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SMOOTH MUSCLE RELAXING DRUGS and GUINEA PIG ILEUM Teiichi MUKAI, Eiichi YAMAGUCHI, Jun GOTO and Keijiro TAKAGI Department Of

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SMOOTH MUSCLE RELAXING DRUGS and GUINEA PIG ILEUM Teiichi MUKAI, Eiichi YAMAGUCHI, Jun GOTO and Keijiro TAKAGI Department Of SMOOTH MUSCLE RELAXING DRUGS AND GUINEA PIG ILEUM Teiichi MUKAI, Eiichi YAMAGUCHI, Jun GOTO and Keijiro TAKAGI Departmentof Pharmacotherapeutics,Faculty of PharmaceuticalScience, Science Universityof Tokyo,Tokyo 162, Japan Accepted September25, 1980 Abstract-The effects of various smooth muscle relaxing drugs on con tractile responses to acetylcholine (ACh), Ba2+ and Ca", and on the tissue cyclic AMP levels were examined in the guinea pig ileum. Papaverine and theophylline caused a decrease both in the maximum height and the slope of dose-response curves induced by the three stimulants, and an increase in the cyclic AMP levels. Diltiazem and D-600 produced a decrease in the maximum and the slope of ACh and Ba2+ dose-response curves, shifted the Ca" dose-response curves to higher concentrations, in a parallel manner, but failed to change the cyclic AMP levels. Etomidoline and benactyzine shifted the curves for the three stimulants in parallel to the right, but at higher concentrations depressed the maximum of ACh and Ba2+ responses with a further parallel shift. These drugs exerted little influence on the basal level of tissue cyclic AMP, but etomidoline signifi cantly depressed the Bat+-induced increase in cyclic AMP level. The smooth muscle relaxing drugs used could be classified in three types, thereby suggesting that there are at least three different mechanisms involved in smooth muscle relaxing action. Antispasmodic action is classified into isopentanols (group I) have different modes neurotropic and musculotropic action. The of action from strong bases, Aspaminol and former is anticholinergic as shown in the benactyzine (group II). Later, two barbi case of atropine. The latter is interpreted as turates were added to group I (2), and 13 effects on post-receptor sites because anti derivatives of diphenylmethoxyalkylamine to spasmodics with the musculotropic action group II (3). Aspaminol in group II was inhibit Ba2+ contraction of smooth muscle proved to have no effect on cyclic AMP preparations. Papaverine has only musculo levels of the intestinal smooth muscle, in tropic activity and also inhibits histamine contrast to papaverine which inhibits phos and/or ACh-induced contraction in similar phodiesterase (PDE) (4). concentrations (1) and so it is termed a Diltiazem is a coronary vasodilator as a non-specific antispasmodic. Takagi et al. specific Ca antagonist (5), but inhibits ACh (1) have studied nonspecific antispasmodic or Ba2+ contraction, apparently in a non activity of various compounds, and concluded competitive manner and in a similar manner that weak bases such as papaverine and as papaverine (6). Although theophylline dihydroneuspasverine, and neutral esters of also depresses various smooth muscle con tractions (7) and inhibits PDE (8), anti-Ba2+ curve for the stimulant in the presence of the or anti-Ca" action by theophylline was not relaxing drug was recorded. When ap clarified. In our present paper, we compared plication of relaxing drugs reduced the level nonspecific antispasmodic (smooth muscle of smooth muscle tone, the reduced level relaxing) action of papaverine, theophylline, was used as a basal one to obtain the con diltiazem and D-600 as Ca antagonists, and tractile ratio. benactyzine and etomidoline as tertiary amine Cyclic AMP assay: The ileum was removed antispasmodics. Quaternary ammonium from the guinea pig. The longitudinal muscle bases, benactyzine methylbromide and pro was then separated from the underlying pantheline bromide were added although circular muscle. The preparation from one they probably have little musculotropic animal was divided into 2 pieces which were activity. Effects of all tested compounds on suspended in a 10 ml organ bath filled with cyclic AMP level of ileum preparations were the Locke-Ringer solution, kept at 32'C and also determined. bubbled with air. One was used for measuring a control level of the tissue cyclic AMP and MATERIALSAND METHODS the other for studying the influence of a drug Male guinea pigs (250-450 g) were after incubation for 5 min. To measure the sacrificed by a blow on the neck. Pieces of tissue cyclic AMP level, the ileal longitudinal the ileum were suspended in a 10 ml organ smooth muscle was immediately frozen in bath filled with Locke-Ringer solution, kept liquid nitrogen and weighed. The muscle at 32'C and bubbled with air. The solution preparation was homogenized with a glass had the following composition (mM); NaCI homogenizer in 3 ml of cold 5% trichloroacetic 154.0, KCI 5.6, CaCl2 1.1, MgCI2 2.1, NaHCO3 acid and the homogenate centrifuged at 6000 