title: Oxidized LDL increases the sensitivity of the contractile apparatus in isolated resistance arteries for Ca(2+) via a rho- and rho kinase-dependent mechanism.
abstract: BACKGROUND
  Oxidized LDL reduces NO-mediated and endothelium-derived hyperpolarizing factor-mediated dilations. We studied, in hamster skeletal muscle resistance arteries (213+/-8 micrometer n=51), whether an altered vascular smooth muscle (VSM) response, particularly sensitization of the VSM contractile apparatus to Ca(2+), is involved in this oxLDL effect. Methods and Results-VSM or endothelial [Ca(2+)](i) and vascular diameter were measured in response to norepinephrine (0.3 micromol/L), sodium nitroprusside (10 micromol/L), C-type natriuretic peptide (1 to 100 nmol/L), papaverine (0.1 to 10 micromol/L), or the endothelial agonist acetylcholine (ACh, 0.01 to 1 micromol/L). OxLDL significantly increased resting VSM [Ca(2+)](i) (11+/-3%), decreased diameter (8+/-2%), and enhanced norepinephrine-induced constrictions. Dilations to sodium nitroprusside and C-type natriuretic peptide were significantly reduced (by 10+/-2% and 35+/-6%), whereas dose-response curves for papaverine and ACh were shifted to the right, despite unchanged increases in endothelial Ca(2+) after ACh. OxLDL significantly shifted the Ca(2+)-diameter relation to the left, as assessed by stepwise increasing extracellular Ca(2+) (0 to 3 mmol/L) in depolarized skeletal muscle resistance arteries. This sensitization to Ca(2+) by oxLDL was abolished after inhibition of Rho (C3 transferase) or Rho kinase (Y27632).
  
  
  CONCLUSIONS
  OxLDL reduces VSM responsiveness to vasodilators by increasing VSM Ca(2+) but preferentially by sensitizing VSM to Ca(2+) via a Rho- and Rho kinase-dependent pathway.
authors.affiliation: Physiologisches Institut, Ludwig Maximilians Universität, München, Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany. bolz@lrz.uni-muenchen.de
authors.forename: S S
authors.initials: SS
authors.lastname: Bolz
authors.forename: J
authors.initials: J
authors.lastname: Galle
authors.forename: R
authors.initials: R
authors.lastname: Derwand
authors.forename: C
authors.initials: C
authors.lastname: de Wit
authors.forename: U
authors.initials: U
authors.lastname: Pohl
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D006224:Cricetinae; D016232:Endothelins / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D045283:Natriuretic Agents / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009609:Nitrous Oxide / Q000494:pharmacology*; D010208:Papaverine / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D012234:Rho Factor; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D054460:rho-Associated Kinases
chemical_list: D016232:Endothelins; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D045283:Natriuretic Agents; D012234:Rho Factor; C099252:oxidized low density lipoprotein; D009599:Nitroprusside; D010208:Papaverine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009609:Nitrous Oxide; D000109:Acetylcholine; D002118:Calcium