Resveratrol-Induced Relaxation of the Human Saphenous Vein in Patients with and Without Type 2 Diabetes Mellitus: The Role of Nickel-Sensitive Pathways and Phrixotoxin-Sensitive Vascular Kv4 Channels

Background: Graft stenosis and graft failure remain frequent complications of coronary artery bypass grafting (CABG). People with type 2 diabetes mellitus (T2DM) represent a significant proportion of patients requiring CABG surgery, as T2DM induces vascular damage and impairs vasorelaxation. Resveratrol (RSV), a naturally occurring polyphenol with potent vasorelaxant properties, has emerged as a potential adjuvant for graft preservation solutions. While multiple pathways contribute to its effects, RSV-induced relaxation in endothelium-denuded segments is driven by direct action on vascular smooth muscle tissue, involving various voltage-dependent potassium (Kv) channels and sodium–calcium exchanger type 1 (NCX-1). Therefore, this study aimed to investigate the mechanism of RSV-induced relaxation in the human saphenous vein (HSV) from patients with and without T2DM, focusing on the roles of specific 4-AP-sensitive Kv channels, particularly margatoxin-sensitive (Kv1.2 and Kv1.3) and phrixotoxin-sensitive (Kv4.1-Kv4.3) subtypes, as well as the nickel-sensitive NCX-1. Methods: Samples of HSVs were taken after CABG surgery in two national cardiovascular clinics. Pharmacological experiments were conducted using isolated organ baths. To test the involvement of Kv1.2, Kv1.3, Kv4.1-Kv4.3, and the nickel-sensitive NCX-1 pathway in RSV-induced relaxation, the following blockers were utilized: 4-aminopyridine (4-AP), margatoxin (MgTox), phrixotoxin (PhTox), and nickel. Protein expression was investigated via Western blot. Results: A total of 112 HSV segments obtained from 49 patients (27 with T2DM; 22 non-diabetic controls (NDM)) were analyzed. RSV caused a concentration-dependent relaxation of the HSV, which was significantly less effective in the T2DM group than in the NDM group (pD2 = 4.79 ± 0.05 vs. pD2 = 5.04 ± 0.05, respectively, p = 0.001). 4-AP significantly antagonized RSV-induced relaxation of the HSV in both groups. MgTox did not block the relaxant response in either group, though a distinct variation in maximal efficacy (Emax) was noted in the T2DM group. Notably, PhTox and nickel significantly attenuated RSV-induced relaxation in the NDM group but exerted no significant effect in the T2DM group. Conclusions: RSV induces concentration-dependent relaxation in endothelium-denuded HSV segments from both NDM and T2DM patients. In non-diabetic patients, this relaxation is partially mediated by 4-AP-sensitive and PhTox-sensitive Kv channels, alongside nickel-sensitive pathways, likely corresponding to NCX-1. Conversely, these specific pathways appear compromised and do not contribute to RSV-induced relaxation in patients with T2DM. The involvement of alternative 4-AP-sensitive K channels, including other subtypes of Kv channels, cannot be ruled out in either patient group.