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Effect of Y-20811, a potent and new thromboxane A2 synthetase inhibitor, on experimental asthma in guinea pigs and rats
in the airway tissue increased in STA,inhalated animal but no modifications on Furthermore, inhalation of STAz and PAF increased ACh (lo-’ M)-iiduced Ca uptake suppressed the increase in Ca uptake using PAF but not STA,. TKA, should act on the airway smooth muscle or alter functions of muscarinic and and LTs receptors which are responsible for the contraction of smooth muscle. By these actions, rease the membrane permeability to extracellular Ca 2+ . We also assume that OKY-046 can inhibit rresponsiveness by suppressing the generation of TK&.
et al.: Akay hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation. J. Pharmacol r. 2X5,580-584 (1986a). et al.: Inhibition of antigen-induced airway hyperresponsiveness by a thromboxane synthetase inhibitor (OKY-046) in Am. Rev. Respir. Qis. 134,258-261 (1986b). Aizav,a, H. et al.: !Gignificanceof thromboxane generation in ozoneinduced hay hyperresponsiveness in dogs. J. A@. Physiol. 59, 19184923 (1985).
bitor,
M&a&ma,
H., Terasawa,
M., Tomomatsu,
N., Setoguchi,
M. and Tahara,
T.
Research Laboratories, Yashitomi Pharmaceutical Industries, Ltd, Yoshitomi-cho. Chikujo-gun, Fukuoka 871, Japan Thromboxane A, (TXA,) is known to be a potent bronchial constrictor in addition to being a platelet aggregator (Tad, 1985). Y-20811 (4-[a-hydroxy-s-(imidazolylzolyl)-2-methylbenzyl]-3,%limethyl benzoate has dihydrate) already proven to be a potent and long-acting TKA, synthetase, inhibitor, and it also inhibits platelet aggregation and arachidonic acid (AA)-induced sudden death (Mikashima, 1986). We examined the effect of Y-20811 on experimental asthma in guinea pigs and rats. 1. Y-20811 (10 mg/kg, p-0. and i.v.) had an inhibitory effect on active anaphylactic bronchoconstriction (slow reacting substance of anaphylaxis, SRSA related phase) using a modified method of Konzett and Rossler in guinea pigs pretreated with mepyramine and propranolol. 2. Activeiy sensitized guinea pig lung was inflated 2.4 times by antigen aerosol inhalation. Mepyramine inhibited this response only about 50%, even at S mg/kg, iv. Y-20811 (0.3-3 mg/kg, p.o.) exhibited a significant inhibition of pulmonary inflation in combination with mepyramine. 3. At oral doses of 0.3 and 3 mg/kg, Y-20811 significantly inhibited the IgE-mediated anaphylactic bronchoconstriction in actively sensitized rats. Moreover, Y-20811 (0.01-I mg/rat, i.p.) dose-dependently inhibited the production and/or release of SRSA and histamine in the passive peritoneal anaphylaxis of rats induced by the IgE-like antibody against DNP hapten. These results demonstrate that Y-20811 inhibits the IgG and IgE related anaphylactic reactions. 4. Y-20811 (0.1-l mg/kg, i.v.) inhibited bronchoconstriction in guinea pigs induced by an AA, leukotriene D4 (LTD,), and platelet-activating factor (PAF) in a dose-dependent manner. Furthermore, Y-20811 (0.3-10 mg/kg, p.o.) also reduced the LTD,-induced bronchoconstriction with a long duration of action. In an isolated ileum preparation from guinea pigs, Y-20811 (10-’ M) exhibited no antagonism to the constriction caused by histamine, LTD, and PAF. These results suggest that AA, LTD, and PAF may act in part through the TXA, production. 5. When administered to rats, Y-20811 (3 mg/kg, p.o.) significantly inhibited the TXA2 (estimated as TX&) production in lung perfused with Kreb’s solution, as well as in whole blood for at least 24 hours. In in vitro experimentation, Y-20811 (1O-7-1O-5 M) inhibited the antigen-kduced production of TXA, and enhanced the Production of prostaglandin E, from the actively sensitized chopped guinea pig lung tissues, while indomethacin (IO-7-IO-5 M) inhibited both productions in a concentration-dependent manner.
225
Conclusion: These results suggest that TXAl would be a major participator drug.
in the pathogenesis
of asthma and
Y-20811 may be useful as an anti-asthmatic
References Tod, M.L. and Cassin, S., 1985, J. Appl. Physiol. 58, 710. Mikashima, H., Ochi, H., Muramoto, Y., Yasuda, H., Tsuruta, M. and Maruyama. Y.. 1986, Thromb. Res. 43,455.
1 P.mo.014 1
Ohmori,
K., Sasaki, Y., Ishii, H., M&i, I. and I&ii, A.
