cp-99994 and Capillary-Leak-Syndrome

Various volatile organic compounds (VOCs) act as a causative agent of skin inflammation. We investigated the effect of topical application of several VOCs and formalin on microvascular leakage in rat skin. We tested capsaicin, which is a reagent that specifically causes the skin response via endogenously released tachykinins. Evans blue dye extravasation served as an index of the increase in skin vascular permeability. After shaving the abdomen, we applied formalin, m-xylene, toluene, styrene, benzene, ethylbenzene, acetone, diethyl ether, hexane, heptane, cyclohexane and capsaicin to the skin. At 40min after application, skin samples were collected. Among all of the VOCs tested, all of the aromatic compounds significantly produced skin microvascular leakage that was similar to formalin and capsaicin. We also investigated the skin responses seen after the intravenous administration of CP-99,994 (1.5 or 5mg/kg), which is a tachykinin NK1 receptor antagonist, ketotifen (1 or 3mg/kg), which is a histamine H1 receptor antagonist that stabilizes the mast cells, and the topical application of capsazepine (22.5 or 50mM), which is the transient receptor potential vanilloid 1 (TRPV1) antagonist. The response induced by formalin and capsaicin was completely inhibited by CP-99,994. On the other hand, the antagonist partially reduced the response induced by m-xylene, toluene and styrene by 39%, 50% and 46%, respectively. Capsazepine and ketotifen did not alter the response induced by formalin or any of the aromatic compounds. Like capsaicin, formalin and the aromatic compounds at least partially caused skin microvascular leakage, which was due to tachykinin NK1 receptor activation related to the release of tachykinins from the sensory nerve endings. However, it is unlikely that mast cells and TRPV1 play an important role in the skin response.

Topics: Administration, Topical; Animals; Antipruritics; Capillary Leak Syndrome; Capsaicin; Cell Degranulation; Disinfectants; Dose-Response Relationship, Drug; Formaldehyde; Hydrocarbons, Aromatic; Ketotifen; Male; Mast Cells; Neurogenic Inflammation; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Wistar; Regional Blood Flow; Skin

We have investigated the effects of CP-99,994 [(+)-(2s,3s)-3-(2-methoxybenzylamino)-2-phenylpiperidine], a tachykinin NK1 receptor antagonist, HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and ketotifen (4-(1-methyl-4-piperidylidene)4 H-benzo[4,5]cycloheptal[1,2-b]thiophen-10(9H)-one hydrogen fumarate), a histamine H1 receptor antagonist with mast cell-stabilizing properties, on microvascular leakage induced by gaseous formaldehyde. Extravasation of Evans blue dye into airway tissues was used as an index of airway microvascular leakage. Leakage of dye in the trachea and main bronchi increased significantly in a concentration-dependent fashion after 10 min inhalation of formaldehyde (5-45 parts per million (ppm)). The airway response induced by 10 min inhalation of 15 ppm formaldehyde (trachea: 119.5 +/- 13.9 ng/mg, n = 7; main bronchi: 139.6 +/- 7.9 ng/mg, n = 7) was abolished by the administration of CP-99,994 (3 and 6 mg/kg i.v.), but not by the administration of HOE 140 (0.65 mg/kg i.v.) nor ketotifen (1 mg/kg i.v.). The increase in vascular permeability induced by formaldehyde in the rat airway was mediated predominantly by NK1 receptor stimulation. Activation of bradykinin receptors and mast cells did not appear to play an important role in this airway response.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Bronchi; Capillary Leak Syndrome; Capillary Permeability; Formaldehyde; Histamine H1 Antagonists; Ketotifen; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Wistar; Receptor, Bradykinin B2; Specific Pathogen-Free Organisms; Trachea