piperidines and exendin-(9-39)

Ample evidence demonstrates cardiovascular protection by incretin-based therapy using dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 (GLP-1) under either diabetic or nondiabetic condition. Their action on myocardium is mediated by the cyclic AMP (cAMP) signal; however, the pathway remains uncertain. This study was conducted to address the effect of DPP4i/GLP-1/cAMP axis on cardiac dysfunction and remodeling induced by pressure overload (thoracic aortic constriction [TAC]) independently of diabetes mellitus.. DPP4i (alogliptin, 10 mg/kg per day for 4 weeks) prevented TAC-induced contractile dysfunction, remodeling, and apoptosis of myocardium in a GLP-1 receptor antagonist (exendin [9-39])-sensitive fashion. In TAC, circulating level of GLP-1 (in pmol/L; 0.86 ± 0.10 for TAC versus 2.13 ± 0.54 for sham control) unexpectedly declined and so did the myocardial cAMP concentration (in pmol/mg protein; 33.0 ± 1.4 for TAC versus 42.2 ± 1.5 for sham). Alogliptin restored the decline in the GLP-1/cAMP levels observed in TAC, thereby augmented cAMP signaling effectors (protein kinase A [PKA] and exchange protein directly activated by cAMP 1 [EPAC1]). In vitro assay revealed distinct roles of PKA and EPAC1 in cardiac apoptosis. EPAC1 promoted cardiomyocyte survival via concomitant increase in B cell lymphoma-2 (Bcl-2) expression and activation of small G protein Ras-related protein 1 (Rap1) in a cAMP dose-dependent and PKA-independent fashion.. DPP4i restores cardiac remodeling and apoptosis caused by the pathological decline in circulating GLP-1 in response to pressure overload. EPAC1 is essential for cardiomyocyte survival via the cAMP/Rap1 activation independently of PKA.

Topics: Animals; Apoptosis; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Guanine Nucleotide Exchange Factors; Heart Failure; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Peptide Fragments; Piperidines; Proto-Oncogene Proteins c-bcl-2; rap1 GTP-Binding Proteins; Signal Transduction; Uracil; Ventricular Remodeling

To extend preliminary studies on the effects on food intake of the combined use of cannabinoid (CB) 1 and glucagon-like peptide-1 (GLP-1) receptor agonists and antagonists, the effect of these drugs on the feeding behavior in rats maintained on a free-choice, high-carbohydrate diet was investigated over a longer period of time. Rats were fed a standard diet for 3 days and then fed with both the standard and the high-sucrose chow. After 4 days of the high-calorie diet, the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days: 1 mg/kg AM 251 (a CB1 receptor antagonist) or 1 mg/kg WIN 55,212-2 (a CB1 receptor agonist) together with 3 µg/kg exendin-4 (Ex-4, a GLP-1 receptor agonist) or 160 µg/kg exendin (9-39) [Ex (9-39), a GLP-1 receptor antagonist]. The total daily caloric intake and body weight were significantly reduced in rats treated with Ex-4 and AM 251 or WIN 55,212-2 compared with either of the drugs injected alone and the saline-injected controls. Both drug combinations selectively inhibited ingestion of the high-sucrose chow. Although Ex (9-39) administration did not significantly affect food consumption, it resulted in a marked body weight gain, indicating that the GLP-1 receptor antagonist caused a positive energy balance. It is concluded that AM 251 or WIN 55,212-2 and Ex-4, injected together, exert additive, inhibitory effects on the consumption of high-sugar food.

Topics: Analysis of Variance; Animals; Benzoxazines; Body Weight; Dietary Carbohydrates; Drug Interactions; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Male; Morpholines; Naphthalenes; Peptide Fragments; Peptides; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Glucagon; Venoms

The use of glucagon-like peptide-1 (7-36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Previous studies using Suncus murinus revealed that the GLP-1 receptor agonist, exendin-4, induces emesis via the brainstem and/or hypothalamus. The present study investigated the mechanism of exendin-4-induced emesis in more detail. Ondansetron (1 mg/kg, s.c.) and CP-99,994 (10 mg/kg, s.c) failed to reduce emesis induced by exendin-4 (3 nmol, i.c.v.), suggesting that 5-HT3 and NK1 receptors are not involved in the mechanism. In other studies, the GLP-1 receptor antagonist, exendin (9-39), antagonised emesis and c-Fos expression in the brainstem and the paraventricular hypothalamus induced by the chemotherapeutic drug cisplatin (30 mg/kg, i.p.; p < 0.05), but not the emesis induced by nicotine (5 mg/kg, s.c.; p > 0.05), or copper sulphate pentahydrate (120 mg/kg, p.o.; p > 0.05). GLP-1 receptors may therefore represent a potential target for drugs to prevent chemotherapy-induced emesis in situations where 5-HT3 and NK1 receptor antagonists fail.

Topics: Animals; Antiemetics; Brain; Exenatide; Glucagon-Like Peptide-1 Receptor; Male; Ondansetron; Peptide Fragments; Peptides; Piperidines; Proto-Oncogene Proteins c-fos; Receptors, Glucagon; Shrews; Venoms; Vomiting