Pharmaceutical Research Laboratories. Kyowa Hakko KOQO Co., Ltd., Nagaizumi. Shizuoka 411, Japan
KW-4099, sodium ll-[2-(4-benzyl-l-piperidinyl)ethyl]t~o-6,ll-d~ydrodibe~[~,e]-oxep~e-2~~boxylate, is a newly synthesized antiallergic agent with thromboxane A, (TXA,) antagonistic properties. The aim of this study was to evaluate some of the in uiuo and in vitro pharmacologies of this compound. Oral administration of KW-4099 showed a dose-dependent inhibition on homologous passive cutaneous anaphylaxis in rats with ED5, value of 2.0 mg/kg. This inhibitory effect of KW-4099 persisted for 9 hr. This compound inhibited the liberation of histamine from rat peritoneal exudate cells induced by antigen-antibody reaction at concentrations of 1 X 10B5 M or higher. In anesthetized ventilated guinea pigs, pretreatment with KW-4099 inhibited the anaphylactic bronchoconstriction dose-dependently. KW-4099, 3-30 mg/kg (p-o.), also inhibited the broncboconstriction induced by a prostaglandin endoperoxide analogue (U-46619). prostaglandin 4, platelet activating factor (PAF) and histamine in propranolol (3 mg/kg, i.p.) pretreated guinea pigs (Table 1). In isolated guinea pig tracheal preparations, KW-4099 competitiveiy inhillited the contractile response to U-46619 with pAz valx of 7.00. Table 1 Inhibition of bronchoconstriction by KW-4099 in guinea-pigs. Treatment
Dose tmg/kg, p.o.)
Antigen
U-46619 (1.05)
Hist IlO)
PAF (0.3)
PGD w3)
KW-4099
1 3 10 30
3.0* 1.3 24.7 f 10.7 80.5* 3.5 NT
NT 15.gf1.6 47.3 f 9.0 70.6 f 5.3
13.9*5.7 83.8 f 5.2 NT NT
NT 13.6 f 2.7 28.6 f 6.4 59.9 + 6.0
NT 9.0 rf:3.3 40.7 * 9.7 77.5+2.9
Numbers in each column indicate 4; inhibition* S.E. in groups of 5-10 animals. Numbers in parentheses indicate the dose of spasmogen used (mcg/kg, i.v.) NT: Not tested.
Receptor blockade activities were measured by receptor binding assay. The guinea pig cerebellum, guinea pig platelets and rat frontal cortex were used for histamine H, TXAz and 5-HT, receptor binding assay, respectively. Inhibition constant values {Ki) of KW-4099 were 18 nM for histamine Hl receptor, 140 nM for TXAz receptor and 180 nM for 5-HT, receptor, respectively. In addition, KW-4099 at concentrations of 1 x 10m6 M or higher inhibited the intracellular Ca*+ increase in guinea pig platelets by the stimulation with U-46619. These results suggest that KW-4099 is a novel antiallergic agent with well-balanced multiple actions.
et al.: Akay hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation. J. Pharmacol r. 2X5,580-584 (1986a). et al.: Inhibition of antigen-induced airway hyperresponsiveness by a thromboxane synthetase inhibitor (OKY-046) in Am. Rev. Respir. Qis. 134,258-261 (1986b). Aizav,a, H. et al.: !Gignificanceof thromboxane generation in ozoneinduced hay hyperresponsiveness in dogs. J. A@. Physiol. 59, 19184923 (1985).
bitor,
M&a&ma,
H., Terasawa,
M., Tomomatsu,
N., Setoguchi,
M. and Tahara,
T.
Research Laboratories, Yashitomi Pharmaceutical Industries, Ltd, Yoshitomi-cho. Chikujo-gun, Fukuoka 871, Japan Thromboxane A, (TXA,) is known to be a potent bronchial constrictor in addition to being a platelet aggregator (Tad, 1985). Y-20811 (4-[a-hydroxy-s-(imidazolylzolyl)-2-methylbenzyl]-3,%limethyl benzoate has dihydrate) already proven to be a potent and long-acting TKA, synthetase, inhibitor, and it also inhibits platelet aggregation and arachidonic acid (AA)-induced sudden death (Mikashima, 1986). We examined the effect of Y-20811 on experimental asthma in guinea pigs and rats. 1. Y-20811 (10 mg/kg, p-0. and i.v.) had an inhibitory effect on active anaphylactic bronchoconstriction (slow reacting substance of anaphylaxis, SRSA related phase) using a modified method of Konzett and Rossler in guinea pigs pretreated with mepyramine and propranolol. 2. Activeiy sensitized guinea pig lung was inflated 2.4 times by antigen aerosol inhalation. Mepyramine inhibited this response only about 50%, even at S mg/kg, iv. Y-20811 (0.3-3 mg/kg, p.o.) exhibited a significant inhibition of pulmonary inflation in combination with mepyramine. 3. At oral doses of 0.3 and 3 mg/kg, Y-20811 significantly inhibited the IgE-mediated anaphylactic bronchoconstriction in actively sensitized rats. Moreover, Y-20811 (0.01-I mg/rat, i.p.) dose-dependently inhibited the production and/or release of SRSA and histamine in the passive peritoneal anaphylaxis of rats induced by the IgE-like antibody against DNP hapten. These results demonstrate that Y-20811 inhibits the IgG and IgE related anaphylactic reactions. 4. Y-20811 (0.1-l mg/kg, i.v.) inhibited bronchoconstriction in guinea pigs induced by an AA, leukotriene D4 (LTD,), and platelet-activating factor (PAF) in a dose-dependent manner. Furthermore, Y-20811 (0.3-10 mg/kg, p.o.) also reduced the LTD,-induced bronchoconstriction with a long duration of action. In an isolated ileum preparation from guinea pigs, Y-20811 (10-’ M) exhibited no antagonism to the constriction caused by histamine, LTD, and PAF. These results suggest that AA, LTD, and PAF may act in part through the TXA, production. 5. When administered to rats, Y-20811 (3 mg/kg, p.o.) significantly inhibited the TXA2 (estimated as TX&) production in lung perfused with Kreb’s solution, as well as in whole blood for at least 24 hours. In in vitro experimentation, Y-20811 (1O-7-1O-5 M) inhibited the antigen-kduced production of TXA, and enhanced the Production of prostaglandin E, from the actively sensitized chopped guinea pig lung tissues, while indomethacin (IO-7-IO-5 M) inhibited both productions in a concentration-dependent manner.
