Shoichi Goto

Studies on Vascular Permeability Increasing Factors Involved in 48-Hour Homologous PCA in the Mouse Ear

Several attempts were made to elucidate the possible role of histamine, serotonin, leukotrienes C4 (LTC4) and D4 (LTD4), and prostaglandin E1 (PGE1) as vascular permeability increasing factors involved in 48-hour homologous passive cutaneous anaphylaxis (PCA) in the mouse ear. Increased vascular permeability in the mouse ear caused by the mediator injection or PCA was assessed quantitatively by measuring the amount of extravasated dye. In skin reactions, all of the mediators used in the present study significantly increased vascular permeability. The most potent mediator was serotonin, which increased the vascular permeability from a concentration of 10(-8) g/ml, and the activity was about 100 times higher than that of histamine on a weight basis. Vascular permeability increasing activity of LTC4 was about 10 times higher than that of histamine, and LTD4 and PGE1 were also more potent than histamine. Increases of vascular permeability caused by histamine, serotonin, LTC4 and LTD4 were significantly potentiated by injecting 10(-6) g/ml of PGE1 simultaneously. Histamine-, serotonin- and LTC4-induced skin reactions in the mouse ear were suppressed significantly by the administrations of chlorpheniramine, methysergide and FPL 55712, respectively. In contrast, though chlorpheniramine and methysergide suppressed also mouse ear PCA (about 50 and 40%, respectively), neither FPL 55712, indomethacin nor BW 755C suppressed it. These results strongly suggest that the most important mediator involved in mouse ear PCA is histamine and that serotonin also plays an important role in the increase of vascular permeability caused by PCA. Despite their potent vascular permeability increasing activity LTC4, LTD4 and PGE1 do not seem to play an important role in mouse ear PCA.

Homologous Passive Cutaneous Anaphylaxis in Various Strains of Mice

Passive cutaneous anaphylaxis (PCA) was elicited both in the ear and in the dorsal skin of 13 strains of mice at the same time and assessed quantitatively by measuring the amount of extravasated dye. Body pigments of colored mice such as DBA/2 (chocolate), C3H/He (brown) and C57BL/6 (black) did not interfere with the measurement of dye. In the ear response, ICR was a higher responder, C57BL/6 and BALB/c-nu/nu were lower responder strains. In the dorsal skin response, however, ICR was a lower responder, BALB/c-nu/nu, Hairless and WBB6F1-+/+ were higher responders. WBB6 F1-W/Wv was a nonresponder in both responses. The ear response was highly reproducible and the dorsal skin response of each strain was 1/2-1/10 of its ear response except for BALB/c-nu/nu. The PCA bluing regions on the dorsal skin of BALB/c-nu/nu were clearly delineated and the response was almost comparable to its ear response.

Mouse Ear PCA as a Model for Evaluating Antianaphylactic Agents

Passive cutaneous anaphylaxis (PCA) reaction elicited in ears of male ddY mice was studied by means of assessing dye leakage. In the ear, PCA reaction was more sensitive and reproducible than that in the dorsal skin. The reaction was significantly suppressed by ketotifen, one of antianaphylactic agents.

Leukotriene receptors in the skin of rats differ from those of mouse skin or rat stomach strip

Abstract To compare the receptors for cystcinyl-leukotriene (cys-LT) in rat skin with those in other tissues, we investigated the effects of specific cys-LT receptor antagonists (FPL 55712, LY171883, MCI-826 and L-648051) on cys-I T-induccd cutaneous reactions in rats and mice, and on cys-LT-induced contractile responses in rat stomach smooth muscle. We also studied the effects of these drugs un homologous passive cutaneous anaphylaxis. The four cys-LT receptor antagonists dose dependently inhibited cys-LT-induced cutaneous reactions in mouse car, but failed to inhibit passive cutaneous anaphylaxis and the histamine-induced cutaneous reaction. In rats, only MCI-826 inhibited cys-LT-induced cutaneous reactions although the other three drugs failed to inhibit these reactions. In contrast, the cys-LT-induced contractile responses of rat stomach smooth muscle were inhibited by all these drugs in a concentration-dependent manner. These results suggest that cys-LT receptors in rat skin have an affinity different from that of receptors in mouse skin and rat stomach. They also suggest that cys-LTs arc not involved in passive cutaneous anaphylaxis in mice and rats.

Pharmacological model for airway hypersensitivity produced by propranolol and reserpine in guinea pigs

Combined treatment with propranolol and reserpine enhanced acetylcholine-induced dose-response curves for bronchoconstriction in guinea pigs in vivo. This airway hyperreactivity model was investigated pharmacologically. (1) Increased capillary permeability and increases in leukocytes in bronchoalveolar lavage fluid (BALF) were not observed after this combined treatment. (2) The increased airway sensitivity to acetylcholine produced by propranolol and reserpine was inhibited by ketotifen and theophylline, reported in clinical studies to inhibit airway hyperreactivity. (3) Two leukotriene (LT) receptor antagonists, MCI-826 and FPL-55712, clearly inhibited this increased airway reactivity. (4) A thromboxane A2 (TXA2) receptor antagonist, ONO-3708, and TXA2 synthetase inhibitor, OKY-046, also inhibited this increased airway reactivity. These results suggest that the airway hyperreactivity model produced by propranolol and reserpine in guinea pigs is a valuable pharmacological tool for investigating a remedy and LT and TXA2 may be involved in the onset of this airway hyperreactivity.