Possible mechanism of the cardio-renal protective effects of AVE-0991, a non-peptide Mas-receptor agonist, in diabetic rats

Abstract

Hypothesis: This study was designed to investigate the cardio-renal protective effect of AVE-0991, a non-peptide Masreceptor agonist, and A-779, a Mas-receptor antagonist, in diabetic rats. Materials and methods: Wistar rats treated with streptozotocin (50 mg/kg, i.p., once), developed diabetes mellitus after 1 week. After 8 weeks, myocardial functions were assessed by measuring left ventricular developed pressure (LVDP), rate of left ventricular pressure development (dp/dt max ), rate of left ventricular pressure decay (dp/dt min ) and left ventricular end diastolic pressure (LVEDP) on an isolated Langendorff's heart preparation . Further, mean arterial blood pressure (MABP) was measured by using the tail-cuff method. Assessment of renal functions and lipid profile was carried out using a spectrophotometer. Results: The administration of streptozotocin to rats produced persistent hyperglycaemia, dyslipidaemia and hypertension which consequently produced cardiac and renal dysfunction in 8 weeks. AVE0991 treatment produced cardio-renal protective effects, as evidenced by a significant increase in LVDP, dp/dt max , dp/dt min and a significant decrease in LVEDP, BUN, and protein urea. Further, AVE-0991 treatment for the first time has been shown to reduce dyslipidaemia and produced antihyperglycaemic activity in streptozotocin-treated rats. However, MABP and creatinine clearance remained unaffected with AVE-0991 treatment. Conclusions: AVE-0991 produced cardio-renal protection possibly by improving glucose and lipid metabolism in diabetic rats, independent of its blood pressure lowering action.

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

“…The main pharmacological tools used to study the ACE2/ ANG-(1-7)/MAS axis are shown in FIGURE 3. Many are MAS agonists that stimulate NO production/release [ANG- (1)(2)(3)(4)(5)(6)(7), AVE 0991, CGEN 861, CGEN 856, CGEN 856S, cyclic ANG-(1-7)] (3,147,163,281,424,449,489,490,509,545,594), NorLeu3-A(1-7) (2,448). There are also two antagonists [D-Ala 7 -ANG-(1-7) (A-779) and D-Pro 7 -ANG-(1-7)].…”

New agents modulating the renin-angiotensin-aldosterone system—Will there be a new therapeutic option?

“…30 The beneficial effects of AVE 0991 were confirmed in various experimental models of CVD and diabetes ( Table 1). [31][32][33][34][35][36][37][38][39][40] Despite the promising results of experimental studies, the development of AVE 0991 has been stopped for unknown strategic reasons.…”

New and old agents in the management of diabetic nephropathy

“…The two small-molecule ACE2 activators, xanthenone (XNT) and DIZE 16 increased ACE2 activity and significantly decreased blood pressure in animal models 17 and correct dysfunctional vascular repair mechanisms seen in CD34+ cells isolated from diabetic individuals 16 . Non-peptide Mas-receptor agonists are also under investigation to determine if activation of Ang(1-7)-Mas pathways produce cardio-renal protective effects in experimental models of diabetes 18 . Despite the strong mechanistic rationale for ACE2 renal protection based on animal models, very little is currently known about this emerging class in humans.…”