Novel ATR agonist, β-ProAng III, is cardio- and vaso-protective in diabetic spontaneously hypertensive rats.

Stimulation of the angiotensin II type 2 receptor (ATR) evokes protective effects in various cardiovascular diseases. Thus, this study aimed to investigate the effects of ATR stimulation, with or without ATR blockade, in a model of hypertension with concomitant type 1 diabetes mellitus (T1DM). Spontaneously hypertensive rats (SHRs) were given either citrate or a single dose of streptozotocin (STZ; 55 mg/kg, i.p.) to induce diabetes. After 4 weeks of diabetes, animals were administered either a vehicle (saline), ATR agonist, β-ProAng III (0.1 mg/kg/day via osmotic mini-pump), ATR blocker, candesartan (2 mg/kg/day via drinking water), or a combination of both for a further 8 weeks. β-ProAng III treatment had no effect on blood pressure, but attenuated the significant increase in cardiac interstitial collagen and protein expression of fibrotic and inflammatory markers, and superoxide levels that was evident in diabetic SHRs. These effects were not observed with candesartan, despite its blood pressure lowering effects. Although β-ProAng III had no effect on aortic fibrosis, it significantly attenuated MCP-1 protein expression and superoxide levels when compared to both the non-diabetic and diabetic SHRs, to a similar extent as candesartan. In both the heart and vasculature, the effects of β-ProAng III in combination with candesartan were similar to those of β-ProAng III alone, and superior to candesartan alone. It was concluded that in hypertension with concomitant diabetes, ATR stimulation with a novel ligand alone, or in combination with ATR blockade, improved the cardiac and vascular structural changes that were strongly associated with inflammation and oxidative stress, independent of blood pressure regulation.