Effects of an NK1 receptor antagonist, FK888, on constriction and plasma extravasation induced in guinea pig airway by neurokinins and capsaicin

• Published in: European journal of pharmacology Vol. 236; no. 1; pp. 7 - 13
• Main Authors: MURAI, M, MAEDA, Y, HAGIWARA, D, MIYAKE, H, IKARI, N, MATSUO, M, FUJII, T
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 12.05.1993
• Subjects: Animals; Biological and medical sciences; Capillary Permeability - drug effects; Capsaicin - antagonists & inhibitors; Capsaicin - pharmacology; Dipeptides - pharmacology; Guinea Pigs; In Vitro Techniques; Indoles - pharmacology; Male; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth - blood supply; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Neurokinin A - antagonists & inhibitors; Neurokinin A - pharmacology; Pharmacology. Drug treatments; Receptors, Neurokinin-2; Receptors, Neurotransmitter - antagonists & inhibitors; Respiratory system; Substance P - antagonists & inhibitors; Substance P - pharmacology; Trachea - blood supply; Trachea - drug effects; Trachea - physiology; Intravenous administration; Respiratory disease; Capsaicin; Substance P; Rodentia; Experimental study; Obstruction; Asthma; Blood plasma; Local administration; Vertebrata; Mammalia; Guinea pig; Animal; Extravasation; Neuromedin L; Obstructive pulmonary disease; Antagonist; Mechanism of action; Trachea
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(93)90220-C

The effects of FK888, an NK1 receptor antagonist, on airway constriction and airway plasma extravasation induced by neurokinins and capsaicin were investigated in guinea pigs. FK888 inhibited substance P (10(-8) M)- and neurokinin A (10(-9) M)-induced contraction of isolated guinea pig trachea, with IC50 values of 3.2 x 10(-8) and 4.2 x 10(-6) M, respectively. FK888 given i.v. inhibited substance P (13.5 micrograms kg-1)-induced airway constriction with an ED50 value of 0.40 mg kg-1 but did not inhibit neurokinin A (1.1 micrograms kg-1)- and capsaicin (3.1 micrograms kg-1)-induced airway constriction at a dose of 1 mg kg-1. On the other hand, FK888 given i.v. inhibited airway plasma extravasation induced by substance P (1.3 micrograms kg-1), neurokinin A (11 micrograms kg-1) and capsaicin (100 micrograms kg-1) with equal potency and ED50 values of 0.011, 0.0063 and 0.019 mg kg-1, respectively. When FK888 was given locally (into the airway directly) inhibitory activities were more potent than following i.v. administration. In this case FK888 inhibited substance P-, neurokinin A- and capsaicin-induced airway constriction with ED50 values of 3.2, 190 and 550 micrograms kg-1, respectively, suggesting that an about 100 times higher dose is required to inhibit neurokinin A- and capsaicin-induced airway constriction than substance P-induced constriction. FK888 given orally was also effective in substance P-, neurokinin A- and capsaicin-induced airway plasma extravasation with ED50 values of 4.2, 5.9 and 9.5 mg kg-1.