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 Mas-receptor 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.

Keywords

A-779 AVE-0991 diabetes mellitus lipids Mas receptor

Get full access to this article

View all access options for this article.

References

Kannel

Hjortland

Castellim

WP.

Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974; 34: 29–34

Dhalla

Liu

Panagia

. Subcellular remodelling and heart dysfunction in chronic diabetes. Cardiovasc Res 1998; 40: 239–247.

Dronavalli

Duka

Babris

GL.

The pathogenesis of diabetic nephropathy. Nat Clin Prac Endocrinol Metab 2008; 4: 444–452.

Donoghue

Hsieh

Baronas

. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000; 87: E1–E9.

Santos

Campagnole-Santos

Andrade

SP.

Angiotensin-(1–7): an update. Regul Pept 2000; 91: 45–62.

Pinheiro

Simoes

Silva

Sampaio

. Nonpeptide AVE-0991 is an angiotensin-(1–7) receptor Mas agonist in the mouse kidney. Hypertension 2004; 44: 490–496.

Ferreira

Santos

RAS

. Cardiovascular actions of angiotensin-(1–7). Braz J Med Biol Res 2005; 38: 499–507.

Singh

Sharma

PL.

Ameliorative potential of angiotensin1–7/Mas receptor axis in streptozotocin-induced diabetic nephropathy in rats. Meth Find Exp Clin Pharmacol 2010; 32: 19–25.

Grobe

Der

Sarkissian

. ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts. Clin Sci (Lond) 2007; 113: 357–364.

10.

Santos

RAS

Castro

Gava

. Impairment of in vitro and in vivo heart function in angiotensin-(1–7) receptor Mas knockout mice. Hypertension 2006; 47: 996–1002.

11.

Yamada

Iyer

Chappell

. Converting enzyme determines plasma clearance of angiotensin (1–7). Hypertension 1998; 32: 496–502.

12.

Wiemer

Dobrucki

Louka

. AVE-0991, a nonpeptide mimic of the effects of angiotensin-(1–7) on the endothelium. Hypertension 2002; 40: 847–852.

13.

Benter

Yousif

MHM

Anim

. Angiotensin-(1–7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol 2007; 292: H666–H672.

14.

Singh

Sharma

PL.

Beneficial effects of angiotensin (1–7) in diabetic rats with cardiomyopathy. Ther Adv Cardiovas Dis 2011; 5; 159–167.

15.

Al-Maghrebi

Benter

Diz

DI.

Endogenous angiotensin-(1–7) reduces cardiac ischemia-induced dysfunction in diabetic hypertensive rats. Pharmacol Res 2009; 59: 263–268.

16.

Trinder

Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 1969; 6: 24–25.

17.

Allain

Poon

Chan

CSG

. Enzymatic determination of total serum cholesterol. Clin Chem 1974; 20: 470–475.

18.

Folch

Lees

Sloane-Stanley

GH.

A simple method for isolation and purification of total lipids from animal tissue. J Biol Chem 1956; 226: 497–509.

19.

Deepa

Varalakshmi

Beneficial cardio-renovascular effects of low-molecular-weight heparin-derivative on adriamycin-induced glycosaminoglycanuria and tissue lipid abnormalities. Toxicology 2005; 211: 77–85.

20.

Cho

BHS

. Improved enzymatic determination of total cholesterol in tissues. Clin Chem 1983; 29: 166–168.

21.

Bonsnes

Taussky

HH.

On the colorimetric determination of creatinine by the Jaffe reaction. J Biol Chem 1945; 158: 581–591.

22.

Shargel

Wu-Pong

ABC

. Serum creatinine and creatinine clearance. Applied biopharmaceutics and pharmacokinetics, vol. 1. New Delhi: McGraw Hill, 2005, pp. 678–683.

23.

Fawcett

Scott

JE.

A rapid and precise method for the determination of urea. J Clin Pathol 1960; 13: 156–159.

24.

Watanabe

Kamei

Ohkubo

. Urinary protein as measured with a pyrogallol red–molybdate complex, manually and in a Hitachi 726 automated analyzer. Clin Chem 1986; 32: 1551–1554.

25.

Chang

Kim

Lee

. Effect of rosuvastatin on cardiac remodeling, function, and progression to heart failure in hypertensive heart with established left ventricular hypertrophy. Hypertension 2009; 54: 591–597.

26.

Keane

WF.

The role of lipids in renal disease: Future challenges. Kidney Int 2000; 57: S27–S31.

27.

Finck

Han

Courtois

. A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci U S A 2003; 100: 1226–1231.

28.

Jayasooria

Mathai

Walker

. Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance. Proc Natl Acad Sci U S A 2008; 105: 6531–6536.

29.

Santos

Braga

Mario

. Improved lipid and glucose metabolism in transgenic rats with increased circulating angiotensin-(1–7). Arterioscler Thromb Vasc Biol 2010; 30: 953–961.

30.

Dhaunsi

Yousif

MHM

Akhtar

. Angiotensin (1–7) prevents diabetes-induced attenuation in PPAR-γ and catalase activities. Eur J Pharmacol 2010; 638: 108–114.

31.

Walter

Balschum

Voigit

. Sustined long-term potentiation and anxiety in mice lacking the Mas protoncogene. J Biol Chem 1998; 273: 11867–11873.

32.

Sampaio

Santos

RAS

Faria-Silva

. Angiotensin-(1–7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension 2007; 49: 185–192.

33.

Lemos

Silva

Walther

. The endothelium-dependent vasodilator effect of the nonpeptide Ang-(1–7) mimic AVE-0991 is abolished in the aorta of Mas-knockout mice. J Cardiovasc Pharmacol 2005; 46: 274–279.

34.

Ruggenenti

Mise

Pisoni

. Diverse effects of increasing lisinopril doses on lipid abnormalities in chronic nephropathies. Circulation 2003; 107: 586–592.

35.

Gerstein

Mann

JFE

. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001; 286: 421–426.

36.

Mann

Gerstein

Pogue

. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001; 134: 629–636.

37.

Adler

Stevens

Manley

. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63: 225–232.