title: Vasorelaxing effects of the soluble guanylyl cyclase activator BAY 60-2770 in nitrate-tolerant monkey and canine coronary arteries.
abstract: Nitrate tolerance is an important problem in the treatment of ischemic heart diseases. The present study investigated whether or not a soluble guanylyl cyclase (sGC) activator can be used as a coronary vasodilator under nitrate-tolerant conditions. Helically cut strips of endothelium-denuded monkey and canine coronary arteries were suspended in organ chambers for isometric tension recording. Nitrate tolerance was induced by a 1-h treatment with nitroglycerin (0.1 mM) followed by 1-h washout of the agent. Control strips were not exposed previously to nitroglycerin, but otherwise were treated identically. The relaxant response to nitroglycerin was dramatically impaired by previous exposure to the drug for 1 h in either monkey or canine coronary arteries, indicating the development of nitrate tolerance. In contrast, development of nitrate tolerance did not affect the relaxant potency and efficacy of the sGC activator BAY 60-2770 in either the monkey or canine coronary arteries. These findings suggest that it may be possible to use sGC activators as substitute drugs for nitroglycerin if tolerance is developed during the treatment of ischemic heart diseases.
authors.affiliation: Department of Pharmacology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, 520-2192, Shiga, Japan, tawa@belle.shiga-med.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimosato
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Tomio
authors.initials: T
authors.lastname: Okamura
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D009566:Nitrates; D005996:Nitroglycerin / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D006845:Hydrocarbons, Fluorinated; D009566:Nitrates; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005996:Nitroglycerin