Adrenergic Receptor Mechanisms in Spontaneous Contractile Activity of Rat Ileal Longitudinal Smooth Muscle

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α- and β-Adrenergic Receptor Mechanisms in Spontaneous Contractile Activity of Rat Ileal Longitudinal Smooth Muscle

Roland Seiler, B.A., Andreas Rickenbacher, B.A., Sidney Shaw, Ph.D., Bruno M. Balsiger, M.D.

Gastrointestinal motility is inﬂuenced by adrenergic modulation. Our aim was to identify speciﬁc subtypes of adrenergic receptors involved in inhibitory mechanisms that modulate gut smooth muscle contractile activity. Muscle strips of rat ileal longitudinal muscle were evaluated for spontaneous contractile activity and Ϫ Ϫ for equimolar dose-responses (10 7 to 3 × 10 5 M) to the adrenergic agents norepinephrine (nonselective α α β β agonist), phenylephrine ( 1-agonist), clonidine ( 2-agonist), prenalterol ( 1-agonist), ritodrine ( 2- β agonist), and ZD7114 ( 3-agonist) in the presence and absence of tetrodotoxin (nonselective nerve blocker). Ϫ Norepinephrine (3 × 10 5 M) inhibited 65 Ϯ 6% (mean Ϯ SEM) of spontaneous contractile activity. The same molar dose of ritodrine, phenylephrine, or ZD7114 resulted in less inhibition (46 Ϯ 7%, 31 Ϯ 5%, and 39 Ϯ 3%, respectively; P Ͻ 0.05). The calculated molar concentration of ZD7114 needed to induce 50% inhibition was similar to that of norepinephrine, whereas higher concentrations of phenylephrine or ritodrine were required. Clonidine and prenalterol had no effect on contractile activity. Blockade of intramural neural transmission by tetrodotoxin affected the responses to ritodrine and phenylephrine (but not to norepinephrine or ZD7114), suggesting that these agents exert part of their effects via neurally mediated enteric pathways. Our results suggest that adrenergic modulation of β β α contractile activity in the rat ileum is mediated primarily by muscular 3-, 2-, and 1-receptor mechanisms; the latter two also involve neural pathways. (J GASTROINTEST SURG 2005;9:227–235) Ć 2005 The Society for Surgery of the Alimentary Tract

KEY WORDS: Contractility, motility, ileum, rat, in vitro, adrenergic, adrenergic receptor, α-adrenergic receptors, β-adrenergic receptors

Coordination and modulation of gastrointestinal In the small bowel, vagal inputs are supplied to myen- motor activity are dependent on the interaction of two teric neurons.3 These enteric neurons influence the complex neural inputs: the enteric nervous system, generation of motor patterns. which is completely intrinsic within the bowel wall, The intestinal sympathetic nervous system consists and the central nervous system, sending its influences of nerve cell bodies located in the prevertebral ganglia through the extrinsic nerves to the gut (vagal, sympa- with their postganglionic fibers entering the gut. No thetic).1 Interactions between the central nervous adrenergic nerve cell bodies are present in the gut system and the enteric nervous system are important wall.1 Most, if not all, sympathetic postganglionic in gastrointestinal responses to stress, eating, and fibers affecting motility are thought to synapse in the behavior.2 enteric nervous system and not directly on smooth Vagal motor pathways modulate mainly the upper muscle cells. Indeed, adrenergic nerves do not syn- gastrointestinal tract and the distal colon and rectum. apse directly on nonsphincter muscle cells in the gut.4

Presented in part at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (poster presentation). From the Gastroenterology Unit (R.S., A.R., B.M.B.) and the Department of Clinical Research (R.S., A.R., S.S., B.M.B.), University of Bern, Bern, Switzerland. Supported by Nycomed AG Switzerland, Ethicon, Switzerland, and the Swiss National Science Foundation (B.M.B.; Nr. 31-61583.00). Reprint requests: Dr. Balsiger, Gastroenterology Unit and Dept. of Clinical Research, University of Bern, Tiefenaustrasse 120, 3004 Bern, Switzerland. e-mail: [email protected] Ć 2005 The Society for Surgery of the Alimentary Tract 1091-255X/05/$—see front matter Published by Elsevier Inc. doi:10.1016/j.gassur.2004.05.012 227 Journal of 228 Seiler et al. Gastrointestinal Surgery

