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


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.
Liu
Que
Q
Amylin Pharmaceuticals, Inc., San Diego, CA, USA.
Adams
Lisa
L
Broyde
Anatoly
A
Fernandez
Rayne
R
Baron
Alain D
AD
Parkes
David G
DG
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004359:Drug Therapy, Combination; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D006943:Hyperglycemia / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D014688:Venoms
C553564:AC3174; D000959:Antihypertensive Agents; D001786:Blood Glucose; D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D010455:Peptides; D017673:Sodium Chloride, Dietary; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D002216:Captopril; D000077270:Exenatide