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Effects of Histamine H1-, H2- and H3-Receptor Selective Drugs on the Mechanical Activity of Guinea-Pig Small and Large Intestine R

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Effects of Histamine H1-, H2- and H3-Receptor Selective Drugs on the Mechanical Activity of Guinea-Pig Small and Large Intestine R Br. J. Pharmacol. (1991),102, 179-185 (D Macmillan Press Ltd, 1991 Effects of histamine H1-, H2- and H3-receptor selective drugs on the mechanical activity of guinea-pig small and large intestine R. Leurs, M.M. Brozius, M.J. Smit, A. Bast & H. Timmerman Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands 1 In this study we have evaluated the possible contribution of acetylcholine release in histamine-induced contractions of guinea-pig large and small intestinal smooth muscle. Moreover, the presence of the hista- mine receptor types involved in smooth muscle relaxations and inhibition of electrically-induced twitches was studied by use of several selective agents. 2 Histamine-induced contractions appeared to be a pure H1-receptor-mediated effect. Responses were not attenuated by the presence of 0.1 ,UM atropine and were competitively and stereoselectively inhibited by the two enantiomers of chlorpheniramine with pA2 values of 6.73 + 0.08, 7.30 + 0.06, 6.93 + 0.03 and 7.19 + 0.04 for the L-isomer and 8.63 + 0.09, 8.85 + 0.09, 9.01 + 0.16 and 8.98 + 0.11 for the D-isomer in the duodenum, jejunum, ileum and colon, respectively. 3 There appeared to be a marked regional difference in sensitivity to histamine. In ileal and jejunal preparations pD2 values of 6.24 + 0.06 (n = 22) and 6.37 + 0.07 (n = 22) were found, whereas the pD2 values in the duodenum and colon were 5.55 + 0.05 (n = 36) and 5.68 + 0.06 (n = 31) respectively. 4 This regional difference in sensitivity to histamine was not due to variations in receptor affinity since pA2 values for the two enantiomers of chlorpheniramine did not differ markedly among the four tested preparations. Since a similar variation in sensitivity was found for methacholine, it is likely that the signal transfer mechanism in guinea-pig ileum and jejunum is more efficient than in the duodenum and colon. 5 The H2-agonists dimaprit and impromidine relaxed methacholine-precontracted (± 70% of maximum contraction) intestine at high concentrations (pD2 values of 3.79 + 0.03 and 4.44 + 0.09 for the jejunum). These relaxations could not be antagonized by 0.1 fM tiotidine, famotidine or mifentidine and were observed in all parts of the intestine investigated. 6 The dimaprit analogues nordimaprit and homodimaprit (inactive at H2-receptors) were equipotent in relaxing the methacholine-precontracted smooth muscle. Since several H2-antagonists were also able to produce relaxations, we do not consider these relaxations to be mediated by a H2-receptor subtype, but to be due to some nonspecific effects at the high concentrations used. 7 The histamine receptor involved in the inhibition of electrically-induced contractions in the presence of atropine could be classified as an H3-receptor effect. In all parts of the intestine the H3-agonist R-a- methylhistamine inhibited the twitches with pD2 values ranging from 8.10 + 0.06 (ileum) to 8.27 + 0.03 (colon). This effect was competitively antagonized with the selective H3-antagonist thioperamine (pA2 values are 8.09 + 0.07, 8.13 + 0.05, 8.15 + 0.04 and 8.36 + 0.04 in duodenum, jejunum, ileum and colon, respectively. 8 The guinea-pig intestine is a suitable preparation for the evaluation of either H1- or H3-receptor effects. H2-receptors, causing smooth muscle relaxation appear not to be present in our preparations. At high concentrations of H2-receptor agents (agonists and antagonists) relaxations might be observed, due to unknown nonspecific effects. Introduction a2-agonist), caused relaxations with a potency lower than that usually found for e.g. the positive chronotropic effect on In their original paper, describing the subclassification of his- guinea-pig right atrium (Bertaccini & Zappia, 1981). The tamine receptors into H1- and H2-receptors, Ash & Schild relaxations could however not be inhibited by the (1966) used the in vitro contraction of guinea-pig isolated H2-antagonists metiamide, cimetidine, ranitidine or oxmeti- ileum as a test system for H1-receptor activity. Although the dine, nor by tetrodotoxin, propranolol or phentolamine intestinal preparation has become a very valuable tool for the (Bertaccini & Zappia, 1981). Moreover, Fjalland (1979) also screening of Hl-receptor selective drugs, the original notion of suggested the existence of an H2-receptor subtype in guinea- guinea-pig ileum as an H1-receptor preparation (Ash & pig ileum because histamine was shown to suppress Schild, 1966) has been complicated by the outcome of several electrically-induced twitches of ileal smooth muscle, although investigations. the order of potency of H2-antagonists in inhibiting this It has been suggested that the contractile effects of hista- action of histamine did not correlate with the known activity mine on guinea-pig ileum are partly dependent on a of the compounds at the H2-receptor of guinea-pig right tetrodotoxin-sensitive release of acetylcholine (Rubenstein & atrium (Fjalland, 1979). Recently the