title: AMPK Dilates Resistance Arteries via Activation of SERCA and BKCa Channels in Smooth Muscle.
abstract: The protective effects of 5'-AMP-activated protein kinase (AMPK) on the metabolic syndrome may include direct effects on resistance artery vasomotor function. However, the precise actions of AMPK on microvessels and their potential interaction are largely unknown. Thus, we set to determine the effects of AMPK activation on vascular smooth muscle tone and the underlying mechanisms. Resistance arteries isolated from hamster and mouse exhibited a pronounced endothelium-independent dilation on direct pharmacological AMPK activation by 2 structurally unrelated compounds (PT1 and A769662). The dilation was associated with a decrease of intracellular-free calcium [Ca(2+)]i in vascular smooth muscle cell. AMPK stimulation induced activation of BKCa channels as assessed by patch clamp studies in freshly isolated hamster vascular smooth muscle cell and confirmed by direct proof of membrane hyperpolarization in intact arteries. The BKCa channel blocker iberiotoxin abolished the hyperpolarization but only partially reduced the dilation and did not affect the decrease of [Ca(2+)]i. By contrast, the sarcoplasmic/endoplasmic Ca(2+)-ATPase (SERCA) inhibitor thapsigargin largely reduced these effects, whereas combined inhibition of SERCA and BKCa channels virtually abolished them. AMPK stimulation significantly increased the phosphorylation of the SERCA modulator phospholamban at the regulatory T17 site. Stimulation of smooth muscle AMPK represents a new, potent vasodilator mechanism in resistance vessels. AMPK directly relaxes vascular smooth muscle cell by a decrease of [Ca(2+)]i. This is achieved by calcium sequestration via SERCA activation, as well as activation of BKCa channels. There is in part a mutual compensation of both calcium-lowering mechanisms. However, SERCA activation which involves an AMPK-dependent phosphorylation of phospholamban is the predominant mechanism in resistance vessels.
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Holger
authors.initials: H
authors.lastname: Schneider
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Kai Michael
authors.initials: KM
authors.lastname: Schubert
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Blodow
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Claus-Peter
authors.initials: CP
authors.lastname: Kreutz
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Serap
authors.initials: S
authors.lastname: Erdogmus
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Margarethe
authors.initials: M
authors.lastname: Wiedenmann
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Jiehua
authors.initials: J
authors.lastname: Qiu
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Theres
authors.initials: T
authors.lastname: Fey
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Lubomir T
authors.initials: LT
authors.lastname: Lubomirov
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pfitzer
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Michael
authors.initials: M
authors.lastname: Mederos Y Schnitzler
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: D Grahame
authors.initials: DG
authors.lastname: Hardie
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.affiliation: From the Walter-Brendel Centre of Experimental Medicine and Biomedical Center (H.S., K.M.S., S.B., C.-P.K., M.W., J.Q., T.F., U.P.) and Walther Straub Institute, Pharmacology (S.E., M.M.y.S., T.G.), Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (H.S., K.M.S., S.B., U.P.); DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S., K.M.S., S.B., T.F., M.M.y.S., T.G., U.P.); Division of Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom (D.G.H.); Institute of Vegetative Physiology, University of Cologne, Köln, Germany (L.T.L., G.P.); and Pharmacology, Toxicology and Clinical Pharmacy, Department of Pharmacy, Universität Tübingen, Tübingen, Germany (P.R.). upohl@lmu.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pohl
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014666:Vasomotor System / Q000187:drug effects* / Q000502:physiology; D000099211:Phospholamban
chemical_list: D055372:AMP-Activated Protein Kinases; D002135:Calcium-Binding Proteins; D007211:Indoles; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D010455:Peptides; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019284:Thapsigargin; D000099211:Phospholamban; C048220:paxilline; C064719:iberiotoxin
keywords: muscle, smooth, vascular; phospholamban; vasodilation