225
Conclusion: These results suggest that TXAl would be a major participator drug.
in the pathogenesis
of asthma and
Y-20811 may be useful as an anti-asthmatic
References Tod, M.L. and Cassin, S., 1985, J. Appl. Physiol. 58, 710. Mikashima, H., Ochi, H., Muramoto, Y., Yasuda, H., Tsuruta, M. and Maruyama. Y.. 1986, Thromb. Res. 43,455.
1 P.mo.014 1
Ohmori,
K., Sasaki, Y., Ishii, H., M&i, I. and I&ii, A.
Pharmaceutical Research Laboratories. Kyowa Hakko KOQO Co., Ltd., Nagaizumi. Shizuoka 411, Japan
KW-4099, sodium ll-[2-(4-benzyl-l-piperidinyl)ethyl]t~o-6,ll-d~ydrodibe~[~,e]-oxep~e-2~~boxylate, is a newly synthesized antiallergic agent with thromboxane A, (TXA,) antagonistic properties. The aim of this study was to evaluate some of the in uiuo and in vitro pharmacologies of this compound. Oral administration of KW-4099 showed a dose-dependent inhibition on homologous passive cutaneous anaphylaxis in rats with ED5, value of 2.0 mg/kg. This inhibitory effect of KW-4099 persisted for 9 hr. This compound inhibited the liberation of histamine from rat peritoneal exudate cells induced by antigen-antibody reaction at concentrations of 1 X 10B5 M or higher. In anesthetized ventilated guinea pigs, pretreatment with KW-4099 inhibited the anaphylactic bronchoconstriction dose-dependently. KW-4099, 3-30 mg/kg (p-o.), also inhibited the broncboconstriction induced by a prostaglandin endoperoxide analogue (U-46619). prostaglandin 4, platelet activating factor (PAF) and histamine in propranolol (3 mg/kg, i.p.) pretreated guinea pigs (Table 1). In isolated guinea pig tracheal preparations, KW-4099 competitiveiy inhillited the contractile response to U-46619 with pAz valx of 7.00. Table 1 Inhibition of bronchoconstriction by KW-4099 in guinea-pigs. Treatment
Dose tmg/kg, p.o.)
Antigen
U-46619 (1.05)
Hist IlO)
PAF (0.3)
PGD w3)
KW-4099
1 3 10 30
3.0* 1.3 24.7 f 10.7 80.5* 3.5 NT
NT 15.gf1.6 47.3 f 9.0 70.6 f 5.3
13.9*5.7 83.8 f 5.2 NT NT
NT 13.6 f 2.7 28.6 f 6.4 59.9 + 6.0
NT 9.0 rf:3.3 40.7 * 9.7 77.5+2.9
Numbers in each column indicate 4; inhibition* S.E. in groups of 5-10 animals. Numbers in parentheses indicate the dose of spasmogen used (mcg/kg, i.v.) NT: Not tested.
Receptor blockade activities were measured by receptor binding assay. The guinea pig cerebellum, guinea pig platelets and rat frontal cortex were used for histamine H, TXAz and 5-HT, receptor binding assay, respectively. Inhibition constant values {Ki) of KW-4099 were 18 nM for histamine Hl receptor, 140 nM for TXAz receptor and 180 nM for 5-HT, receptor, respectively. In addition, KW-4099 at concentrations of 1 x 10m6 M or higher inhibited the intracellular Ca*+ increase in guinea pig platelets by the stimulation with U-46619. These results suggest that KW-4099 is a novel antiallergic agent with well-balanced multiple actions.