title: KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine.
abstract: Hydrogen peroxide (H2O2) and voltage-dependent K(+) (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Goodwill
authors.affiliation: California Medical Innovations Institute, San Diego, California.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Fu
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Jillian N
authors.initials: JN
authors.lastname: Noblet
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Eli D
authors.initials: ED
authors.lastname: Casalini
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-6785-4663
authors.initials: D
authors.lastname: Sassoon
authors.affiliation: California Medical Innovations Institute, San Diego, California.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Berwick
authors.affiliation: California Medical Innovations Institute, San Diego, California.
authors.forename: Ghassan S
authors.initials: GS
authors.lastname: Kassab
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
authors.affiliation: California Medical Innovations Institute, San Diego, California gdick@calmi2.org.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
mesh_terms: D063194:Adventitia / Q000378:metabolism; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D051656:KCNQ Potassium Channels / Q000235:genetics* / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D051658:KCNQ2 Potassium Channel / Q000235:genetics; D051659:KCNQ3 Potassium Channel / Q000235:genetics; D019899:Paracrine Communication / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D007211:Indoles; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D026902:Potassium Channel Blockers; D011725:Pyridines; D014665:Vasodilator Agents; C061017:linopirdine; C034161:flupirtine; D001920:Bradykinin
keywords: KCNQ; coronary circulation; hydrogen peroxide; linopirdine; metabolic vasodilation
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