Role of KCNQ Channels in Skeletal Muscle Arteries and Periadventitial Vascular Dysfunction

Abstract

KCNQ channels have been identified in arterial smooth muscle. However, their role in vasoregulation and chronic vascular diseases remains elusive. We tested the hypothesis that KCNQ channels contribute to periadventitial vasoregulation in peripheral skeletal muscle arteries by perivascular adipose tissue and that they represent novel targets to rescue periadventitial vascular dysfunction. Two models, spontaneously hypertensive rats and New Zealand obese mice, were studied using quantitative polymerase chain reaction, the patch-clamp technique, membrane potential measurements, myography of isolated vessels, and blood pressure telemetry. In rat Gracilis muscle arteries, anticontractile effects of perivascular fat were inhibited by the KCNQ channel blockers XE991 and linopirdine but not by other selective K + channel inhibitors. Accordingly, XE991 and linopirdine blocked noninactivating K + currents in freshly isolated Gracilis artery smooth muscle cells. mRNAs of several KCNQ channel subtypes were detected in those arteries, with KCNQ4 channels being dominant. In spontaneously hypertensive rats, the anticontractile effect of perivascular fat in Gracilis muscle arteries was largely reduced compared with Wistar rats. However, the vasodilator effects of KCNQ channel openers and mRNA expression of KCNQ channels were normal. Furthermore, KCNQ channel openers restored the diminished anticontractile effects of perivascular fat in spontaneously hypertensive rats. Moreover, KCNQ channel openers reduced arterial blood pressure in both models of hypertension independent of ganglionic blockade. Thus, our data suggest that KCNQ channels play a pivotal role in periadventitial vasoregulation of peripheral skeletal muscle arteries, and KCNQ channel opening may be an effective mechanism to improve impaired periadventitial vasoregulation and associated hypertension.

Contribution of Kv7.4/Kv7.5 Heteromers to Intrinsic and Calcitonin Gene-Related Peptide–Induced Cerebral Reactivity

“…4 protein is observed without a change in transcription 2,4,13 (and present study). Interestingly, responses to retigabine and 2 novel Kv7 activators are no different in the gracillus artery from normotensive rats and SHRs, 17 although Kv7.4 levels were not determined. Trafficking of ion channel proteins to plama membranes and the regulation of channel activity once inserted are very complicated processes.…”

“…17,18 We now reveal that CGRP-mediated relaxation of cerebral arteries is highly dependent on Kv7 activity and Kv7.4, in particular. CGRP produces relaxations through stimulation of the CGRP receptor, which is an amalgamation of the calcitonin receptor protein and receptor activitymodifying protein 1, 19,20 and is positively coupled to adenylate cyclase, leading to a rise in cAMP and usually recruitment of protein kinase A.…”

Contribution of K v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

“…In contrast to the rat aorta, 6 there was no change in KCNQ expression in the coronary arteries or mesenteric arteries (also observed in gracilis muscle arteries from SHRs). 10 This suggests that the decrease in K V 7.4 reflects an alteration in protein handling rather than transcriptional control. It is worth stressing that we detected an even greater reduction in KCNQ1 and KCNQ4 transcripts in the aorta compared with our previous study because we used a more rigorous quantification technique based around the geNorm analysis of stable housekeeping genes.…”

“…Voltage-gated potassium channels (K V ) have been implicated in the control of the coronary circulation and reactive hyperemia, 1,2 but little is known about the specific molecular components. Kv channels encoded by KCNQ1-5 (K V 7.1-K V 7.5) are important regulators of the smooth muscle resting membrane potential and contractility in several different rodent and human arteries, [3][4][5][6][7][8][9][10][11] which are known to be compromised in animal models of primary and secondary hypertension. 3,6 These channels, in particular K V 7.4, are also functional end points in β-adrenoceptor-mediated relaxations.…”

KCNQ Channels and Novel Insights Into Coronary Perfusion

“…KCNQ1, 3, 4, and 5 gene products are widely expressed in systemic arteries with KCNQ 4 and 5 being predominant. [3][4][5] Current data suggest important roles for K V 7 family in systemic peripheral arteries, namely myogenic response 6 and vasoregulation by vasopressin, 7 β-adrenoceptors, 8 hydrogen sulfide, and perivascular adipose tissue. 5,9 In this current issue, Khanamiri et al 10 have examined the possible role of K V 7 channels in the rat coronary circulation.…”