1 Gastroenterology Research Unit and 2 Section of Biostatistics, Mayo Clinic, Rochester, Minnesota 55905
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ABSTRACT |
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The effects of
pharmacological modulation of adrenergic receptors on colonic motor and
sensory function are unclear. We studied 40 healthy volunteers in a
single-blind design; 12 received saline, and the remaining 28 received
either clonidine, yohimbine, phenylephrine, or ritodrine. A
barostat-manometric assembly in the left colon recorded drug effects on
fasting and postprandial motor function, compliance, and sensation in
response to standardized phasic balloon distensions delivered in random
order. Clonidine reduced and yohimbine increased fasting, but not
postprandial tone, by 63.2 ± 22.3% and 24.8 ± 8.8% (SE),
respectively. Clonidine tended to reduce fasting phasic activity in the
descending and sigmoid colon. A power exponential model provided the
best fit to the compliance curve. Clonidine significantly increased
colonic compliance. Clonidine reduced and yohimbine increased colonic
perception of pain but not gas sensation during distension.
Phenylephrine and ritodrine did not influence colonic motor or sensory
function in the present studies. Thus
2-receptors modulate fasting
colonic tone and compliance and alter perception of pain but not gas
during mechanical stimulation of the colon.
colonic tone; sensation; compliance
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INTRODUCTION |
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SYMPATHETIC STIMULATION is one of the putative
mechanisms of paralytic ileus and even isolated colonic
pseudo-obstruction (13). Conversely, pharmacological sympathetic
blockade increases colonic motility in animals (14), and some patients
with diabetic autonomic neuropathy have diarrhea that is attributable
to loss of the "sympathetic brake." Clonidine, an
2-agonist, can ameliorate diabetic diarrhea (10); the precise mechanisms for this beneficial clinical response are unclear.
2-Agonists probably
slow gut transit by enhancing
2-mediated fluid and
electrolyte absorption (30) and by inhibiting fasting and postprandial
small intestinal contractile activity (35, 36). However, the effects of
2- and other adrenergic receptors on gut neuromuscular function in vivo require further elucidation. For example, the effects of pharmacological modulation of
2- and other adrenergic
receptor subtypes on colonic motor and sensory function in humans are
unknown. In addition to the effects of
2-agents, the
1- and
2-receptors may also contribute to the overall effects of the sympathetic brake, since the
1-agonist phenylephrine and the
2-agonist terbutaline also
reduce colonic contractile frequency in primates (26).
We have previously demonstrated that a pressure-clamped polyethylene balloon distended with air in the descending colon can measure colonic compliance, fasting tone, and its response to meal ingestion (11); the same balloon can be used as a distension stimulus to assess sensation (12). The colonic contractile response after ingestion of a meal has been demonstrated in several species, including humans (5, 11, 31). It has been suggested that a reduction in the tonic inhibitory sympathetic input to the colon contributes to the colonic meal response in primates (6).
The role of the adrenergic nervous system in mediation or modulation of
colonic sensation in humans is unclear.
2-Receptors are found along
nociceptive pathways in the spinal cord, brain stem, and forebrain
(37), which are important relay stations in the three-neuron chain
delivering visceral sensation from the colon to conscious perception.
Moreover, although clonidine has been used for postoperative analgesia
(4), its effects on colonic sensation have not been evaluated.
In this study, our aims were to compare the effects of saline
(control), clonidine
(2-agonist), yohimbine
(
2-antagonist), phenylephrine
(
1-agonist), and ritodrine
(
2-agonist) on colonic motility, compliance, and sensation in healthy human volunteers. We
have not yet studied the
2-system with an antagonist,
since a selective
2-antagonist
is unavailable for human studies.
