Biol. Pharm. Bull. 30(11) 2063—2068 (2007)

“nantenjitsu” in Japan, have been used for the treatment of respiratory diseases such as asthma, whooping cough and pharynx tumor for many years in Japan. However, little is known about mechanisms underlying its pharmacological action. Since the trachea is a lower respiratory tract that controls respiratory air flow, it is possible that ND improves breathing difficulty by relaxing tracheal smooth muscles. To examine this possibility, in the present study, we investigated effects of the crude extract from ND (NDE) on contractile responses of isolated trachea in vitro. Although chemical studies on the constituents of NDE have revealed that it contains numerous alkaloids, it remains unclear which constituent is responsible for beneficial effects of NDE in treating respiratory disorders. Nantenine (9,10methylenedioxy-1,2 dimethoxyaporphine or O-methyldomesticine) is a major alkaloid isolated from NDE, and has been reported to show several pharmacological activities. For example, nantenine (3 mM) competitively inhibited serotonin-induced contractile responses in isolated rabbit aorta and isolated rat stomach, suggesting that it is a serotonergic receptor antagonist. Nantenine (0.3—3 mM) competitively inhibited phenylephrine-induced contraction in isolated rat aorta, suggesting that it is also an a1-adrenoceptor antagonist. Nantenine at higher concentrations (2.35, 4.7 10 4 M) inhibited KCl-induced increase in intracellular Ca concentration and contraction in isolated rat vas deferens, suggesting that it works like Ca antagonists. Intravenous administration of nantenine (3—6 mg/kg) produced dose-dependent decreases in mean arterial blood pressure and heart rate in anesthetized rats. Intraperitoneal administration of nantenine (20— 50 mg/kg) inhibited pentylenetetrazoland electroshock-induced seizures in mice. The chemical structure of nantenine is similar to that of 3,4-methylenedioxymethamphetamine (MDMA), which is a “club drug” often sold under the name of ecstasy, and nantenine blocked MDMA-induced hyperthermia in mice. However, to the best of our knowledge, there has been no report describing pharmacological effects of nantenine on the respiratory system. Therefore, we compared the effects of NDE and nantenine in the present study. Contractile responses of tracheal smooth muscles are regulated by various neurotransmitters and autacoids including acetylcholine, histamine, serotonin, etc. As mentioned above, nantenine has been reported to inhibit serotonin-induced contractile responses in isolated rabbit aorta and isolated rat stomach. It is possible that NDE and nantenine affect serotonin-induced contraction of tracheal smooth muscles. Therefore, in the present study, we used acetylcholine, histamine and serotonin as stimulants to induce tracheal contraction. Furthermore, we chose the guinea pig as an experimental animal, because it is well known that the guinea pig trachea responds more sensitively to histamine and serotonin than the rat trachea.