The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats

Que Liu,David G Parkes,Rayne Fernandez,Anatoly Broyde,Lisa Adams,Alain D Baron

doi:10.1186/1475-2840-9-32

Abstract

BackgroundActivation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats.MethodsDSS rats were fed low salt (LS, 0.3% NaCl) or high salt (HS, 8% NaCl) diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min), or GLP-1 (25 pmol/kg/min) for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day) or AC3174 plus captopril.ResultsHS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP) was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p < 0.05). AC3174 plus captopril attenuated the deleterious effects of high salt on posterior wall thickness, LV mass, and the ratio of LV mass to body weight (P ≤ 0.05). In contrast, GLP-1 had no effect on these cardiovascular parameters. All treatments reduced LV wall stress. GLP-1, AC3174, captopril, or AC3174 plus captopril normalized fasting insulin and HOMA-IR (P ≤ 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P ≤ 0.05). Renal morphology in HS rats was associated with extensive sclerosis. Monotherapy with AC3174, captopril, or GLP-1 attenuated renal damage. However, AC3174 plus captopril produced the most effective improvement.ConclusionsThus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.

Highlights

Activation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis
The purpose of the present study was to determine whether hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats fed a high-salt diet could be attenuated by the exenatide analogue, AC3174 [32], alone or in combination with the angiotensin-converting enzyme (ACE) inhibitor captopril
Treatment with AC3174, captopril, GLP-1, or the combination of AC3174 plus captopril reduced systolic blood pressure (BP) compared with high salt diet alone (P ≤ 0.05), but had no effect on body weight gain

Summary

Introduction

Activation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. Chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats. In 2003, ~65 million adults had diagnosed hypertension, a key risk factor for cardiovascular disease and kidney failure [1,2]. Congestive heart failure with left ventricular (LV) dysfunction is often found in patients with hypertension [2,3,4,5,6]. Hypertension is the strongest risk factor for heart failure. It is known that during this transition insulin resistance develops, cardiac glucose uptake down-regulates, angiotensin-converting enzyme (ACE) levels increase, and the renin-angiotensin aldosterone system (RAAS) becomes hyperactivated [2,4,6]

Objectives

Methods

Results

Discussion

Conclusion