Canagliflozin produces a vasorelaxation effect on isolated rat thoracic aorta via NO/cGMP pathways

Abstract

Abstract Canagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2i) an oral hypoglycemic agent. The present study was performed to determine the vasorelaxant response of canagliflozin along with the underlying mechanism. In diabetes-associated complications, those involving blood vessels remain a high cause of morbidity. The diabetes-related cardiovascular complications should be treated with newer drugs that could cure both complications concurrently. The study was conducted on the aortic rings of Wistar rats of either sex. Canagliflozin (10-8-10-4 M) induces relaxation in phenylephrine (PE 100 µM) and 80 mM KCl pre-contracted rings significantly in a cumulative manner acquiring endothelium. The canagliflozin mechanism of vasorelaxant was established by incubating endothelium intact aortic rings for 30 minutes before PE with; nitro-L-arginine methyl ester (L-NAME 100 µM), methylene blue (10 µM), barium chloride (BaCl2: 10 µM), glibenclamide (1 µM) and indomethacin (10 µM). To estimate the role of calcium (Ca+ 2), cumulative Ca2+ (0.01- 10.0 mM) was added in a bath containing Ca+ 2 free Krebs-Henseleit solution. It was repeated by pre-incubating strips with nifedipine (1 µM) and canagliflozin (1 µM, 10 µM and 100 µM) respectively. The relaxant response of canagliflozin involves the release of nitric oxide, cyclic guanosine monophosphate, prostacyclin, and membrane hyperpolarization from endothelium as pretreatment with L-NAME (IC50: 2.166 × 10− 7 ± 7 M ), methylene blue (IC50 : 1.738 × 10− 7 ± 7 M), indomethacin (IC50: 2.269 × 10− 7± 7 M), BaCl2 (IC50 : 3.320 × 10− 6 ± 7 M) and glibenclamide (IC50: 3.960 × 10− 7 ± 7 M) diminished the response. Additionally, canagliflozin relaxing effects include both decreased Ca+ 2 influx and release from sarcoplasmic reserves. Thus, canagliflozin is a possible adjuvant in diabetes with concurrent hypertension.