Endothelium-dependent and -independent vasorelaxation induced by CIJ-3-2F, a novel benzyl-furoquinoline with antiarrhythmic action, in rat aorta

Aims: 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. Main 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. Key findings: CIJ-3-2F relaxed both phenylephrine (PE) and high KCl (60 mM)-induced contractions with respective pEC(50) (-log EC50) 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-(1,2,41 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 BaCl2. CIJ-3-2F non-competitively antagonized the contractions induced by PE, Ca2+, 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 Ba2+ inward current through L-type Ca2+ channel (IC50=4.1 mu M) and enhanced the voltage-dependent K+ (Ku) current in aortic VSMCs. Significance: 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 Ca2+ influx or inositol 1,4,5-triphosph.ate (IP3)-sensitive intracellular Ca2+ release, or through activation of K-v channels. (C) 2010 Elsevier Inc. All rights reserved.