This study focuses on the effects of long-term renin-angiotensin system suppression and/or incretin mimetic therapies on the regulation and binding affinity of GLP-1 to its receptor in the coronary endothelium (CE) and cardiomyocytes (CMs) of type 1 diabetic male Sprague-Dawley rats. The groups assessed are normal (N), streptozotocin-induced diabetic (D), Insulin treated (DI), Exendin-4 treated (DE), Aliskiren treated (DA), cotreated with Insulin and Aliskiren (DIA) and cotreated with exendin-4 and Aliskiren (DEA). Heart perfusion with 125I-GLP-1 was performed to estimate GLP-1 binding affinity (τ = 1/k-n) to its receptor in the heart. Western Blotting was assessed to determine the expression variation of GLP-1 receptor in the heart. Plasma GLP-1 levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Diabetes decreased the τ value on CE and increased it on CMs compared to normal. The combination of Exendin-4 with Aliskiren showed a normalizing effect on the binding affinity of GLP-1 at the coronary endothelium, while at the cardiomyocyte level Exendin-4 treatment alone was the most effective.

This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [(125)I]-ET-1 was employed to estimate ET-1 binding affinity (τ = 1/K-n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the τ of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the τ value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus.

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Cardiovascular disease is a major complication in diabetes. Its management includes renin‐angiotensin‐system components, endothelial factors (Nitric Oxide), or Endothelin‐1 (ET‐1) regulation. This study focuses on long‐term ET‐1 receptor regulation by ω‐3 and Statin at coronary endothelium (CE) and cardiomyocytes (CM) levels in diabetic rats. Sprague Dawley male rats (n=24) were assigned to 7 groups: normal (N); streptozotocin (STZ)‐induced diabetic (D); normal rats treated with ω‐3 (0.085g/kg) (NO) or Statin (0.89 mg/kg) (NS); diabetic rats treated with ω‐3(DO), Statin (DS) or both (DOS). After a month of treatment, their hearts were perfused with [125I]‐ET‐1 (CHAPS‐untreated for CE and CHAPS‐treated for CM analyses) to estimate ET‐1 receptor‐binding affinity (τ = 1/K−n) on CE and CM. Tissue samples were analyzed by western blot for ET‐1 receptor subtypes A (ETAR) and B (ETBR). Residency time constant, τ, of ETBR increased in all groups as compared to N (1.05 ± 0.06), except for DS (1.18 ± 0.07) which was normalized. As for ETAR, τ increased in all groups but normalized in DO (1.18 ± 0.07). In western blot, ETAR increased (1.31 ± 0.09 vs 0.96 ± 0.05) and ETBR decreased (1.00 ± 0.06 vs 1.30 ± 0.07) in D, but both values were corrected in all other groups. Thus, ω‐3 and Statin therapy improved ETAR and ETBR functions respectively in diabetics; however, ω‐3 dosage regimens needs further analysis in healthy subjects.