Bimodal effects of the K_v7 channel activator retigabine on vascular K⁺ currents

Abstract

Background and purpose: This study investigated the functional and electrophysiological effects of the K v 7 channel activator, retigabine, on murine portal vein smooth muscle. Experimental approach: KCNQ gene expression was determined by reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemical experiments. Whole cell voltage clamp and current clamp were performed on isolated myocytes from murine portal vein. Isometric tension recordings were performed on whole portal veins. K þ currents generated by KCNQ4 and KCNQ5 expression were recorded by two-electrode voltage clamp in Xenopus oocytes. Key results: KCNQ1, 4 and 5 were expressed in mRNA derived from murine portal vein, either as whole tissue or isolated myocytes. K v 7.1 and K v 7.4 proteins were identified in the cell membranes of myocytes by immunocytochemistry. Retigabine (2-20 mM) suppressed spontaneous contractions in whole portal veins, hyperpolarized the membrane potential and augmented potassium currents at À20 mV. At more depolarized potentials, retigabine and flupirtine, decreased potassium currents. Both effects of retigabine were prevented by prior application of the K v 7 blocker XE991 (10 mM). Recombinant KCNQ 4 or 5 channels were only activated by retigabine or flupirtine. Conclusions and implications: The K v 7 channel activators retigabine and flupirtine have bimodal effects on vascular potassium currents, which are not seen with recombinant KCNQ channels. These results provide support for KCNQ4-or KCNQ5-encoded channels having an important functional impact in the vasculature.

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

“…We found expression of all K V 7 subtypes in the left and right ventricles of the rat heart. K V 7.1, K V 7.4, and K V 7.5 channels have previously been identified in rat (Khanamiri et al, 2013;Morales-Cano et al, 2015) and porcine (Hedegaard et al, 2014) coronary arteries as well as in extracardiac vessels (Yeung et al, 2007(Yeung et al, , 2008bMackie and Byron, 2008). In mice, K V 7.1 and K V 7.4 were found in coronary arteries (Lee et al, 2015) and K V 7.1, K V 7.4, and K V 7.5 were found in aorta (Yeung et al, 2007).…”

Downregulation of Kv7.4 Channel Activity in Primary and Secondary Hypertension

“…Kv7 channels have an important physiological role in vascular tissues, [11][12][13][14][15][16][17][18][19][20][21] as well as nonvascular tissues, [43][44][45] in addition to their established role in neurons, cardiomyocytes, and epithelia. In each vascular tissue studied previously, quantitative polymerase chain reaction and protein analysis revealed that KCNQ1, KCNQ4, and KCNQ5 were predominant, with a minimal contribution from KCNQ2 and KCNQ3.…”

“…13,[15][16][17][18]21 Conversely, agents such as retigabine and S-1, which enhance Kv7.2-Kv7.5-mediated currents but not Kv7.1-mediated currents, 22-25 hyperpolarize the membrane potential 16,17,20 and relax precontracted rodent or human arteries. 13,[15][16][17][18]20,26 Kv7 channels have been identified as effective regulators of vascular smooth muscle contractility in various blood vessels from normotensive animals; however, there is no information about the distribution and function of these channels in hypertension. To that end, we used a range of structurally disparate modulators of Kv7 channels to eluci- date the functional impact of Kv7 channels in the thoracic aorta, third-order branches of the superior mesenteric artery, and coronary circulation of normotensive rats and spontaneously hypertensive rats (SHRs), as well as the mesenteric artery of normotensive mice and angiotensin II (Ang II)-induced hypertensive mice.…”

“…15,19 Modulation of these channels provokes profound changes in vascular smooth muscle membrane potential and consequently vascular tone. [13][14][15][16][17]20 Thus, the nonselective Kv7.1 through Kv7.5 channel blockers linopirdine and XE991 produce membrane depolarization and concomitant vasoconstriction by enhancing Ca 2ϩ influx through voltagedependent calcium channels. 13,[15][16][17][18]21 Conversely, agents such as retigabine and S-1, which enhance Kv7.2-Kv7.5-mediated currents but not Kv7.1-mediated currents, [22][23][24][25] hyperpolarize the membrane potential 16,17,20 and relax precontracted rodent or human arteries.…”

“…[13][14][15][16][17]20 Thus, the nonselective Kv7.1 through Kv7.5 channel blockers linopirdine and XE991 produce membrane depolarization and concomitant vasoconstriction by enhancing Ca 2ϩ influx through voltagedependent calcium channels. 13,[15][16][17][18]21 Conversely, agents such as retigabine and S-1, which enhance Kv7.2-Kv7.5-mediated currents but not Kv7.1-mediated currents, [22][23][24][25] hyperpolarize the membrane potential 16,17,20 and relax precontracted rodent or human arteries. 13,[15][16][17][18]20,26 Kv7 channels have been identified as effective regulators of vascular smooth muscle contractility in various blood vessels from normotensive animals; however, there is no information about the distribution and function of these channels in hypertension.…”