Inhaled Pinacidil, an ATP-Sensitive K Channel Opener, and Moguisteine
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Jpn. J. Pharmacol. 89, 171 – 175 (2002) Inhaled Pinacidil, an ATP-Sensitive K+ Channel Opener, and Moguisteine Have Potent Antitussive Effects in Guinea Pigs Kayo Morita1, Kenji Onodera2 and Junzo Kamei1,* 1Department of Pathophysiology & Therapeutics, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo 142-8501, Japan 2Department of Dental Pharmacology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8525, Japan Received December 10, 2001 Accepted March 18, 2002 ABSTRACT—We investigated whether inhaled pinacidil and moguisteine inhibit capsaicin-induced coughs in guinea pigs. Inhaled pinacidil (15 – 60 mg/ml), an ATP-sensitive K+ channel opener, and moguisteine (15 – 60 mg/ml) each dose-dependently inhibited the number of capsaicin-induced coughs. The antitussive effects of pinacidil and moguisteine were significantly antagonized by pretreatment with glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel blocker. However, pretreatment with naloxone methiodide (10 mg/kg, s.c.) had no significant effect on the antitussive effects of either pinacidil or moguisteine. On the other hand, inhaled dihydrocodeine (15 – 60 mg/ml) also dose-dependently suppressed the number of capsaicin-induced coughs. The antitussive effect of inhaled dihydrocodeine was significantly antagonized by pretreatment with naloxone methiodide (10 mg/kg, s.c.), but not by glibenclamide (10 mg/kg, i.p.). These results indicate that inhaled pinacidil and moguisteine both attenuate capsaicin-induced coughs. Pinacidil and moguisteine may exert their antitussive effects through the activation of ATP-sensitive K+ channels in the tracheobronchial tract. Furthermore, it is possible that ATP-sensitive K+ channels may be involved in the antitussive effects of peripherally acting non-narcotic antitussive drugs. Keywords: Cough reflex, Antitussive effect, ATP-sensitive K+ channel, Moguisteine, Peripherally acting non-narcotic antitussive drug Moguisteine ((R,S)-2-(2-methoxyphenoxy)-methyl-3- relax smooth muscle and may have therapeutic potential in ethoxycarbonyl-acetyl-1,3-thiazolidine), a non-opioid com- the treatment of asthma (8, 9). Recently, Poggioli et al. (10) pound, has been shown to be as active as codeine in reduc- demonstrated that pinacidil and cromakalim, which open ing coughs induced in guinea pigs by chemical irritants, ATP-sensitive K+ channels, reduced citric acid-induced such as citric acid and capsaicin, or by mechanical or elec- coughs in guinea pigs. They also reported that the antitus- trical stimulation of the trachea (1). Data from several re- sive effect of ATP-sensitive K+ channel openers was not a searchers suggest that the antitussive action of moguisteine consequence of a bronchodilating effect (10). Previously, depends on a peripheral mechanism (2 – 4). Previously, we we suggested that ATP-sensitive K+ channels are not asso- demonstrated that moguisteine dose-dependently inhibited ciated with the central mechanisms of antitussive drugs, the enhancement of capsaicin-induced coughs associated since the antitussive effect of morphine was not antago- with angiotensin converting enzyme inhibitor (5). Further- nized by pretreatment with intracerebroventricular (i.c.v.) more, we suggested that moguisteine may be of a thera- glibenclamide (11, 12). Furthermore, we also demonstrated peutic benefit in reducing allergic coughs (6). Recently, that systemic pinacidil and moguisteine may exert their we also reported that the systemic administration of mogu- antitussive effects through the activation of ATP-sensitive isteine may have an antitussive effect through the activation K+ channels (7). These results suggest that ATP-sensitive of ATP-sensitive K+ channels (7). However, the detailed K+ channels may be involved in the antitussive effects of mechanism of the antitussive effect of moguisteine is not peripherally acting non-narcotic antitussive drugs. clearly understood. In clinical studies in asthmatic patients, orally admin- ATP-sensitive K+ channel openers are novel agents that istered cromakalim has been shown to attenuate nocturnal bronchoconstriction (13). This finding, together with its plasma half-life of 22 h (14), appeared to give this drug *Corresponding author. FAX: 81-3-5498-5029 E-mail: [email protected] considerable potential as an oral bronchodilator. However, 171 172 K. Morita, K. Onodera & J. Kamei the oral dose may be limited by vasodilatation and a Drugs decrease in blood pressure (15). In view of the side effects Moguisteine was generously supplied by Boehringer of the systemic administration of cromakalim, it is unlikely Mannheim Italia (Monza, Italy). Dihydrocodeine hydro- to be benefical in the treatment of asthma. However, K+ chloride