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

• Published in: Cardiovascular diabetology 2010-08, Vol.9 (1), p.32-32, Article 32
• Main Authors: Liu, Que, Adams, Lisa, Broyde, Anatoly, Fernandez, Rayne, Baron, Alain D, Parkes, David G
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Blood Glucose - drug effects; Captopril - pharmacology; Cardiotonic Agents - pharmacology; Drug Therapy, Combination; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Hyperglycemia - drug therapy; Hyperglycemia - mortality; Hyperglycemia - physiopathology; Hypertension, Renal - drug therapy; Hypertension, Renal - mortality; Hypertension, Renal - pathology; Hypoglycemic Agents - pharmacology; Insulin Resistance - physiology; Kidney Diseases - drug therapy; Kidney Diseases - mortality; Kidney Diseases - pathology; Male; Original Investigation; Peptides - pharmacology; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary - pharmacology; Venoms
• ISSN: 1475-2840; 1475-2840
• DOI: 10.1186/1475-2840-9-32

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. 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. 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 < or = 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 < or = 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P < or = 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. 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.