title: Tolerance to the vascular effect of a novel nitric oxide-donating vasodilator, FK409.
abstract: We investigated whether tolerance develops to the vasorelaxant effects of a new vasodilator, (+-)-(E)-4-ethyl-2-[(E)-hydroxy-imino]-5-nitro-3-hexenamide (FK409), in isolated canine coronary artery strips and to its hypotensive effect in rats, and whether FK409 activates soluble guanylate cyclase isolated from vascular tissues in the absence of L-cysteine. No tolerance to FK409 (0.46 nM to 0.46 microM or 1-1000 micrograms/kg, i.v.) or cross-tolerance between FK409 and glyceryl trinitrate was demonstrated in in vitro and in vivo experiments, whereas the tolerance to glyceryl trinitrate (0.44 nM to 4.4 microM or 1-1000 micrograms/kg, i.v.) was marked in both conditions. In addition, FK409 (0.1-10 microM) activated soluble guanylate cyclase without L-cysteine, but glyceryl trinitrate (1-100 microM) required the addition of L-cysteine (5 mM) for the activation of the enzyme. The results suggest that FK409 may be advantageous compared to tolerance-producing nitrates currently in clinical use, and that this property of FK409 is probably due to its independence of a sulfhydryl group donor.
authors.affiliation: Pharmacological Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Isono
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Sawada
authors.forename: S
authors.initials: S
authors.lastname: Yamazaki
authors.forename: S
authors.initials: S
authors.lastname: Miura
authors.forename: A
authors.initials: A
authors.lastname: Furuichi
authors.forename: R
authors.initials: R
authors.lastname: Ozaki
authors.forename: Y
authors.initials: Y
authors.lastname: Koibuchi
authors.forename: M
authors.initials: M
authors.lastname: Ohtsuka
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects*; D003545:Cysteine / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D009574:Nitro Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D009574:Nitro Compounds; D013438:Sulfhydryl Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; C061872:FK 409; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D003545:Cysteine