Despite the predominant, direct adrenergic input to the direction of the longitudinal muscle. Silk loops the enteric nervous system, we found strong, adrener- were tied at both ends of the strips. The muscles were gically mediated inhibitory motor mechanisms in rat suspended vertically in 5-ml organ chambers (Radnoti jejunum and ileum occurring preferentially at the Glass Technology Inc., Monrovia, CA) filled with level of these smooth muscle cells rather than in modified Krebs-Ringer bicarbonate solution main- 5,6 the enteric nervous system ; these effects appeared tained at 37.5Њ C and bubbled with 95% O2 and 5% to be independent of input from the enteric ner- CO2 (Carbagas, Bern, Switzerland). The lower end vous system. of the muscle strip was connected to a fixed glass Therefore, one approach to target gastrointes- hook in the chamber, and the upper end was attached tinal motility disorders through adrenergic pathways to a noncompliant force transducer (Radnoti Glass would be to direct the pharmacologic therapy at the Technology Inc.), thereby allowing measurement of receptors occurring in the gut on smooth muscle cells. isometric force. To date, therapeutic approaches targeting adrenergic pathways in the gastrointestinal tract have not been Experimental Design very successful, in part because of substantial cardio- 7 After an equilibration period of 80–90 minutes with vascular side effects of the agents used. change of the buffer solution every 20–25 minutes, Therefore, mechanisms involved in modulating each strip was stretched incrementally at 10- to 15- contractile activity of the gut mediated by specific minute intervals to its optimal length (Lo). Lo is de- subtypes of adrenergic receptors are of considerable fined as the length beyond which further stretching interest. Our first aim was to identify which adrener- did not increase the amplitude of spontaneous con- gic receptor subtypes mediate inhibition of spon- tractions. The entire experiment was then performed taneous contractile activity. Second, we wanted to at this Lo; strips without spontaneous activity were determine if these receptor-specific mechanisms were not used (2% of all muscle strips). mediated at the level of the smooth muscle and/or After recording of baseline spontaneous activity, via the enteric nervous system. Our hypothesis was α β one substance was administered per chamber in a that both 1- and 2-receptor mechanisms mediate cumulative manner every 10 minutes. Norepineph- the inhibitory responses and that these mechanisms rine (NE) was chosen as the nonselective adrenergic are active directly at the level of the smooth muscle and α α agonist; phenylephrine and clonidine as 1- and 2- not indirectly via effects mediated through the enteric selective agonists; and prenalterol, ritodrine, and nervous system. β β β ZD7114, as 1-, 2-, and 3-selective agonists, respec- Ϫ tively. Drugs were added in cumulative doses (10 7 to Ϫ 3 × 10 5 M) every 10 minutes. The highest dose used Ϫ METHODS was 3 × 10 5 M according to our previous work using Preparation of Tissue only NE.5,6 One chamber contained a control strip Procedures and animal care were performed ac- to confirm stable activity during the duration of the cording to the guidelines of the Department of Agri- experiment, and the final chamber contained a spare culture of the Canton of Bern, Switzerland. Male strip. Wistar rats were used in all experiments. Anesthesia After the dose-response experiment, the chambers was achieved with intraperitoneal sodium pentobarbi- were washed 4 times with modified Krebs-Ringer tal (5 mg/100 g; Abbott Laboratories, North Chicago, buffer. When spontaneous contractions returned to Ϫ IL). A 5-cm segment of the ileum was removed begin- baseline activity, tetrodotoxin (TTX; 10 6 M) was ning 2 cm orad to the ileocecal valve and stored in cold added to every chamber. TTX is thought to abolish Krebs-Ringer buffer (concentration in mM: NaCl most all enteric neural input by blocking neuronal 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, sodium channels. After a 15- to 20-minute equilibra- NaHCO3 25.0, calcium disodium edetate 0.26, and tion, the same dose-response experiment was re- glucose 11.1). The distal end of the specimen was peated in each chamber with the same agonist. marked. At the conclusion of the experiment, the length of each strip between the two ties of silk loops and wet Recording of Contractile Activity weight was measured. The segment of the distal ileum was immersed in Data Analysis chilled, modified Krebs-Ringer bicarbonate solution and opened along the mesenteric border. The Total spontaneous contractile activity was quanti- tissue was pinned flat in a Petri dish, and eight fied as the integral of the generated force (g × time full-thickness muscle strips per rat were prepared in as total area under the contractile curve) measured Vol. 9, No. 2 2005 Adrenergic Mechanisms of Ileal Contractility 229

