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The Guinea-Pig Distal Colon - a Sensitive Preparation for the Investigation of 5-HT4 Receptor-Mediated Contractions 'Kay A

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The Guinea-Pig Distal Colon - a Sensitive Preparation for the Investigation of 5-HT4 Receptor-Mediated Contractions 'Kay A '." 0 Macmillan Press Ltd, 1993 Br. J. Pharmacol. (I993), 110, 1593 1599 Macmillan Press Ltd, 1993 The guinea-pig distal colon - a sensitive preparation for the investigation of 5-HT4 receptor-mediated contractions 'Kay A. Wardle & Gareth J. Sanger SmithKline Beecham Pharmaceuticals, Coldharbour Road, The Pinnacles, Harlow, Essex CM 19 5AD 1 Experiments were designed to characterize pharmacologically the contractile responses to 5-hydroxy- tryptamine (5-HT) in the guinea-pig isolated distal colon longitudinal muscle-myenteric plexus prepara- tion (LMMP). 2 In the presence of methiothepin (100 nM) and granisetron (1 0tM), 5-HT (10 pM- 10 nM) produced concentration-dependent contractile responses of the guinea-pig distal colon LMMP, with a pEC50 of 9.2 ± 0.08. 3 Responses to 5-HT were mimicked by a series of tryptamine analogues, with the following rank order of potency; 5-HT> 5-MeOT> >5-CT> tryptamine> 2-Me-5-HT. All were found to be full agonists. 4 Responses to 5-HT were also mimicked by a series of substituted benzamide analogues. Their rank order of potency was 5-HT > renzapride > cisapride > (S)-zacopride > (R)-zacopride > metoclopramide. All were full agonists relative to 5-HT. 5 The benzimidazolone derivatives, BIMU 1 and BIMU 8 were approximately equipotent partial agonists (intrinsic activities of 0.8 ± 0.07 and 0.5 ± 0.08 respectively) in the guinea-pig distal colon. 6 Tropisetron produced a rightward displacement of the 5-HT concentration-effect curve, yielding an apparent pA2 of 6.4 ± 0.1. The slope of the Schild plot (1.3 ± 0.1) was significantly greater than unity. 7 SDZ 205 557 produced a concentration-dependent shift to the right of the 5-HT concentration- response curve, yielding an estimated pA2 of 7.8 ± 0.1 and a slope which did not significantly deviate from unity. SDZ 205 557 produced similar pKB estimates (7.3-7.9) when tested against 5-MeOT, renzapride and 5-CT, indicating a common site of action. 8 The pharmacological profile of the 5-HT-evoked contractions of the guinea-pig distal colon LMMP are consistent with activity at the 5-HT4 receptor. Furthermore, of the models of this receptor described in the literature, the guinea-pig distal colon appears to be the most sensitive model to date, making it a useful tool in the investigation of 5-HT4 receptor-mediated events. Keywords: Guinea-pig colon; 5-HT4 receptors; 5-HT (5-hydroxytryptamine); tryptamine analogues; substituted benzamide analogues; benzimidazolone derivatives; tropisetron; SDZ 205 557 Introduction Based on an elegant series of experiments carried out in the 5-HT4 receptor, namely the guinea-pig distal colon long- mouse embryo colliculi neurones and guinea-pig hippocam- itudinal muscle myenteric plexus (LMMP). pus (Dumuis et al., 1988a,b; Bockaert et al., 1990) it has been Some of these results have been presented to the British proposed that at least some of the reported 'atypical' res- Pharmacological Society (Wardle & Sanger, 1992). ponses to 5-hydroxytryptamine (5-HT) can be attributed to stimulation of a novel receptor, termed 5-HT4. Thus, the 5-HT4 receptor is characterized by a high sensitivity to both Methods 5-HT and 5-methoxytryptamine (5-MeOT) and is stimulated by certain substituted benzamides such as renzapride, cisa- Preparation of tissues pride and metoclopramide. Antagonists at this site include high concentrations of tropisetron (ICS 205 930, Dumuis et Distal colon (approximately 7-8 cm from the anus) was al., 1988a), SDZ205 557 (Buchheit et al., 1991; 1992) and removed from young male Dunkin Hartley guinea-pigs (200- DAU 6285 (Dumuis et al., 1992). 300 g) and placed in Krebs solution of the following com- 5-HT4 receptor-mediated functional responses have been position (mM): NaCl 121.5, CaCl2 2.5, KH2PO4 1.2, KCI 4.7, detected in a variety of tissues including the guinea-pig ileum MgSO4 1.2, NaHCO3 25.0, glucose 5.6 (Craig & Clarke, 1990) and ascending colon (Elswood et al., Sections of colon (2-3 cm in length) were slipped over a 1991), rat oesophagus (Baxter et al., 1991), frog and human glass rod. With a scalpel blade, the longitudinal muscle layer adrenocortical cells (Idres et al., 1991; Lefebvre et al., 1992), was cut along the mesenteric border, taking care not to cut sheep pulmonary vein (Cocks & Arnold, 1992) and in both through all the muscle layers. The longitudinal muscle- pig (Villalon et al., 1990) and human heart (Kaumann et al., myenteric plexus was then stripped off with a piece of moist 1990a,b). The sensitivity of each of these preparations to cotton wool and mounted under a 0.5 g load in a 10 ml tissue 5-HT is in the sub-micromolar range, with pECm values bath. Tissues were bathed with Krebs solution at 37°C gassed ranging from 6.7 in the piglet heart (Lorrain et al., 1992) to with 5% CO2 in °2 and containing granisetron (1 ;M) and 8.6 in the guinea-pig ileum (Craig & Clarke, 1990). In the methiothepin (100 nM) to inhibit responses mediated by 5- current investigation we describe a highly sensitive model of HT3 receptors and 5-HTIl.ik. and 5-HT2 receptors respectively. Responses were recorded isotonically and displayed on a Lectromed MT8P multitrace chart recorder. Tissues were allowed to stabilize for 45 min (washing every 15 min) prior ' Author for correspondence. to starting the experiment. 