that DM, similar to other first-line antihypertensives, could effectively reduce BP, prevent vascular damage, and improve vascular function in experimental hypertension. Besides, in this study, combination therapy of DM with AM, a CCB, may give the synergetic effects on BP reduction. Interestingly, low dose rather than high dose of DM could give more additional BP reduction top on the AM treatment.