for 5 minutes at Lo, whereas responses to adrenergic estimated for each agonist based on the dose-response agonists were quantified by measuring the integral of curve. A greater EC50 represents a smaller concentra- force for 5 minutes immediately after drug adminis- tion of an agonist needed to induce 50% inhibition tration. The integral of force was calculated by of spontaneous activity. computerized methodology using special software Values are presented as mean Ϯ SEM. Student’s (AcqKnowledge, Biopac Systems, Inc., Goleta, CA), t tests with a Bonferroni correction were used to normalized per millimeter squared of cross-sectional compare the effects of each specific agonist with spon- area (CSA) for each muscle strip. taneous activity at all doses and with the respective The CSA was calculated using the following effect of NE. The effect of TTX on spontaneous equation: activity, on EC50, and on each dose of the respective agonist was evaluated in the same way. CSA (mm2) ϭ Tissue wet weight (mg)/Tissue length (mm) × Tissue density (mg/mm3) Drugs Tissue length and weight were measured at the end of the experiment, and smooth muscle tissue density L-Phenylephrine hydrochloride, clonidine hydro- was assumed to be 1.05 mg/mm.3,8 chloride, ritodrine hydrochloride, and norepineph- The dose-response curve for each agonist was ob- rine bitartarate salt were purchased from Sigma (St. tained by defining spontaneous contractile activity as Louis, MO). Prenalterol and ZD7114 hydrochloride 100%. To quantify these dose-response curves, the were purchased from Astra Zeneca (So¨ derta¨lje, negative of the natural log (In) of the equipotent Sweden). TTX was purchased from Juro (Luzern, concentration that caused a 50% response (EC50)was Switzerland).

α Fig. 1. Effect of norepinephrine (A) and phenylephrine ( 2)(B) on spontaneous activity. Cumulatively administered molar doses of agents caused a dose-dependent decrease in contractile activity. Journal of 230 Seiler et al. Gastrointestinal Surgery

