Vildagliptin induced a strong concentration-dependent relaxation of human internal mammary artery rings (maximal response 83.20 ± 8.5%), likely mediated by KV and BKCa channels.
Does vildagliptin induce vasorelaxation in human internal mammary artery segments, and what is the role of K+ channels?
Vildagliptin acts as a potent vasorelaxant of human arterial bypass grafts, likely mediated through KV and BKCa channels.
Effect estimate: pD2 6.02
p-value: p=<0.01
Abstract Background The prevalence of diabetes mellitus type 2, along with the mortality rate directly connected to its cardiovascular complications, has been increasing. Vildagliptin, an oral antidiabetic drug from the class of Dipeptidyl Peptidase-4 (DPP-4) inhibitors, is perceived to have cardioprotective properties besides its hypoglycaemic effect. Cardioprotective abilities of vildagliptin partly attribute to its vasodilator properties. Purpose Considering that exact mechanisms of vildagliptin-induced vasodilation are still undefined, we aimed to investigate vasorelaxant effect of vildagliptin on a human internal mammary artery (HIMA) and to determine involvement of different K+ channel subtypes in its action on this blood vessel. Methods Discarded segments of HIMA were collected from patients undergoing coronary artery bypass grafting and studied in organ baths. HIMA rings were pre-contracted by phenylephrine. Results Vildagliptin (0.1 – 10 μМ) induced a strong concentration-dependent relaxation of HIMA rings with endothelium (pD2 value 6.02 ± 0.02; maximal response 83.20 ± 8.5%). The predominant blocker of voltage-gated K+ (KV) channels, 4-aminopyridine (0.5 mM), significantly diminished vildagliptin-induced relaxation of HIMA (p 0.01), whereas margatoxin (10 nM), a potent inhibitor of KV1.3 channels, partly antagonized vasorelaxant effect of vildagliptin (p 0.05). Iberiotoxin (100 nM), a most selective blocker of large-conductance Ca2+-activated (KCa) K+ channels (BKCa), caused significant inhibition of HIMA relaxation (p 0.01). Effect of vildagliptin was not significantly affected by glibenclamide (10 μM), a selective ATP-sensitive K+ (KATP) channel blocker (p 0.05). Conclusion Our research demonstrated for the first time that vildagliptin acts as a potent vasorelaxant agent of a human arterial bypass graft. The mechanism of vildagliptin-induced vasorelaxation of HIMA probably includes 4-aminopyridine- and margatoxin-sensitive KV channels, as well as BKCa channels. In addition, it seems that KATP channels are not part of a vildagliptin mechanism of action on this blood vessel.
Marinko et al. (Fri,) conducted a other in Patients undergoing coronary artery bypass grafting. Vildagliptin vs. K+ channel blockers (4-aminopyridine, margatoxin, iberiotoxin, glibenclamide) was evaluated on Vasorelaxation of HIMA rings pre-contracted by phenylephrine (pD2 6.02, p=<0.01). Vildagliptin induced a strong concentration-dependent relaxation of human internal mammary artery rings (maximal response 83.20 ± 8.5%), likely mediated by KV and BKCa channels.