The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats
Open Access
- 3 August 2010
- journal article
- Published by Springer Science and Business Media LLC in Cardiovascular Diabetology
- Vol. 9 (1), 32
- https://doi.org/10.1186/1475-2840-9-32
Abstract
Background Activation 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. Methods DSS 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. Results HS 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. Conclusions Thus, 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.Keywords
This publication has 43 references indexed in Scilit:
- Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trialsVascular Health and Risk Management, 2009
- Exendin-4 has an anti-hypertensive effect in salt-sensitive mice modelBiochemical and Biophysical Research Communications, 2009
- Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug—naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallel-group studyClinical Therapeutics, 2008
- Diastolic dysfunction: A link between hypertension and heart failureDrugs of Today, 2008
- Genetic and dietary salt contributors to insulin resistance in Dahl salt-sensitive (S) ratsCardiovascular Diabetology, 2008
- Important genetic checkpoints for insulin resistance in salt-sensitive (S) Dahl ratsCardiovascular Diabetology, 2008
- The role of gut hormones in glucose homeostasisJCI Insight, 2007
- Prevalence, Awareness, Treatment, and Control of Hypertension Among United States Adults 1999–2004Hypertension, 2007
- AT1 Receptor Blocker Added to ACE Inhibitor Provides Benefits at Advanced Stage of Hypertensive Diastolic Heart FailureHypertension, 2004
- Abnormalities of carbohydrate and lipid metabolism in Dahl rats.Hypertension, 1991