title: Effects of the tripeptide substance P antagonist, FR113680, on airway constriction and airway edema induced by neurokinins in guinea-pigs.
abstract: FR113680 is a newly developed tripeptide substance P (SP) receptor antagonist. The effects of FR113680 on airway constriction and airway edema induced by neurokinins were investigated in guinea-pigs. In in vitro experiments, FR113680 inhibited the contraction of isolated guinea-pig trachea induced by SP and neurokinin A (NKA) in a dose-dependent manner with IC50 values of 2.3 x 10(-6) and 1.5 x 10(-5) M, respectively. The tracheal contraction induced by histamine and acetylcholine was not affected by FR113680. FR113680 (5 x 10(-5) M) also significantly inhibited the atropine-resistant contraction of isolated guinea-pig bronchi induced by electrical field stimulation. In in vivo experiments, FR113680 given i.v. inhibited SP-induced airway constriction in guinea-pigs at doses of 1 and 10 mg kg-1. However, FR113680 only inhibited NKA- and capsaicin-induced airway constriction by 40-50% even at a dose of 10 mg kg-1. FR113680 also inhibited SP-induced airway edema in guinea-pigs with the same potency as it inhibited SP-induced airway constriction. Histamine-induced airway constriction and airway edema were not affected at a dose of 10 mg kg-1. These results suggest that FR113680 preferentially inhibits responses induced by NK1 receptor activation (SP-induced airway constriction and airway edema), but is less effective on a NK2 receptor-induced response (airway constriction by NKA and neurogenic stimulation).
authors.affiliation: Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Murai
authors.forename: H
authors.initials: H
authors.lastname: Morimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: T
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007705:Kinins; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015288:Neurokinin A / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
chemical_list: D007705:Kinins; D009842:Oligopeptides; C076202:FR 113680; D013373:Substance P; D006632:Histamine; D015288:Neurokinin A; D002211:Capsaicin