We have studied whether the elevated prorenin levels in diabetes exert detrimental vascular effects via binding to the (pro)renin receptor ((P)RR). Diabetic TGR(mREN2)27 rats were treated with vehicle, the renin inhibitor aliskiren, or aliskiren plus the (P)RR antagonist HRP. Blood pressure and heart rate were monitored with telemetry transmitters. After 3 weeks rats were sacrificed, and mesenteric arteries (MA) were removed. Aliskiren lowered blood pressure by maximally 40 mmHg, without altering heart rate. HRP did not change this. Acetylcholine (ACh) fully relaxed preconstricted MA of vehicle-treated rats. The NO synthase inhibitor L-NAME partially blocked the effect of ACh, whereas adding Tram34 and apamin (inhibitors of intermediate and small conductance Ca²⁺-dependent K+ channels) on top of L-NAME reversed the relaxant ACh response into a contractile effect. COX2 inhibition with NS398 and removal of the endothelium abolished this contractile response. Aliskiren did not alter the relaxant effect of ACh, nor the degree of blockade by L-NAME, but prevented the contractile response to ACh in the presence of L-NAME+Tram34+apamin. Yet, following co-treatment with HRP, the contractile response returned. Treatment did not alter the NO-responsiveness of the vascular smooth muscle cells, evaluated with the NO donor SNAP. Endothelin-1 constricted MA identically with and without treatment. Yet, the ETA receptor antagonist BQ123 inhibited this effect in aliskiren+HRP-treated rats only, suggesting selective upregulation of ETA receptors by HRP. HRP upregulates vascular ETA receptors and the generation of an endothelial contractile factor by COX2, thereby counteracting the beneficial vascular effects of aliskiren. This occurs in a blood pressure-independent manner, and argues against detrimental effects of (P)RR-prorenin interaction.