RESULTS Table 2. Reduction of baseline tone induced by Spontaneous Contractile Activity adrenergic agonist without or with tetrodotoxin Ϫ (TTX; 10 6 M) Spontaneous phasic contractile activity was re- ؊ corded shortly after suspending the muscle strips in Response to 3 × 10 5 M dose* the organ chambers. After the addition of TTX (after Without TTX With TTX the ﬁrst adrenergic dose-response experiments, wash- out, and restoration of spontaneous activity), contrac- Norepinephrine 75 Ϯ 980Ϯ 6 α Ϯ Ϯ † tile activity was reduced slightly from 77 Ϯ 8to Phenylephrine, 1 35 5434 α Ϯ Ϯ Ϯ 2 Ͻ Clonidine, 2 7 4204 73 8 (g/5 min/mm ; P 0.01). β Ϯ Ϯ Prenalterol, 1 26 4326 β Ϯ Ϯ † Ritodrine, 2 66 8456 Effect of Nonselective Adrenergic Stimulation β Ϯ Ϯ ZD7114, 3 58 7607 In all strips treated with NE, the amplitude and *Values represent percent (mean Ϯ SEM; n у 8 rats) reduction of Ϫ the baseline tone were reduced in a dose-dependent baseline (one after the highest dose of agonist (3 × 10 5 M) compared manner, whereas the frequency of contractions re- with baseline tone before dose-response experiment (100%). † Ͻ mained unchanged. At the higher doses, an initial P 0.05 compared with without TTX. increase in basal tone was observed (Fig. 1A). Inhibi- tion of spontaneous contractile activity induced by the Ϯ Ͻ Ϫ versus 43 4%, P 0.05; Table 2). Clonidine highest dose of norepinephrine (3 × 10 5 M) was (α2-agonist) with and without TTX had no demon- 65 Ϯ 6%. Blocking all neural activity within the bowel Ϫ strable effect on contractile activity. wall with TTX (10 6 M) did not change the dose- response to NE (Table 1) nor the effect of the highest Effect of b-Agonists dose of NE on baseline tone (Table 2). Differing effects of the three β-adrenergic agonists were noted. Prenalterol (β -agonist) with or Effect of a-Agonists 1 without TTX had no effect. In contrast, ritodrine α β β Phenylephrine ( 1-agonist) inhibited contractile ( 2-agonist) and ZD7114 ( 3-agonist) both induced activity by reducing the amplitude but not the basal a marked, dose-dependent effect with inhibitions of Ϫ tone in a dose-dependent fashion (Fig. 1B). However, 39 Ϯ 3% and 46 Ϯ 7% at 3 × 10 5 M doses, respec- the EC50 was less than that for NE, and the inhibition tively (Table 1, Figs. 2B, 3). TTX did not inﬂuence the × Ϫ5 β (at 3 10 M) was less compared with an equimolar dose-response of ZD7114 ( 3-agonist), but TTX Ϫ dose of norepinephrine (Table 1; Figs. 1, 2A). TTX reduced the inhibitory effect of 3 × 10 5 M ritodrine α β Ϯ Ϯ Ͻ had no effect on 1-receptor–mediated inhibition in- ( 2-agonist) from 46 7% to 35 6% (P 0.05); duced by phenylephrine. However, if only changes the EC50, however, did not change (Table 1). This in baseline tone were analyzed, TTX slightly in- decrease in inhibition seems to be due primarily to creased the change of baseline tone induced by the a lesser reduction in the basal tone (Fig. 4). Ritodrine × Ϫ5 Ϯ × Ϫ5 β highest dose of phenylephrine (3 10 M; 35 5% (3 10 M; 2-agonist) reduced basal tone by

Table 1. Inhibitory effect of selective adrenergic agonists on rat ileal longitudinal muscle without Ϫ and with tetrodotoxin (TTX; 10 6 M)

؊5 × Response to 3 10 M dose* EC50 Without TTX With TTX Without TTX With TTX

Norepinephrine 65 Ϯ 6† 70 Ϯ 5† 5 Ϯ 0.3 5.3 Ϯ 0.7 α Ϯ †‡ Ϯ †‡ Ϯ ‡ Ϯ ‡ Phenylephrine, 1 31 5 30 6 1.5 0.7 2.3 1.2 α Ϯ ‡ Ϯ ‡ Clonidine, 2 5 3 13 7 NA NA β Ϯ ‡ Ϯ †‡ Prenalterol, 1 9 4 15 2 NA NA β Ϯ †‡ Ϯ †‡§ Ϯ ‡ Ϯ ‡ Ritodrine, 2 46 7 35 6 3.5 0.4 3.0 0.6 β Ϯ †‡ Ϯ †‡ Ϯ Ϯ ZD7114, 3 39 3 42 4 4.4 0.6 4.4 0.4 ϭ ϭ EC50 calculated negative log of molar value resulting in 50% inhibition of spontaneous activity; NA not applicable, because no inhibition was seen. *Values given as percent inhibition, mean Ϯ SEM; n у 8 rats. †P Ͻ 0.005 compared with norepinephrine. ‡P Ͻ 0.06 compared with spontaneous activity before adding respective drug. §P Ͻ 0.05 compared with same dose without TTX. Vol. 9, No. 2 2005 Adrenergic Mechanisms of Ileal Contractility 231

α α Fig. 2. Dose-responses of (A) clonidine (CLON) ( 1) and phenylephrine (PHEN) ( 2) and of (B) β β β prenalterol (PREN) ( 1), ritodrine (RIT) ( 2) and ZD7114 (ZD) ( 3) compared with norepinephrine (NE). Values given as mean Ϯ SEM; n ϭ 9 rats. *P Ͻ 0.05 versus NE. Journal of 232 Seiler et al. Gastrointestinal Surgery

β Fig. 3. Effect of ZD7114 ( 3) on spontaneous activity. ZD7114 was administered cumulatively and caused a dose-dependent decrease in basal tone and thus in contractile activity.

Ϯ α β 66 8%. In the presence of TTX, the reduction in Our main findings were that 2- and 1-receptor baseline tone was smaller (45 Ϯ 6%, P Ͻ 0.05). mechanisms do not appear to be involved in the adren- The EC50 for ZD7114 did not differ from the ergic modulation of gut contractile activity in the rat, Ϯ Ϯ EC50 of NE (4.4 0.6 versus 5.0 0.3), suggesting neither directly on the smooth muscle cells nor indi- α a similar molar inhibitory effect by ZD7114. The rectly via the enteric nervous system. In contrast, 1, Ϯ Ϯ β β EC50 of ritodrine and NE (3.5 0.4 versus 5.0 0.3, 2, and 3 pathways reproduced, in part, the inhibition P Ͻ 0.05) differed; the dose-response curve for rito- induced by norepinephrine, a nonselective, global ad- drine was shifted to the right, compared with NE renergic agonist. Blocking enteric neural activity Ϫ (Fig. 2B). within the muscle strip (with TTX 10 6 M) par- β tially reduced the response of 2-receptor and slightly α increased the response of 1-receptor stimulation, suggesting involvement of enteric neural mechanisms. The involvement of α - but not α -receptors in DISCUSSION 1 2 the control of motor activity in the rat ileum is of Our study was designed to characterize the special interest, because in general not much is known α α β β α involvement of specific adrenergic 1-, 2-, 1-, 2-, about the role of -receptors in intestinal contract- β or 3-receptor mechanisms in the inhibition of con- ility. A case report of a patient with pheochrom- tractile activity of longitudinal smooth muscle in the ocytoma in whom paralytic ileus was treated rat ileum. These contractile responses are of particu- successfully with the α-receptor antagonist phentol- lar interest, because modulation of gut motility via amine and later with prazosin (selective α1-receptor adrenergic pathways may represent a novel therapeu- agonist)9 suggests that α-mechanisms may be in- tic target for motility disorders. This pharmacologic volved in human small bowel contractile activity, α approach would require identification of specific re- whereas in an in vitro study in human tissue, 2 ceptor subtype mechanisms such that effects on intes- pathways did not seem to play a role.10 Therefore, tinal contractile function can be targeted, possibly it seems likely that in control of human small bowel minimizing or even avoiding cardiovascular side contractility, α-adrenergic influence is dependent on α effects. 1-receptors. This would be in accordance with our Vol. 9, No. 2 2005 Adrenergic Mechanisms of Ileal Contractility 233

β Fig. 4. (A) Effect of ritodrine ( 2) on spontaneous activity. Ritodrine was administered cumulatively and caused a dose-dependent decrease in contractile activity. (B) In presence of tetrodotoxin, the dose- dependent reduction in basal tone was smaller, thus reducing the overall inhibitory effect induced by ritodrine. α α β results in rat ileum where 1 mechanisms but not 2 3-Receptors have been of particular interest be- pathways appear to influence contractile properties cause they seem to be abundantly present in gastroin- in vitro. However, in the gut of other species, the testinal tissue.18,19 Our results are in accordance with role of α-receptors is different: in guinea pig ileum, the data of Brown and Summers,20 who showed that α α 11 β both 1- and 2-receptors mediate inhibition, and 3 pathways play a major role in the inhibition of α in canine and mouse ileum and in rat colon, only 2, rat ileum. In guinea pig ileum, contractile activity α β 21 not 1, inhibitory mechanisms have been de- is also inhibited by 3-receptor stimulation, whereas 12–14 scribed. In rabbit, α1 mechanisms can be part of canine ileum does not seem to be influenced by β3- inhibitory pathways in other anatomic regions of the receptors.12 15 16 β β gut such as jejunum and duodenum. Because of As discussed earlier, 2- and 3-receptor–specific marked species differences, broad generalizations be- inhibition plays a role in inhibiting contractile activ- β tween species must be made with caution. ity, whereas 1-receptor mechanisms do not appear β Inhibitory mechanisms mediated by 2-adrenergic to be involved in the inhibition of longitudinal muscle receptors were identified in our study. This finding of the rat ileum. Our latter finding contrasts with is consistent with results in rabbit ileum,17 whereas data from Brown and Summers,20 who reported a β β in canine ileum, 2 pathways had no influence on slight effect of 1-receptor mechanisms in rat ileum. contractile activity.12 Differences in the muscle layers investigated and in Journal of 234 Seiler et al. Gastrointestinal Surgery

β the experimental protocols, such as different sub- from 3-adrenoceptor knock-out mice, and Susulic stances that were used and conduction of the experi- et al.28 Suggest that “cross-talk” might exist between β β ment in precontracted muscle strips, may explain 3-adrenoceptors and 1-adrenoceptor gene expression. some of these differences. We have shown previously Our results, when compared with the literature, that different contractile responses in circular versus underline the high degree of variability not only in longitudinal muscle layers are as important as are regional dependent differences (anatomic and muscle differences between anatomic regions of jejunum layer) but also between species. It is of interest that 22,23 α α versus ileum. In an in vivo study in canine 1-receptor mechanisms (but not 2 pathways) played β ileum that supports our results, 1-receptors were a role in our rat ileum study. The scarce data from found to not be important.12 the literature suggest a similar constellation of con- In our experiments, we tried to distinguish between tractile α mechanisms in human small bowel. If this muscle-related mechanisms and pathways involving similarity is confirmed in the future, the rat ileum α the enteric nervous system, because under pathologic might be attractive to further model 1 pathways in conditions, adrenergic mechanisms might be com- pathologic states. 5,24,25 β β promised at either level of control. None of the For 2- and 3-receptors, species differences are α β β specific adrenergic 2-, 1-, or 3-receptor mecha- evident as well, but we do not have comparable data nisms were TTX sensitive, and therefore the path- for human ileum. Species differences, especially for β ways seem to be independent of the enteric nervous 3 pathways, would be of interest, because these re- β α system. Interestingly, part of the 2 and 1 inhibition ceptors are abundantly present not only in adipose in our experiments appears to be modulated by pre- tissue but also in gastrointestinal tissue and there- β synaptic mechanisms. Blockade of neural 2 mecha- fore are of interest for the study of gastrointestinal 29,30 β nisms by TTX resulted in a lesser inhibition of motility. To our knowledge the role of 3-recep- contractile activity. This neurally mediated effect ap- tors in human contractility has not been carefully pears to occur via a reduction in baseline tone rather investigated in vitro. than a reduction in phasic activity. In contrast, the Because of the species differences of adrenoceptor α1-adrenergic effect appears to be related to a slight distribution and function, choosing the right animal increase in baseline tone. The physiologic relevance model is crucial. This has been noted for cardiovascu- of these findings as seen in our in vitro measurement of lar studies17 and will be the same for contractile stud- isometric contractions is not yet known. In other ies of the gastrointestinal tract. study designs, the distinction between muscle or neurally mediated inhibition was not made.17 However, it is conceivable that part of the gastrointestinal motility The authors thank Dr. M. G. Sarr for his valuable input to the disorders in neurologic diseases such as diabetic neu- manuscript. ropathy or other postneurotomy syndromes (e.g., postvagotomy gastroparesis) are linked with an im- β REFERENCES paired modulation of contractile activity via 2 and α mechanisms. Thus, further studies are required. 1. Goyal RK, Hirano I. Mechanisms of disease: The enteric 1 nervous system. N Engl J Med 1996;334:1106–1115. 2. Tache Y, Monnikes H. 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