2.4 and glucose 2.8. Responses of the r.p.m. at 0°C for 10 min. Trichloroacetic ileum to smooth muscle stimulants were acid in the supernatant was extracted with recorded isotonically. ether and the preparation lyophylized to Dose-response curves for BaCI2 and ACh dryness and dissolved with 0.4 ml of were obtained by cumulative applications acetate buffer, pH 4.0. The tissue cyclic after the preparations were allowed to AMP was measured by a competitive protein equilibrate for 30 min. To obtain the dose binding assay with a cyclic AMP kit obtained response curves of CaCl2, the preparations from Boehringer Mannheim GmbH. The were bathed for 60 min in Ca-free Locke methods employed were essentially similar to Ringer solution identical to the Locke-Ringer those described by Gilman (9). In this solution except for the omission of CaCl2 experiment, the paired t-test was used. and then immersed for 6 min in Ca-free K Drugs used: Papaverine hydrochloride Locke-Ringer solution in which NaCI was (Wako Pure Chemical Co.), theophylline replaced by equiosmotic KCI; finally CaCl2 (Tokyo Kasei Co.), diltiazem hydrochloride was cumulatively added to the Ca-free K (Tanabe Seiyaku Co.), D-600 hydrochloride Locke-Ringer solution. (Knoll A.G.), etomidoline (Yamanouchi Contractile responses of the guinea pig ileum to each smooth muscle stimulant became constant with repeated application of the stimulants. Thereafter, the preparation was treated for 5 min with each smooth muscle relaxing agent and the dose-response Fig. 1. Structural formula of etomidoline. Seiyaku Co.), benactyzine hydrochloride were more potent in inhibiting ACh responses (Tokyo Kasei Co.), benactyzine methyl than Ba2+ responses, displacing the ACh bromide (Fukuju Seiyaku Co.) and propan dose-response curves parallelled to the right. theline bromide (Dainippon Seiyaku Co.). Additionally etomidoline at a high concen Structural formula of a new smooth muscle tration depressed the maximum response relaxing drug etomidoline is shown in Fig. 1. together with the shift of the curve. Etomidoline was first dissolved in dilute HCI, Benactyzine methylbromide and propan and adjusted with 1 N NaCI to about pH 7.0. theline bromide in lower concentrations than 3x10-' M, as were expected, effectively RESULTS shifted the ACh contraction curves to the Effects of smooth muscle relaxing drugs on right in a parallel manner (data not shown). dose-response curves for ACh: Papaverine, Effects of smooth muscle relaxing drugs on theophylline (Fig. 2a), diltiazem (Fig. 2b) dose-response curves for BaCI2: Papaverine, and D-600 produced a downward displace theophylline, diltiazem and D-600 caused a ment of the maximum without a parallel decrease both in the maximum height and shift. Etomidoline (Fig. 2c) and benactyzine the slope of the dose-response curves by Ba21 Fig. 2. Effects of theophylline (a), diltiazem (b) or etomidoline (c) on ACh dose response curves. Theophylline: 0 (=control) (0), 10-g M (0) or 3 x 10-g M (x). Diltiazem: 0 (•), 3x 10-7 M (0) or 10-6 M (x ). Etomidoline: 0 (®), 10-' M (0), 10-6 M (X), 10-5 M (A) or 10-' M (V). Number of observations in parentheses. (Fig. 3a, b, c, d). To produce the decrease, was the most potent relaxant of Ba2+ con very high concentrations of theophylline traction. Etomidoline in concentrations of were required. D-600, on the other hand, up to 3x10-5 M and benactyzine in concen Fig. 3. Effects of papaverine (a), theophylline (b), diltiazem (c), D-600 (d), etomidoline (e), benactyzine (f), benactyzine methylbromide (g) or propanthelline bromide (h) on Ba2+ dose-response curves. Papaverine: 0 (=control) (0), 3 x 10-6 M (0) or 10-5M (X). Theophylline: 0 (0),10-1 M (0) or 3 x 10-3 M (X). Diltiazem: 0 (0), 3x10_, M (0), 10-6 M (X) or 3x10-6 M (A). D-600: 0 (•), 3x10-' M (0) or 10-6 M (X). Etomidoline: 0 (0), 10-5 M (0), 3 x 10-5 M (x) or 10-4 M (A). Benactyzine: 0 (•), 3 x 10-6 M (0), 10-' M (X) or 3 x 10-4 M (A). Benactyzine Bethylbromide: 0 (•), 10-3 M (0) or 10-2 M (X). Propantheline bromide: 0 (•), 10-4 M (0), 3 x 10-4 M (X) or 3 x 10-3 M (A). Number of observations in paren theses. trations of up to 10-4 M shifted the curves to shifted the curves to the right with the the right in a parallel manner but higher concomitant decrease in their maximum concentrations of the two drugs further responses (Fig. 3 e, f). Fig. 4. Effects of papaverine (a), theophylline (b), diltiazem (c), D-600 (d), etomidoline (e), benactyzine (f), benactyzine methylbromide (g) or propantheline bromide (h) on Ca2+ dose-response curves. Papaverine: 0 (=control) (0), 3X10-6 M (0) or 10-5 M (x ). Theophylline: 0 (0), 3 X 10-4 M (0) or 10-3 M (X ). Diltiazem: 0 (•), 3X10-' M (0) or 10-6 M (X). D-600: 0 (0), 10-8 M (0) or 3X10-8 M (X). Etomidoline: 0 (•), 3 X 10-5 M (0) or 10-4 M (X). Benactyzine: 0 (•) , 3 X 10-5 M or 10-4 M (X). Benactyzine methylbromide: 0 (0), 10-4 M (0) or 3 X 10-4 M (X).
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