title: 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.
authors.affiliation: Centre for Biomedicine and Medical Technology Mannheim, Research Division Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Zavaritskaya
authors.forename: Nadezda
authors.initials: N
authors.lastname: Zhuravleva
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleifenbaum
authors.forename: Torsten
authors.initials: T
authors.lastname: Gloe
authors.forename: Lena
authors.initials: L
authors.lastname: Devermann
authors.forename: Reinhart
authors.initials: R
authors.lastname: Kluge
authors.forename: Mitko
authors.initials: M
authors.lastname: Mladenov
authors.forename: Manfred
authors.initials: M
authors.lastname: Frey
authors.forename: Hristo
authors.initials: H
authors.lastname: Gagov
authors.forename: Gabor
authors.initials: G
authors.lastname: Fésüs
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schubert
mesh_terms: D000273:Adipose Tissue / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects / Q000502:physiology*; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D007211:Indoles; D051656:KCNQ Potassium Channels; D026902:Potassium Channel Blockers; D011725:Pyridines; C061017:linopirdine