classification of hista- Cohen, 1985). Moreover, using selective H2-receptor agents mine receptors has been extended (Arrang et al., 1983) and the Barker & Ebersole (1982) reported the presence of presence of an H3-receptor, which is involved in the regulation H2-receptors on guinea-pig myenteric plexus neurones, medi- of neurotransmitter release in both brain and peripheral ating the release of acetylcholine. To complicate the situation tissues (Timmerman, 1990), is currently accepted. Since some even more, Bertaccini & Zappia (1981) described the presence H2-antagonists can also act as H3-antagonists (Schwartz et al., of an H2-receptor subtype on guinea-pig duodenum, medi- 1986) the findings of Fjalland (1979) were re-evaluated by ating relaxations of precontracted muscle. H2-receptor agon- Trzeciakowski (1987) and from the latter study it was con- ists, like dimaprit, impromidine and clonidine (also an cluded that the observed inhibition of the electrically-induced 180 R. LEURS et al. twitches was due to an H3-receptor-mediated reduction of Statistics acetylcholine release (Trzeciakowski, 1987). Previously it has been reported that histamine could also inhibit electrically- All data shown are expressed as mean + s.e.mean. EC5o induced twitches of guinea-pig ileum in the presence of atro- values were transformed to logarithmic values (pD2 values) for pine (Ambache & Zar, 1970; Ambache et al., 1970). Based calculation of a mean value and statistical comparison. Tissue upon the inhibitory action of burimamide Ambache et al. preparations from at least three different animals were used (1973) also suggested the involvement of an H2-receptor for each drug treatment. Statistical analysis was carried out subtype. However, a pharmacological characterization of this with Student's t test; P values <0.05 were considered to indi- effect in view of the currently accepted histamine receptor sub- cate a significant difference. classification has not been provided. In the present study we examined several of the problems Chemicals outlined above, using highly selective histamine receptor agonists and antagonists. In both small and large intestine of Histamine dihydrochloride, procaine hydrochloride, 4- the guinea-pig we investigated the possible indirect contractile aminopyridine, cimetidine and atropine sulphate were pur- effects of histamine (Rubenstein & Cohen, 1985), the existence chased from Sigma Chemical Company Ltd. (St. Louis, of an H2-receptor subtype, possibly mediating relaxations U.S.A.). Ranitidine hydrochloride and tetraethylammonium (Bertaccini & Zappia, 1981), and the inhibition of electrically- chloride were obtained from Research Biochemicals Incorpo- induced twitches of the intestinal smooth muscle in the pre- rated (Natick, U.S.A.). Gifts of famotidine (Merck Sharp & sence of atropine, as originally described by Ambache & Zar Dohme), tiotidine (Imperial Chemical Industries), mifentidine (1970). (De Angeli), thioperamide, R-a-methylhistamine maleate (Dr J.-C. Schwartz, Centre Paul Broca de l'INSERM, Paris), impromidine trihydrochloride (Smith Kline & French), 2- amino - 6 - dimethylamino - 4,5,6,7 - tetrahydrobenzo[d]thiazole Methods (SND 861 C12, Boehringer Ingelheim), D- and L-chlor- pheniramine (Dr A.J. Beld, Catholic University Nijmegen, The Tissue bath studies Netherlands) and pinacidil (Leo Pharmaceuticals) are grate- fully acknowleged. Dimaprit dihydrobromide, nordimaprit Male guinea-pigs (350-450g) were killed by a blow on the dihydrobromide and homodimaprit dihydrobromide were head. Small and large intestine were immediately excised and taken from laboratory stock (Sterk et al., 1984). All other placed in Krebs-buffer (composition mM: NaCl 117.5, KCI 5.6, reagents were of analytical grade. MgSO4 1.18, CaCl2 2.5, NaH2PO4 1.28, NaHCO3 25 and glucose 5.5). The first 12cm of the small intestine was taken as duodenum and the middle portion was used as jejunum. The Results portion of the small intestine that lies 5-15 cm from the ileo- caecal valve was considered to be the ileum. The colonic Histamine contracts smooth muscle of guinea-pig large and smooth muscle was taken from the ascending colon. Intestinal small intestine in a concentration-dependent way. There smooth muscle strips (10mm long, 2mm wide) were prepared appeared to be a significant difference in sensitivity of the by cutting the intestine in the longitudinal direction; the various intestinal preparations to histamine (Table 1). Ileal mucosa was not removed. Muscle strips were mounted in and jejunal smooth muscle have an approximately equal 20ml Krebs buffer, continuously gassed with 95% 02:5% sensitivity to histamine, but are almost 5 fold more sensitive CO2 and maintained at 370C. Contractions were recorded iso- than the duodenal and colonic preparations under the present tonically under 0.4 g tension with a Hugo Sachs Hebel- conditions (Table 1). Similar observations were made for the Messvorsatz (TL-2)/HF-modem (Hugo Sachs Electronik, muscarinic agent methacholine, which was also more potent Hugstetten, West Germany) connected to a pen-recorder. in contracting ileal and jejunal smooth muscle than duodenal After equilibration for at least 45min, with replacement of and colonic preparations (Table 1).
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