The functional effect of visfatin in human internal thoracic arteries

Visfatin, also known as pre-B-cell colony-enhancing factor (PBEF) and nicotinamide phosphoriboslytransferase (Nampt) is a novel adipocyte-derived cytokine (adipocytokine). The expression and secretion of visfatin in perivascular adipose tissue of aorta and coronary artery were shown in both experimental animal models and human studies. It was also shown that visfatin had various functions in vascular system. Human left internal thoracic artery (ITA) is one of the most commonly used coronary artery bypass grafts in myocardial revascularization. Therefore, the present study aimed to investigate the functional effects and the possible underlying mechanism(s) of the effect(s) of visfatin on human ITA preparations. Samples of redundant ITA obtained from patients undergoing a coronary artery bypass surgery were cut into 3-4 mm wide rings and suspended in 20 mL organ baths. Isometric tension was continuously recorded with isometric force transducers connected to a computer-based data acquisition system. Contraction responses of human ITA rings to angiotensin II, endothelin-1, noradrenaline and phenylephrine did not change significantly before and after incubation with different concentrations of visfatin. Visfatin (10-12 - 10-7 M) produced concentration-dependent relaxation responses in human ITA rings precontracted with phenylephrine (10-6 M) that were significantly higher in endothelium-intact than endothelium-denuded preparations. Incubation of tissues with cyclooxygenase inhibitor indomethacin (10-5 M) did not cause a significant alteration, while incubations with nitric oxide (NO) synthase (NOS) inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) (10-4 M) or specific guanylyl cyclase inhibitor ODQ (5x10-5 M) caused statistically significant decreases in relaxant responses to visfatin. Visfatin-induced relaxation responses were almost completely blocked in the presence of Nampt enzyme inhibitor FK866 (10 µM). Incubation of the tissues with a combination of high-conductance Ca2+-activated potassium (BKCa) channel blocker charybdotoxin and small- conductance Ca2+-activated potassium (SKCa) channel blocker apamin (10-7 M, both) did not cause a statistically significant alteration in visfatin-induced relaxations. Acetylcholine-induced (10-10 - 10-5 M) endothelium-dependent relaxations significantly increased whereas sodium nitroprusside-induced (10-10 - 10-5 M) endothelium-independent relaxations did not change following incubation of human ITA rings with 10-9 and 10-8 M visfatin. In conclusion, present study provided, for the first time, pharmacological evidence about the functional relaxant effect of visfatin in human ITA preparations. The findings of the present study demonstrated that visfatin did not alter contraction responses to various contractile agents, but produced concentration-dependent relaxation responses in endothelium-intact human ITA rings. Nampt enzyme activity and endothelium through NO-cGMP pathway played a major role in visfatin-induced relaxation responses. Keywords: Adipocytokine, Human Internal Thoracic Artery, Nitric Oxide, Vasodilation, Visfatin.