was purchased from Sankyo (Tokyo). Pinacidil channel openers should be evaluated as inhaled agents. was purchased from Research Biochemical International Previous studies in guinea pigs have shown that inhaled (Natick, MA, USA). Glibenclamide and naloxone methio- levcromakalim inhibited bronchoconstriction induced by dide were purchased from Sigma (St. Louis, MO, USA). systemically administered histamine (16). It has also been Moguisteine was suspended in 0.5% sodium carboxy- shown that K+ channel openers given by inhalation could methyl cellulose. Glibenclamide was dissolved in 2.5% protect against induced bronchoconstriction and airway Tween 80 solution. Pinacidil was dissolved in 10% di- microvascular leakage (17). methylsulphoxide in saline. All other drugs were dissolved The purpose of this study was to determine if mogu- in saline. Glibenclamide (10 mg/kg, i.p.) and naloxone isteine and pinacidil given by inhalation could protect methiodide (10 mg/kg, s.c.) were injected 30 min before against capsaicin-induced coughs. We also investigated the inhalation of each antitussive drug. the effects of glibenclamide and naloxone methiodide on the antitussive effects of moguisteine and pinacidil in Statistics guinea pigs. Data are expressed as the means ± S.E.M. The statistical significance of differences was assessed by the Mann- MATERIALS AND METHODS Whitney U-test to evaluate the antitussive effect. A level of probability of 0.05 or less was considered significant. Animals Male Hartley guinea pigs (Tokyo Animal Laboratory RESULTS Inc., Tokyo) weighing about 300 – 350 g at the beginning of the experiments were used. The animals were housed in Effects of inhaled pinacidil, moguisteine and dihydro- groups of four per cage under a 12-h light-dark cycle with codeine on capsaicin-induced cough food and water available continuously. This study was Pinacidil, an ATP-sensitive K+ channel opener, and carried out in accordance with the Declaration of Helsinki moguisteine at doses of 15, 30 and 60 mg/ml, dose-depen- and/or with the guide for the care and use of laboratory dently inhibited the number of capsaicin-induced coughs animals as adopted by the committee on care and use of when the antitussive effect was examined 5 min after inha- laboratory animals of Hoshi University, which is accredited lation (Fig. 1: A and B). Inhaled dihydrocodeine, a central- by the Ministry of Education, Culture, Sports, Science and ly acting narcotic antitussive drug, at doses of 15, 30 and Technology, Japan. 60 mg/ml, also dose-dependently inhibited the number of capsaicin-induced coughs (Fig. 1C). Antitussive assay The cough reflex was induced as described previously Effects of glibenclamide and naloxone methiodide on the (18, 19). Briefly, animals were exposed to a nebulized antitussive effects of pinacidil, moguisteine and dihydro- solution of capsaicin (30 mM) under conscious and identi- codeine cal conditions using a body-plethysmograph. Capsaicin The antitussive effects of inhaled pinacidil (60 mg/ml) was dissolved to a concentration of 30 mg/ml in a 10% and moguisteine (60 mg/ml) were each significantly antago- ethanol and 10% Tween 80 saline solution. The solution nized by pretreatment with glibenclamide (10 mg/kg, i.p.). was diluted with saline. The animals were exposed for However, pretreatment with naloxone methiodide (10 mg 7 min to capsaicin 60 min before the inhalation of anti- /kg, s.c.) had no significant effect on the antitussive effects tussive drugs to determine the number of control coughs. of either pinacidil or moguisteine (Fig. 2: A and B). The animals inhaled antitussive drugs for 2 min. The ani- The antitussive effect of inhaled dihydrocodeine (60 mg mals were also exposed for 7 min to capsaicin 5 min after /ml) was significantly antagonized by pretreatment with the inhalation of antitussive drugs. The number of coughs naloxone methiodide (10 mg/kg, s.c.). However, pretreat- produced per 7-min period of exposure to capsaicin was ment with glibenclamide (10 mg/kg, i.p.) had no signifi- counted. The number of coughs produced after antitussive cant effect on the antitussive effect of inhaled dihydro- drug treatment (Ct) was compared with the number of codeine (Fig. 2C). control coughs (Cc). The antitussive effect was expressed Glibenclamide, by itself, had no significant effect on as the % inhibition of the number of control coughs ((Cc - the number of capsaicin-induced coughs (before glibencla- Ct) / Cc ´ 100). mide, 21.8 ± 2.5 coughs/7 min; after glibenclamide, 19.8 ± 2.9 coughs/7min, n= 8). Antitussive Effect of Inhaled Pinacidil 173 Fig. 2. Effects of glibenclamide and naloxone methiodide on the antitussive effects of pinacidil (A), moguisteine (B) and dihydro- codeine (C). Glibenclamide (10 mg/kg, i.p.) and naloxone methio- Fig. 1. Dose-dependent inhibition