The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats - PubMed (original) (raw)

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

Que Liu et al. Cardiovasc Diabetol. 2010.

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 < 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.

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Figures

Figure 1

Figure 1

Development of hypertension in the DSS rat over 4 or 5 weeks of high (8% NaCl) or low (0.3% NaCl) salt diet. (A) Systolic blood pressure measured by tail cuff. No difference among groups at baseline. At week 4, systolic blood pressure was significantly lower in all groups compared with a high salt diet alone (P ≤ 0.05). The pooled-over-time mean of the low salt group was significantly different from the high salt group (p < 0.003) (B) Arterial blood pressure measured by implanted transmitter. *P ≤ 0.05 versus high salt diet alone. (C) Pulse pressure measured by implanted transmitter. *P ≤ 0.05 versus high salt diet alone. (D) Change in body weight. (E) Kaplan-Meier survival curves followed for 8 weeks. N = 7 to 10 rats per group (N = 3 to 8 for telemetry data). Mean ± SEM.

Figure 2

Figure 2

Cardiovascular changes after 4 weeks of treatment demonstrated beneficial effects of AC3174. (A) Systolic blood pressure. P = 0.0226 for one-way ANOVA. The pooled-over-time means of the low salt and AC3174 groups were significantly different from the high salt group (P ≤ 0.05). (B) Posterior left ventricular wall thickness. P = 0.0030 for one-way ANOVA. The pooled-over-time mean of the low salt group was significantly different from the high salt group (P ≤ 0.05). (C) Left ventricular heart mass. P = 0.0002 for one-way ANOVA. The pooled-over-time means of the low salt and AC3174 plus captopril groups were significantly different from the high salt group (P ≤ 0.05). (D) Left ventricular heart mass as a percentage of total body weight. P < 0.0001 for one-way ANOVA. The pooled-over-time means for all treatment groups, except GLP-1, were significantly different from the high salt group (P ≤ 0.05). (E) Left ventricular heart wall stress. P = 0.0512 for one-way ANOVA. The pooled-over-time means of the AC3174 and AC3174 plus captopril groups were significantly different from the high salt group (P ≤ 0.05). There were 10 rats per group at beginning of treatment. N = 3 to 10 rats per group at end of treatment actually shown. *P < 0.05 versus high salt diet alone. Mean ± SEM.

Figure 3

Figure 3

Beneficial effects of AC3174 on fasting glycemic control after 4 weeks of treatment. (A) Fasting serum glucose concentrations. No significant differences among groups. (B) Fasting serum insulin concentrations. P = 0.0020 for one-way ANOVA. The pooled-over-time means of the low salt, AC3174, and captopril groups were significantly different from the high salt group (P ≤ 0.05). (C) HOMA. P = 0.0014 for one-way ANOVA. The pooled-over-time means for all treatment groups except GLP-1 were significantly different from the high salt group (P ≤ 0.05).

Figure 4

Figure 4

Beneficial effects of AC3174 on postprandial glycemic control after 4 weeks of treatment. (A) Serum glucose concentrations after an intraperitoneal bolus of glucose. No significant difference between the GLP-1 and high salt alone groups. At 30 min post-bolus, low salt, AC3174, GLP-1, and combination AC3174 plus captopril treatment significantly lowered glucose concentrations compared with high salt diet alone (P ≤ 0.05). At 60 min post-bolus, low salt, AC3174, and AC3174 plus captopril significantly lowered glucose concentrations compared with high salt diet alone (P ≤ 0.05). At 120 min post-bolus, AC3174 and AC3174 plus captopril significantly lowered glucose concentrations compared with high salt diet alone (P ≤ 0.05). No data were collected from the captopril group. (B) Serum insulin concentrations after an intraperitoneal bolus of glucose. A high salt diet lowered insulin concentrations at all post-bolus time points compared with a low salt diet (P ≤ 0.05). No significant difference between the GLP-1 and high salt groups. Captopril significantly lowered insulin concentrations at 30, 60, and 120 min post-bolus compared with a high salt diet (P ≤ 0.05). Treatment with AC3174 (alone or with captopril) significantly raised insulin concentrations at 15 and 120 min post-bolus compared with high salt diet alone (p < 0.05). *P ≤ 0.05 versus high salt diet. N = 3 to 14 rats per group. Mean ± SEM.

Figure 5

Figure 5

Beneficial effects of AC3174 on renal function after 4 weeks of treatment. (A) Serum creatinine concentrations. P = 0.0003 for one-way ANOVA. (B) Glomerular filtration rate measured by creatinine clearance. P = 0.0001 for one-way ANOVA. *P ≤ 0.05 versus high salt diet. N = 3 to 14 rats per group. Mean ± SEM.

Figure 6

Figure 6

Renal histopathology in DSS rats after 4 weeks of treatment demonstrated beneficial effects of AC3174. (A) Low salt diet exhibiting normal-to-mild scattered sclerosis. (B) High salt diet showing diffuse severe sclerosis. (C) AC3174 treatment on a background of a high salt diet displaying scattered moderate sclerosis. (D) Captopril treatment on a background of a high salt diet showing diffuse mild sclerosis. (E) AC3174 plus captopril treatment on a background of a high salt diet showing scattered mild sclerosis. (F) GLP-1 treatment on a background of a high salt diet exhibiting scattered mild sclerosis. N = 5 to 12 rats per group.

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