1594 K.A. WARDLE & G.J. SANGER In a few experiments, sections of guinea-pig ileum, 10 cm hydrochloride, acetylcholine perchlorate, 1,l-dimethyl-4-phe- proximal to the caecum were removed, dissected and set up nyl-piperazinium iodide (DMPP) (Sigma), methiothepin hy- in the same way as described for the distal colon. drochloride (Roche), 5-methoxytryptamine hydrochloride (5- MeOT, Aldrich), cisapride (Janssen; free base converted into Experimental protocol and concentration-response curves a hydrochloride salt in house), granisetron, renzapride, meto- clopramide (SmithKline Beecham), 2-methyl 5-hydroxytryp- Tissues were first exposed to a supramaximal concentration tamine (2-Me-5-HT), SDZ 205 557 (2-methoxy-4-amino-5- of acetylcholine (ACh, 40 1M) to establish the maximum chloro-benzoic acid 2-diethylamino ethyl ester), tropisetron response evoked by each tissue. Initial responses to 5-HT (ICS 205 903), (R)- and (S)-zacopride, 5-hydroxy-indalpine were found to be small, but increased on repeated dosing. (5-OH-IP), 5-carboxyamidotryptamine (5-CT), (± )-8-hy- Hence it was deemed necessary to sensitize each tissue to droxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT, syn- 5-HT before constructing the first concentration-response thesized in house). BIMU 1 (endo-N-(8-methyl-8-azabi- curve. This was done by dosing the preparations every cyclo[3.2. 1]oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo- IH-benzimi- 15 min with a supramaximal concentration of 5-HT (1I ,M) dazole-l-carboxamide hydrochloride) and BIMU 8 (endo-N- four to five times until consistent responses were produced. (8-methyl-8-azabicyclo[3.2. 1]oct-3-yl)-2,3-dihydro-(1-methyl) Following sensitization, agonist-concentration response cur- ethyl-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride) ves were constructed non-cumulatively, by adding increasing were a kind gift from Dr Carlo Rizzi, Boehringer Ingelheim, concentrations of agonist at 15 min time intervals. The Italy. agonist was left in contact with the tissue until a maximum All drugs were dissolved in 0.9% saline and diluted to response was obtained (usually 30 s). In each tissue, two appropriate concentrations with Krebs solution. With tropi- agonist concentration-response curves were constructed. In setron and cisapride (free base only), a minimum amount of all experiments, the first curve was to 5-HT itself. In ex- tartaric acid was used to dissolve the compounds. periments to investigate 5-HT4 receptor agonist activity, the second curve was constructed to either 5-HT (in time control experiments) or to a test agonist. In time control experi- Results ments, the two concentration-response curves to 5-HT were super-imposable (pEC50 and Emax values for first and second Preliminary experiments curves were respectively 9.2 ± 0.1, 100 ± 0 and 9.2 ± 0.2, 98 ± 4, n = 6). For antagonist experiments, the second curve In the absence of granisetron (but in the presence of meth- was constructed to 5-HT in the presence of the appropriate iothepin (100 nM)), concentration-response curves to 5-HT concentration of antagonist, added immediately after com- (10 pM- 100 liM, n = 4) in the guinea-pig ileum and distal pletion of the first curve. In all experiments, a minimum of colon were biphasic in nature (Figure 1). In the distal colon, 45 min was left between successive curves. Responses were the first phase of the curve had an estimated pEC50 of expressed as a percentage of the maximum 5-HT-evoked 9.2 ± 0.2 and plateaued at 52.5 ± 3.5% of the 5-HT-evoked contraction in the first concentration-response curve in each maximum (n =4). This compares with an estimated pEC50 tissue. value of 7.9 ± 0.04 and maximum of 31.8 ± 1.6% of the All agonist concentration-response curves were fitted using 5-HT maximum in the ileum (n = 4). The second phase of the a non-linear iterative fitting programme (Kaleidagraph, Syn- curves were selectively antagonized by granisetron (1 ,AM, ergy Software, PCS Inc., Reading, Pa) according to the results not shown), leaving a simple monophasic curve. following relationship (Parker & Waud, 1971): In the guinea-pig colon, the concentration-response curve to 5-HT was E = M[A]P/([A]p + [K]P) low concentrations of (10 pM- 10 nM) This relationship describes a curve with a maximum response M, an EC50 equal to K and a slope determined by the power p.
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