Sodium–Glucose Cotransporter-2 Inhibitor Canagliflozin Improves Vascular Graft Function in a Rat Bypass Model

Background: Ischemia/reperfusion (IR) injury during coronary artery bypass grafting surgery has detrimental impacts on endothelial integrity and function, posing a substantial challenge. Studies have suggested that canagliflozin (CANA) mitigates the risk of cardiovascular events, independently of diabetes. We hypothesized that the supplementation and/or administration of CANA protects vascular graft in a bypass model in non-diabetic Lewis rats.

Methods: The aortic arches from control rats (n = 9) were harvested, prepared, and aortic rings were mounted in organ baths. In the IR and IR+CANAsuppl groups (n = 8/group), the aortic arches were preserved in either saline or CANA-supplemented saline (5 µM) for 1 hour at 4°C before transplantation. In the IR+CANAinject and IR+CANAsuppl+inject groups (n = 9/group), aortic arches were preserved in cold saline or CANA for 1 hour, and the rats received either vehicle or CANA (10 µg/kg, iv) 5 minutes prior to reperfusion. Ex vivo vascular function was assessed using an organ bath system, and immunohistochemistry was also performed.

Results: The decreased maximum endothelium-dependent relaxation (Rmax) to acetylcholine in the IR group compared with controls (20 ± 3 vs 83 ± 2%, p < 0.05) was improved in both the IR+CANAinject (36 ± 2% versus 20 ± 3%, p < 0.05) and IR+CANAsuppl+inject (45 ± 3% versus 20 ± 3%, p < 0.05) groups. Additionally, the IR+CANAsuppl+inject rings exhibited a further increased Rmax to acetylcholine compared with both the IR+CANAsuppl (45 ± 3% versus 31 ± 2%, p < 0.05) and IR+CANAinject (45 ± 3% versus 36 ± 2%, p < 0.05) groups. Increased DNA strand breaks in the IR group compared with controls were decreased in all CANA groups. The reduced immunoreactivity of CD-31, a marker indicating the presence of endothelial cells, resulting from the IR injury, was ameliorated in the IR+CANAinject and IR+CANAsuppl+inject groups.

Conclusion: CANA alleviates endothelial dysfunction in a rodent model of revascularization. CANA exhibits greater effectiveness when added to physiological saline for graft preservation and subsequently administered to recipients, whether alone or as a supplementation in a saline solution.

Publication History

Article published online:
11 February 2025