title: Endothelium-dependent and -independent vasorelaxation induced by CIJ-3-2F, a novel benzyl-furoquinoline with antiarrhythmic action, in rat aorta.
abstract: OBJECTIVE
  This study was designed to examine the mechanism of relaxation induced by CIJ-3-2F, a benzyl-furoquinoline antiarrhythmic agent, in rat thoracic aorta at the tissue and cellular levels.
  
  
  METHODS
  Isometric tension of rat aortic ring was measured in response to drugs. Ionic channel activities in freshly dissociated aortic vascular smooth muscle cells (VSMCs) were investigated using a whole-cell patch-clamp technique.
  
  
  RESULTS
  CIJ-3-2F relaxed both phenylephrine (PE) and high KCl (60mM)-induced contractions with respective pEC(50) (-log EC(50)) values of 6.91+/-0.07 and 6.32+/-0.06. Removal of endothelium or pretreatment with nitric oxide (NO)-pathway inhibitors N(omega)-nitro-l-arginine methyl ester (L-NAME), N(G)-monomethyl-l-arginine (L-NMMA), N(5)-(1-iminoethyl)-l-ornithine (L-NIO), hemoglobin, methylene blue or 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ) reduced the relaxant effect of CIJ-3-2F. Relaxation to CIJ-3-2F was also attenuated by K(+) channel blockers tetraethylammonium (TEA) or 4-aminopyridine (4-AP), but not by charybdotoxin plus apamin, iberiotoxin, glibenclamide, or BaCl(2). CIJ-3-2F non-competitively antagonized the contractions induced by PE, Ca(2+), and Bay K8644 in endothelium-denuded rings. In addition, CIJ-3-2F inhibited both the phasic and tonic contractions induced by PE but did not affect the transient contraction induced by caffeine. CIJ-3-2F reduced the Ba(2+) inward current through L-type Ca(2+) channel (IC(50)=4.1microM) and enhanced the voltage-dependent K(+) (K(v)) current in aortic VSMCs.
  
  
  CONCLUSIONS
  These results suggest that CIJ-3-2F induced both endothelium-dependent and -independent vasorelaxation; the former is likely mediated by the NO/cGMP pathway whereas the latter is probably mediated through inhibition of Ca(2+) influx or inositol 1,4,5-triphosphate (IP(3))-sensitive intracellular Ca(2+) release, or through activation of K(v) channels.
authors.affiliation: Graduate Institute of Clinical Medicinal Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333, Taiwan. gjchang@mail.cgu.edu.tw <gjchang@mail.cgu.edu.tw>
authors.forename: Gwo-Jyh
authors.initials: GJ
authors.lastname: Chang
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Lin
authors.forename: Yu-Shien
authors.initials: YS
authors.lastname: Ko
authors.forename: Miao-Sui
authors.initials: MS
authors.lastname: Lin
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D002120:Calcium Channel Agonists; C550028:N-(2-fluoro-benzyl)-7-bromo-2,3,4,9-tetrahydrofuro(2,3-b)quinoline-3,4-dione; D011804:Quinolines; D014665:Vasodilator Agents; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium