Anesth Analg 2005;100:120-127
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000139352.54676.18
ANESTHETIC PHARMACOLOGY
Peristalsis in the Guinea Pig Small Intestine In Vitro Is Impaired by Acetaminophen but Not Aspirin and Dipyrone
Michael K. Herbert, MD*,
Rebecca Weis, MS*,
Peter Holzer, PhD
, and
Norbert Roewer, MD*
*Department of Anesthesiology, University of Wuerzburg, Wuerzburg, Germany; and
Department of Experimental and Clinical Pharmacology-Medical University of Graz, Austria
Address correspondence and reprint requests to M. K. Herbert, MD, Department of Anesthesiology, University of Wuerzburg, Oberduerrbacher Str. 6, D-97080 Wuerzburg, Germany. Address e-mail to herbert_m{at}klinik.uni-wuerzburg.de
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Abstract
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Inhibition of intestinal peristalsis is a major side effect of opioid analgesics. It is unknown whether non-opioid analgesics, such as acetaminophen, acetylsalicylic acid, and dipyrone, exert any effect on intestinal motility. In the current in vitro study we examined the effect of these analgesics on intestinal peristalsis and analyzed some of their mechanisms of action. In isolated segments of the guinea pig small intestine peristalsis was triggered by a perfusion-induced increase of the intraluminal pressure. The peristaltic pressure threshold (PPT) at which peristaltic waves were elicited was used to quantify drug effects on peristalsis. Vehicle (Tyrode’s solution), acetaminophen (0.01–100 µM), acetylsalicylic acid (100–300 µM), and dipyrone (10–100 µM) were added extraserosally to the organ bath. Acetaminophen concentration-dependently increased PPT and abolished peristalsis in four of six segments at the concentration of 10 µM and in all segments tested at 100 µM (EC50 = 6.0 µM). The increase in PPT resulting from 3 µM acetaminophen was reduced by naloxone and apamin but not changed by L-nitro-arginine methylester (L-NAME), its inactive enantiomer D-NAME, acetylsalicylic acid, methysergide, or tropisetron. Acetylsalicylic acid and dipyrone did not affect peristalsis. The results reveal, for the first time, that acetaminophen concentration-dependently impairs intestinal peristalsis, whereas acetylsalicylic acid and dipyrone lacked such an effect. The inhibition caused by acetaminophen involves transmitters acting via small conductance Ca2+-activated potassium channels, endogenous opioidergic pathways, and presumably inhibition of cyclooxygenase-3.
IMPLICATIONS: Acetaminophen (paracetamol) concentration-dependently impairs peristalsis in the guinea pig small intestine in vitro. The inhibitory action is mediated through activation of endogenous opioidergic pathways, small conductance Ca2+-activated potassium channels, and, presumably, cyclooxygenase -3. Acetylsalicylic acid (aspirin) and dipyrone (metamizol) have no inhibitory effect.
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Introduction
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Non-opioid analgesics, such as acetylsalicylic acid (aspirin), acetaminophen (paracetamol, N-acetyl-para-aminophenol), and dipyrone (metamizol), are widely used to treat acute pain after injury or surgical procedures or as supplement treatment to spare opioids (1). Aspirin, acetaminophen, and dipyrone are available for the oral and IV route, acetaminophen in addition as a rectal suppository. Inhibition of gastric emptying and intestinal motility is a major side effect of opioid analgesics (2). Although non-opioid pain-relieving drugs pose no major clinical problems, little is known about their effect on intestinal motility. Because of the difficulties of exploring this question in the human small intestine, we used a preparation of the isolated guinea pig small intestine in vitro (3). In this preparation, peristalsis is triggered by a perfusion-induced increase of the intraluminal pressure, and the peristaltic pressure threshold (PPT) at which peristaltic waves are triggered is used to quantify drug effects on peristalsis.
The present series of experiments was designed to characterize the effect of aspirin, acetaminophen, and dipyrone on intestinal peristaltic motility and to shed some light on their mode of action. The overall aim of this work was to provide a mechanistic background for a better understanding of the influence of analgesics on gut function.
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Methods
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After obtaining approval from the Animal Care and Use Committee at the Government of Lower Franconia in Wuerzburg, Germany, adult guinea-pigs (BFA strain, Charles-River Wiga, Sulzfeld, Germany) of either sex, weighing between 370 and 480 g, were stunned and bled via the carotid arteries. The experimental and recording protocol has been described in detail (3). In brief, the jejunum and ileum were excised, flushed of luminal contents, and placed in Tyrode’s solution at room temperature, then gassed with 95% O2 and 5% CO2, until required. The composition of the Tyrode’s solution was (in mM): NaCl 136.9, KCl 2.7, CaCl2 1.8, MgCl2 1.0, NaHCO3 11.9 and NaH2PO4 0.4, and glucose 5.6. For studying peristalsis, the distal small intestine (at least 10 cm proximal to the ileocecal valve) was divided into segments, each approximately 8 to 10 cm long. Five intestinal segments were set up in parallel in silanized glass organ baths containing 30 mL of Tyrode’s solution at 37°C. The oral end of the intestinal segment was tied to an inflow cannula, which permitted the continuous infusion of prewarmed Tyrode’s solution at a flow rate of 0.5 mL/min. The aboral end of the segment was attached to an intermediate tubing (inner diameter, 4 mm) fixed with a T piece. One arm of the T piece was connected to a pressure transducer for recording of the intraluminal pressure and the other arm of the T piece was fitted with a vertical outlet tubing that ended 4 cm above the fluid level of the organ bath. This arrangement made emptying of the intestinal segment possible when peristaltic contractions increased the intraluminal pressure more than 400 Pascal (Pa). When the intraluminal pressure reached a threshold (PPT, range 32–64 Pa), an aborally moving wave of peristaltic contraction was triggered and the emptying phase of peristalsis initiated. The wave of circular muscle contraction, measured as a spike-like increase in intraluminal pressure, propelled the intraluminal fluid to leave the system via the outlet tubing and thus caused partial emptying of the segment. The intraluminal pressure at the aboral end of the segments was measured with a pressure transducer whose signal was, via an analog/digital converter, fed into a personal computer and recorded simultaneously on a pen-recorder.
The preparations were allowed to equilibrate in the organ bath for a period of 30 min. Thereafter the bath fluid was renewed and peristaltic motility initiated by intraluminal perfusion of the segments. After basal peristaltic activity had been recorded for at least 30 min, the drugs to be tested were added to the bath, i.e., to the serosal surface of the intestinal segments at volumes not exceeding 1% of the bath volume. All vehicle solutions used in this study were tested separately to ensure that they were devoid of any influence on peristaltic activity.
Each segment was exposed to only one drug concentration and discarded 60 min afterwards because drug effects usually became maximal within 30 min. Each concentration of aspirin (100–300 µM), dipyrone (10–100 µM) and acetaminophen (0.01–100 µM) was tested on 6 segments from 6 different guinea pigs of a total of 53 animals. Some of the mechanisms mediating the inhibitory effect of acetaminophen were investigated in separate series of experiments. Twenty minutes before the addition of acetaminophen (3 µM), the following antagonists/blockers were added to the organ bath:
- 0.5 µM naloxone (antagonist at opioid receptors),
- 0.5 µM apamin (blocker of small conductance Ca2+-activated potassium channels),
- 300 µM L-nitro-arginine methylester (L-NAME, nitric oxide [NO] synthase inhibitor) or its inactive enantiomer D-NAME (300 µM),
- 100 µM aspirin (inhibitor of cyclooxygenase [COX] 1 and 2),
- the combination of 1 µM methysergide (nonselective antagonist at 5-hydroxytryptamine [5-HT] receptors) and 1 µM tropisetron (selective 5-HT3 receptor antagonist), and
- the combination of methysergide (1 µM), tropisetron (1 µM), and naloxone (0.5 µM).
In a last set of experiments methysergide (1 µM) and tropisetron (1 µM) were added to the bath 20 min before vehicle administration only to describe the effect of the 5-HT receptor antagonists on intestinal peristalsis. The effect of acetaminophen recorded in the presence of the antagonists was compared with that seen in the presence of vehicle (Tyrode’s solution).
Acetaminophen, dipyrone hydrate, aspirin, methysergide maleate, apamin, and naloxone were purchased from Sigma-Aldrich Chemie Ltd. (Taufkirchen, Germany) and tropisetron was purchased from Novartis Pharma Ltd. (Nuernberg, Germany). All other chemicals were from commercial sources and were of the highest purity available. The chemicals were dissolved in sterile water, and stock solutions were diluted with Tyrode’s solution before use. As a result of the buffer capacity of Tyrode’s solution the pH of the organ bath solution was not influenced by the addition of acetaminophen (100 µM). Similarly, the osmolality of the organ bath solution remained unchanged after acetaminophen (100 µM).
PPT was used to quantify drug effects on peristalsis. After regular peristaltic contractions had been recorded for at least 20 min, the PPT of the last peristaltic wave immediately before drug addition was taken as baseline. After drug administration the PPT of the last complete peristaltic wave within consecutive 5-min periods (i.e., 5, 10, 15, and further up to 60 min) was calculated. Inhibition of peristalsis was reflected by an increase in PPT, and abolition manifested itself in a lack of propulsive motility in spite of an intraluminal pressure of 400 Pa as set by the position of the outlet tubing. Although in this case PPT exceeded 400 Pa, abolition of peristalsis was expressed quantitatively by assigning PPT a value of 400 Pa to obtain numerical results suitable for further statistical evaluation (3,4).
To obtain the net increase of PPT caused by acetaminophen, dipyrone, or aspirin, the baseline PPT was subtracted from the respective PPT values recorded in the presence of acetaminophen, dipyrone, or aspirin.
Because the null hypothesis of normality was not rejected by the Kolmogorov-Smirnov test, all quantitative data are presented as mean ± SEM (standard error of the mean). Significance was evaluated using analysis of variance and post hoc Student-Newman-Keuls or Student’s t-test as appropriate for a level of P < 0.05 (Sigma Stat for Windows, version 2.03, SPSS Inc., Chicago, IL). The 50% effective concentration value (EC50 value) for acetaminophen was calculated by the method of Tallarida and Murray (5).
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Results
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Peristaltic contractions remained constant in all experiments during the control period before any drug administration and were not influenced by the addition of vehicle (Tyrode’s solution, Fig. 1A). The range of PPT for eliciting a wave of circular contraction propelling the intraluminal content to the aboral direction varied between 32–64 Pa during the control period.
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Figure 1. Original recordings of the effect of vehicle and acetaminophen (1–100 µM) on peristalsis in isolated segments of the guinea pig small intestine. The tracings show the intraluminal pressure recorded at the aboral end of the segments. Luminal perfusion of the segments slowly increased the intraluminal pressure; when the peristaltic pressure threshold (PPT, marked by an arrow in the inset of A) was reached, a peristaltic wave shown as a spike-like increase of intraluminal pressure was triggered. (A) Peristaltic activity was constant during a control period and remained uninfluenced by vehicle (Tyrode’s solution). (B) Addition of 1 µM acetaminophen led to a small increase in PPT, whereas (C) a larger concentration of acetaminophen (10 µM) caused a more pronounced but transient increase in PPT. (D) After exposure to 100 µM acetaminophen, peristalsis was completely abolished for approximately 15 min so that despite an intraluminal pressure of 400 Pa no peristaltic movements took place. Thereafter, motility returned, first as irregular contractions and later as peristaltic waves that were elicited when PPT was reached.
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Addition of acetaminophen (0.01–100 µM) to the organ bath concentration-dependently increased PPT (EC50 = 6.0 µM) (Figs. 1–3). Peristalsis was transiently abolished by 10 µM acetaminophen in four of six segments and by 100 µM acetaminophen in all segments; these effects occurred with a latency of 5.7 ± 1.0 min after drug administration (Fig. 1D). In the four segments blocked by 10 µM acetaminophen and the six blocked by 100 µM acetaminophen, peristalsis-like contractions reoccurred 9.3 ± 3.4 min and 17.1 ± 3.3 min after abolition of peristalsis, respectively. Regular peristalsis recovered 25 min after drug administration in one segment blocked by 10 µM acetaminophen and 34.1 ± 3.6 min after drug administration in three segments blocked by 100 µM acetaminophen. After recovery the PPT of the peristaltic contractions remained at a higher level compared with that during the control period before drug administration (Fig. 1D).
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Figure 2. Concentration- and time-related effects of acetaminophen (1–100 µM), relative to vehicle, to increase peristaltic pressure threshold (PPT) during an observation period of 60 min. The time of administration of vehicle and acetaminophen is indicated by an arrow. The symbols represent the mean values of PPT recorded from six segments in the respective 5-min interval; the positive error bars show the standard error of the mean (SEM).
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Figure 3. Concentration-response relationship for the increase in peristaltic pressure threshold (PPT) (Pa) caused by acetaminophen (0.01–100 µM) and vehicle (Tyrode’s solution). The symbols represent the mean values ± SEM of PPT recorded from six intestinal segments.
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Selective antagonists of putative inhibitory transmitters were used to elucidate some of the mechanisms mediating the antiperistaltic action of acetaminophen. The antagonists were tested against a submaximally effective concentration of acetaminophen (3 µM) in parallel with the respective vehicle solutions. Pretreatment with 0.5 µM naloxone attenuated the increase in PPT resulting from 3 µM acetaminophen that could be observed after vehicle pretreatment (Figs. 4A,B, 5A). Addition of 0.5 µM naloxone slightly decreased PPT and increased the frequency of peristaltic contractions (Fig. 4B). Similarly, 0.5 µM apamin reduced the increase in PPT caused by 3 µM acetaminophen (P < 0.05, Fig. 5A). Inhibition of NO synthase by 300 µM L-NAME did not affect the acetaminophen-induced increase of PPT when compared with pretreatment with the inactive enantiomer D-NAME (300 µM, Fig. 5B). Inhibition of COX by aspirin (100 µM) also failed to antagonize the acetaminophen-induced increase in PPT (Fig. 5C). The 5 HT-antagonists methysergide and tropisetron slightly amplified the acetaminophen-induced enhancement of PPT, a change that was absent when methysergide and tropisetron were coadministered with 0.5 µM naloxone (Fig. 5D). Both 5 HT-antagonists themselves were devoid of any action on PPT when followed by vehicle only (Fig. 5E).
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Figure 4. Original recordings of peristaltic contractions in segments of the guinea pig small intestine showing that the acetaminophen-induced impairment of motility is mediated by opioidergic pathways. (A) After pretreatment with vehicle (Tyrode’s solution), peristaltic pressure threshold (PPT) was markedly increased by 3 µM acetaminophen. (B) After pretreatment with 0.5 µM naloxone, the acetaminophen-induced increase of PPT was blunted. Note the increase in the frequency of peristaltic contractions after blockade of enteric opioidergic transmission by naloxone.
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Figure 5. Analysis of the mechanisms mediating the inhibitory action of acetaminophen (AAP, 3 µM) on peristalsis. (A) The increase in peristaltic pressure threshold (PPT) resulting from acetaminophen was attenuated by 0.5 µM apamin and 0.5 µM naloxone, relative to vehicle (Tyrode’s solution). (B) Inhibition of nitric oxide (NO) synthase by L-NAME (300 µM) did not affect the increase in PPT resulting from acetaminophen when compared to that seen after D-NAME (300 µM, inactive enantiomer) pretreatment. (C) The acetaminophen-induced increase of PPT was not influenced by acetylsalicylic acid (ASA, 100 µM). (D) Blockade of 5-HT receptors by the combination of methysergide (1 µM) and tropisetron (1 µM) did not reduce but slightly (though nonsignificantly) amplified the increase of PPT resulting from acetaminophen, an effect that was absent after blockade of opioidergic receptors by naloxone (0.5 µM). (E) Per se, methysergide (1 µM) and tropisetron (1 µM) had a negligible effect on PPT when followed by exposure to vehicle (Tyrode’s solution) only. The columns represent the means and the error bars the SEM of PPT of n = 8 (A,C), n = 6 (B), n = 7 (D), n = 4 (E) gut segments. *P < 0.05.
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Aspirin (100 µM, 300 µM) and dipyrone (10 µM, 100 µM) failed to influence the PPT at which peristaltic contractions were elicited (Table 1).
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Table 1. Mean Increase in Peristaltic Pressure Threshold (PPT) as Observed 60 min after Exposure to Vehicle, Acetylsalicylic Acid (ASA) and Dipyrone
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Discussion
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This study shows, for the first time, that acetaminophen impairs intestinal peristalsis, whereas aspirin and dipyrone are devoid of such an effect. The results were obtained with an in vitro preparation of the isolated guinea pig small intestine,(3) which enabled us to record and quantify drug-induced alterations of intestinal peristalsis. A major advantage of this experimental setup is the high resolution with which changes in the sensitivity of the gut to distension (the stimulus triggering peristalsis) resulting from extraserosally applied substances can be measured. Thus, an increase of PPT by, e.g., 10 Pa reflects an approximate increase of 1 mm hydrostatic pressure. Other points worth noting are that continuous endoluminal perfusion of the intestinal segments with Tyrode’s solution at a constant rate induces regular peristalsis for at least 2 to 3 hours and that drug effects can be evaluated independently of systemic and local blood flow. The study of propulsive peristalsis in isolated gut segments models physiological conditions more closely than the recording of contractions in isolated longitudinal and circular muscle strips because muscle contractions can be evoked even when coordinated propulsive peristalsis is impaired or has ceased. Finally, alterations of intestinal peristalsis in our in vitro setup reflect drug effects directly on the enteric neuronal-smooth muscle circuitry subserving peristalsis.
Aspirin, one of the most widely used drugs for pain relief and prophylaxis of thromboembolic complications (6), had no adverse effect on propulsive motility in the guinea pig small intestine in vitro. The pharmacological actions of aspirin are related to its ability to acetylate COX, thereby irreversibly blocking the conversion of arachidonic acid to prostanoids. Because the inhibitory potency (IC50) of aspirin to block the COX-1 and COX-2 isoenzymes is 2–20 µM (7), the concentrations of aspirin (>100 µM) tested here were sufficient to block both COX-1 and COX-2 in the gut segments. Similar aspirin concentrations are reached under clinical conditions (8). It has been found that salicylate (up to 100 µM) also fails to modify peristalsis in the guinea pig small intestine (9). The lack of an antiperistaltic effect of aspirin concurs with the results of a study in the guinea pig isolated small intestine (9) in which the COX-1/COX-2 nonselective inhibitors flurbiprofen and piroxicam, as well as selective inhibitors of COX-1 and COX-2, failed to grossly alter peristalsis. In contrast to our negative results in the guinea pig small intestine in vitro, experiments with healthy volunteers have shown that gastric emptying is delayed by small doses of aspirin (10).
We found acetaminophen to impair intestinal peristalsis in a concentration-dependent manner. The effect of acetaminophen was short lasting because peristalsis recovered soon from inhibition. Although acetaminophen is extensively used for the treatment of pain, its pharmacological mechanism of action has remained unclear. It is generally accepted that acetaminophen is a centrally acting drug (11) and that 5-HT participates in the central and spinal antinociceptive effects of systemically administered acetaminophen (12,13). In a similar way, tropisetron, a 5-HT3 receptor antagonist, prevents the antinociceptive action of acetaminophen in the paw-pressure test (14). However, the failure of tropisetron and methysergide (an antagonist at several 5-HT receptor types) to modify the inhibitory effect of acetaminophen on intestinal peristalsis speaks against an involvement of 5-HT. Furthermore, transmission via NO as an inhibitory enteric mediator (15) does not seem to be involved in the inhibitory action of acetaminophen because blockade of NO synthase with L-NAME was without effect.
Pretreatment of gut segments with the pan-opioid receptor antagonist naloxone and apamin, a blocker of low conductance Ca2+-activated potassium channels (16), prevented acetaminophen from inhibiting peristalsis. The antagonism by naloxone does not necessarily mean that acetaminophen binds to opioid receptors but rather suggests that acetaminophen activates, by an unknown mode of action, opioidergic pathways in the gut, which dampen peristaltic motility (17). A similar antiperistaltic effect mediated by opioidergic pathways has been observed with clonidine (3), which does not bind to opioid receptors. Although we cannot exclude that naloxone antagonized the inhibitory effect of acetaminophen simply because naloxone per se had a properistaltic action, we think that this explanation is unlikely in view of the weak stimulant effect of naloxone. Like that of clonidine (3), the antiperistaltic action of acetaminophen was attenuated by apamin, which indicates that acetaminophen activated enteric neural pathways that involve a transmitter whose transduction mechanism depends on low conductance Ca2+-activated potassium channels (16).
Although acetaminophen is generally regarded as a nonsteroidal antiinflammatory drug (NSAID), its mechanism of action differs from that of traditional NSAIDs (18). Acetaminophen possesses potent analgesic and antipyretic actions but displays only weak antiinflammatory activity and lacks other typical features of NSAIDs, such as antiplatelet activity and gastrotoxicity. COX-1 and COX-2 are insignificantly affected by acetaminophen (19). The recent discovery of a COX-3 isoform in canine and human tissues has revealed new aspects of the action of acetaminophen and other NSAIDs (19). Alternative splicing generates four different mRNA variants derived from the COX-1 gene, encoding novel variants of the COX-1 protein family, namely the COX-3, COX-1, and the two truncated, partial PCOX-1 sequences, PCOX-1a and PCOX-1b. COX-3 found in neuronal tissues such as the cerebral cortex as well as in the heart and aorta is inhibited by acetaminophen, dipyrone, and other NSAIDs such as indomethacin (19). Indomethacin is in fact a very potent inhibitor of COX-3, which points to a possible mechanism whereby this NSAID disturbs the regularity of peristalsis (9). COX-3 inhibition by acetaminophen is only weak, however, and therefore unlikely to account in full for its analgesic effect in vivo and antiperistaltic action in the gut in vitro.
An important question concerns the acetaminophen concentrations necessary to inhibit intestinal motility in vitro, relative to the concentrations achieved after IV, oral or rectal administration. Although some limitations have to be considered when effective plasma levels of any drug are extrapolated from in vitro organ bath concentrations, the concentration range of acetaminophen found to be antiperistaltic in this in vitro study covers the therapeutic plasma concentration range (55 µM–150 µM) of acetaminophen after IV or rectal application in patients (11,20,21). It should be noted that the local concentration of acetaminophen adjacent to the intestinal wall might be significantly larger after oral ingestion, as 1 g acetaminophen dissolved in 700 mL of fluid would give an intestinal concentration of about 10 mM (22).
Little is known about an inhibitory effect of acetaminophen on gastric and intestinal propulsive motility in vivo because an antiperistaltic effect or even constipation resulting from acetaminophen does not seem to be a major problem in clinical routine. However, our data advocate caution, especially if acetaminophen is administered together with other motility-inhibiting drugs. One experimental study in mice has shown that subcutaneous administration of acetaminophen 30 min before an oral charcoal meal does not change the rate of small intestinal transit (23). Because the inhibitory effect of acetaminophen in our experimental setup was short lasting and transient, it could be reasoned that the 30 min pretreatment time in mice was too long for an effect on small intestinal transit to be demonstrated. It remains to be examined whether the short-lasting inhibition of peristalsis caused by acetaminophen reflects a pharmacodynamic phenomenon (desensitization) or is attributable to pharmacokinetic processes (nonspecific binding to tissue, degradation). In humans acetaminophen is used to assess the rate of gastric emptying in humans, the assumption being that acetaminophen per se does not modify gastric emptying (24,25). In view of our observations it needs to be questioned, however, whether acetaminophen is indeed without acute effect on gastric emptying.
The absence of an inhibitory effect of dipyrone, a pyrazolone derivative, on intestinal peristalsis is in line with results obtained in the rat in which intestinal motility after administration of a charcoal meal remained unaffected by dipyrone and the constipation resulting from morphine was not augmented (26). Similarly, IV-administered dipyrone failed to alter transit in the rat small intestine, although it reduced the rate of gastric emptying (27).
The mechanism of dipyrone’s analgesic and antipyretic activity remained speculative (28,29) until it was shown that the drug inhibits COX-3 more potently than either COX-1 or COX-2 (19). After administration of 1 g dipyrone via the oral route, the metabolite 4-methylaminoantipyrine reaches concentrations of 104 µM and 86 µM in plasma and central nervous system, respectively (29). As bath concentrations of 100 µM dipyrone lacked any effect on peristalsis in the guinea pig small intestine in vitro, it is inferred that dipyrone has no adverse effect on intestinal motility.
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Footnotes
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MKH and RW contributed equally to the work.
Presented, in part, at the Hauptstadtkongress Anaesthesie und Intensivmedizin, June 20, 2003, Berlin, Germany.
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Accepted for publication June 24, 2004.
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Abstract
Introduction
