Different K+ Channels Are Involved in Relaxation of Arterial and Venous Graft Induced by Nicorandil

Abstract

The drug nicorandil is a vasodilator approved for the treatment of angina. In addition to its well-known effect on the opening of ATP-sensitive K (KATP) channels, nicorandil-induced vasorelaxation also involves the opening of Ca-activated K channels. The aim of this study was to investigate the effects of nicorandil on the isolated human internal mammary artery (HIMA) and the human saphenous vein (HSV) and to define the contribution of different K channel subtypes in the nicorandil action on these arterial and venous grafts. Our results show that nicorandil induced a concentration-dependent relaxation of HSV and HIMA rings precontracted by phenylephrine. Glibenclamide, a selective KATP channels inhibitor, partially inhibited the response to nicorandil in both HSV and HIMA. Iberiotoxin, a most selective blocker of large-conductance Ca-activated K (BKCa) channels, partly antagonized relaxation of HIMA. A nonselective blocker of voltage-gated K channels, 4-aminopyridine caused partial inhibition of the nicorandil-induced relaxation of HSV but did not antagonize relaxation of HIMA induced by nicorandil. Margatoxin, a potent inhibitor of KV1.3 channels, did not abolish the effect of nicorandil on HSV and HIMA. Our results showed that nicorandil induced strong endothelium-independent relaxation of HSV and HIMA contracted by phenylephrine. It seems that KATP and 4-aminopyridine-sensitive K channels located in the smooth muscle of HSV mediated relaxation induced by nicorandil. In addition, KATP and BKCa channels are probably involved in the nicorandil action on HIMA.

Different Potassium Channels are Involved in Relaxation of Rat Renal Artery Induced by P1075

“…ATP‐sensitive K + channels openers (K ATP COs), a class of vasodilators, such as pinacidil, nicorandil, levcromakalim and aprikalim, were found to exert their effect on vascular smooth muscles by opening ATP‐sensitive K + (K ATP ) channels, which produces hyperpolarization of the vascular cell membrane leading to vasorelaxation . K ATP channels have been first identified in cardiac muscle, and then they have been found in various cells including vascular smooth muscle .…”

“…So, for example, vasorelaxation induced by K ATP CO, pinacidil, involves the opening of large-conductance K Ca (BK Ca ) channels [7,8]. Novakovic et al [2] have shown that nicorandil-induced relaxation of human saphenous vein (HSV) and human internal mammary artery (HIMA) includes activation of 4-aminopyridine (4-AP)-sensitive K + channels as well as BK Ca channels. Besides, it has been suggested that diazoxide activates K Ca channels and K V channels in smooth muscle cells by a mitochondria-dependent mechanism [9,10].…”

Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective

“…Studies indicate that K V 1.3 have positive effects in the proliferation and cell migration, which can result in neointimal hyperplasia or vascular remodeling. Margatoxin is a potent, highly selective blocker of human K V 1.3 and has no effect on K Ca . It has been demonstrated that K V current in rat small mesenteric artery myocytes consists of two major parts, K V 1.2–1.5–β1.2 and K V 2.1–9.3, along with less functional K V 7.4 and K V 7.5, which were encoded by the KCNQ4 and KCNQ5 , and play a key functional role in regulating vascular tone .…”

“…K ATP are specifically blocked by SUR derivates such as GLI. Since GLI‐induced vasoconstriction was due to a blockade of potassium efflux from the smooth muscle cells, this suggests that under baseline conditions a potassium efflux was responsible for a certain degree of vasorelaxation . K ATP inhibitor GLI (10 μ m ) significantly inhibited both testosterone‐induced relaxation in internal spermatic vein and levosimendan‐induced relaxation in internal mammary artery .…”