David Parkes

Background: Accumulating evidence suggests glucagon-like peptide-1 (GLP-1) exerts cardioprotective effects in animal models of myocardial infarction (MI). We hypothesized that chronic treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac remodeling, insulin sensitivity, and exercise capacity (EC) in rats with MI-induced chronic heart failure (CHF) caused by coronary artery ligation. Methods: Two weeks post-MI, male Sprague-Dawley rats were treated with GLP-1 (2.5 or 25 pmol/kg/min), AC3174 (1.7 or 5 pmol/kg/min) or vehicle via subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body composition measurements were made at study end. Results: Compared with vehicle-treated rats with CHF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV) ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated CHF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four of 16 vehicle control CHF rats died during the study compared with 1 of 44 rats treated with GLP-1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects appears unrelated to changes in GLUT1 or GLUT4 translocation or expression. Conclusions: Chronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects in a rat model of CHF. Hence, GLP-1 receptor agonists may represent a novel approach for the treatment of patients with CHF or cardiovascular disease associated with type 2 diabetes.

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.

Exendin‐4, originally isolated from saliva of the lizard Heloderma suspectum, shares 53% sequence homology and several potentially antidiabetic actions with the mammalian hormone glucagon‐like peptide‐1(7‐36)amide (GLP‐1). It shows a higher potency and longer duration of effect in vivo, which may be partly attributed to pharmacokinetic properties. The present study compares the pharmacokinetics of GLP‐1 and exendin‐4 in rats after intravenous (iv), subcutaneous (sc), or intraperitoneal (ip) administration. Samples were assayed for active GLP‐1 (7‐36) amide using an enzyme‐linked immunosorbent assay that does not detect GLP‐1 (1‐36‐amide), (1‐37), (9‐36‐amide) or (9‐37). In parallel experiments, samples were assayed for exendin‐4 using a two‐site immunoradiometric assay that reacts specifically with full‐length exendin‐4. The estimated half‐life for GLP‐1 and exendin‐4 were 0.8–4.7 min and 18–41 min for iv bolus, and 4.6–7.1 min and 90–216 min for SC administration, respectively. Half‐lives after ip injection were 0.6–13.5 min for GLP‐1 and 125–174 min for exendin‐4. Bioavailability for GLP‐1 and exendin‐4 was 44–71% and 65–75%, respectively, for sc injection. For ip injection, bioavailability for GLP‐1 and exendin‐4 was 36–67% and 74–76%, respectively. Plasma clearance, as determined from iv infusion data, was 35–38 ml/min for GLP‐1 and 4‐8 ml/min for exendin‐4. Both Co/C_max and AUC values were proportional to dose with each route of administration. Plasma clearance of exendin‐4 was reduced by 4.4‐fold in nephrectomized animals. In conclusion, exendin‐4 exhibited a much longer plasma half‐life than GLP‐1 in rats after iv, sc, or ip injection, which may contribute in some part to reported differences in duration of biological action of the two peptides. Drug Dev. Res. 53:260–267, 2001.

Urocortin (Ucn) is a recently isolated peptide related to the corticotropin-releasing factor (CRF) family, which can produce hemodynamic and hormonal actions in conscious rats. This study examined in detail the cardiovascular actions of Ucn and CRF after intravenous injection in chronically instrumented, conscious sheep. Injection of Ucn produced dose-dependent changes in cardiac contractility [rate of increase of aortic flow (dF/dt)], maximum aortic flow (Fmax), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and coronary blood flow (CF). Ucn injected at 100 micrograms produced a potent increase in dF/dt, from 909 +/- 44 to a maximum of 1,849 +/- 901.min-1.s-1, and in Fmax, from 25.5 +/- 0.8 to 36.6 +/- 1.4 l/min. Cardiac contractility increased within 30 min of injection and remained significantly elevated for up to 24 h. MAP increased from 78 +/- 2 to 90 +/- 3 mmHg, and HR increased from 73 +/- 4 to 103 +/- 9 beats/min. CO rose from 5.0 +/- 0.1 to 5.8 +/- 0.2 l/min, whereas central venous pressure, total peripheral conductance, and stroke volume were unchanged. All Ucn-induced cardiovascular effects were inhibited by prior treatment with the CRF antagonist alpha-helical CRF-(9-41). Equimolar doses of CRF produced little change in any hemodynamic parameter. Both peptides increased plasma levels of adrenocorticotropin and cortisol, with Ucn having a more potent effect than CRF. We have shown for the first time that Ucn can produce potent and long-lasting actions to elevate cardiac contractility in conscious animals.