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MATERIALS AND METHODS |
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Healthy Volunteers
Forty healthy volunteers, aged 18-45 yr (mean ± SE, 29 ± 1.1 yr; 22 male and 18 female) were recruited by public advertisement. None had previously undergone abdominal surgery (other than an appendectomy and/or cholecystectomy). None was taking medications with the exception of acetaminophen or oral contraceptives. A clinical interview and physical examination were performed to exclude significant cardiovascular, respiratory, neurological, psychiatric, or endocrine disease. As in previous studies (12), validated screening questionnaires [a Bowel Disease Questionnaire (34) and the Hospital Anxiety and Depression Inventory (38)] were used to exclude subjects with irritable bowel syndrome and to determine anxiety and depression scores. All participants signed informed consent to participate in the studies, which were approved by the Institutional Review Board at the Mayo Clinic.Administration of Drugs
Because of human safety considerations, the subject, but not the investigator, was blinded to the nature of the medication. Of the 40 subjects, 12 were randomized to receive placebo and 7 each to one of the other four agents. Subjects were informed they would be randomized to either a medication or placebo, either intravenous or oral. As control or placebo, we administered 10 ml of 0.9% saline as a "bolus" over 5 min, followed by an infusion at 40 ml/h for the entire study. The bolus volume and rate of administration were similar for yohimbine, the only other agent administered as a bolus followed by an infusion.Clonidine. Clonidine (Zenith, Northvale, NJ), 0.3 mg, was given as a single oral dose after at least 20 min of assessment of fasting colonic tone. This dose has previously been demonstrated to slow small intestinal and colonic transit and to enhance fluid absorption in healthy volunteers for at least 4.5 h (30). Intravenous clonidine is not available for administration to humans in the United States; however, the bioavailability of oral clonidine is nearly 100%. Peak concentrations and maximal antihypertensive effects are achieved at 1-3 h after oral administration (20); this peak time of action coincided with the planned experimental protocol in our studies. Cardiovascular recordings in our studies confirmed our expectation, since there was an obvious effect on colonic motor function after the systolic blood pressure had declined by >10 mmHg. This typically occurred 40-55 min after 0.3 mg clonidine had been administered orally.
Yohimbine hydrochloride.
An intravenous formulation of yohimbine is not available in the United
States. We obtained an IND (Investigational New Drug no.
46,250) from the Food and Drug Administration to use an aqueous solution of yohimbine, prepared by the Mayo Pharmacy from yohimbine hydrochloride (Sigma Chemical, St. Louis, MO). Stability of the aqueous
solution of yohimbine over the 6-mo period required to complete the
study was checked by periodic high-performance liquid chromatography
analysis. Yohimbine was administered as an initial 0.125-mg/kg
intravenous bolus over 5 min followed by an infusion at 0.06 mg · kg1 · h
1.
Yohimbine is used clinically to provoke panic attacks in patients with
a history of panic disorder (15); a similar dose stimulates central
sympathetic outflow increasing plasma norepinephrine levels two- to
threefold (15). The effects of yohimbine on fasting colonic tone were
assessed during the intravenous bolus and during the subsequent
infusion.
Phenylephrine.
Phenylephrine (Elkins-Sinn, Philadelphia, PA), a selective
1-agonist, causes peripheral
venoconstriction, an increase in blood pressure, and reflex
bradycardia. An initial dose of 0.4 µg · kg
1 · min
1
given intravenously was titrated upward in 0.4 µg · kg
1 · min
1
increments at 10-min intervals until the systolic blood pressure increased by 20 mmHg, or until a maximum infusion rate of 2.5 µg · kg
1 · min
1
was achieved. In four of seven volunteers randomized to phenylephrine, the dose at which the blood pressure end point was reached was maintained for the duration of the study. In the remaining three volunteers, the dose was titrated down during the study to maintain a
heart rate of at least 45 beats/min, in accordance with limits set by
our Institutional Review Board. For a 70-kg person, the median maximum
dose of 84 µg/min (range 56-140 µg/min) was in the range
recommended (40-180 µg/min) for treating hypotension in
conditions such as hypovolemic or septic shock (21).
Ritodrine.
Ritodrine (Abbott, Abbott Park, IL), a selective
2-agonist, was infused
intravenously at an initial dose of 50 µg/min, increasing by 50 µg/min at 10-min intervals until the heart rate had increased by 50%
or a maximum dose of 350 µg/min was reached. In four of seven
volunteers randomized to ritodrine, the dose at which the target heart
rate was reached was maintained for the duration of the study; in the
remaining three subjects, the dose was titrated so that the heart rate
did not exceed 120 beats/min, as required by our Institutional Review
Board. The dose range of 100-300 µg/min and the dosing regimen
are similar to those recommended for inhibiting uterine contractions in
preterm labor, that is, 150-350 µg/min (22).
Hemodynamic Monitoring
We continuously monitored arterial oxygen saturation, blood pressure, and cardiac rhythm using a pulse oximeter (CO2SMO, Novametrix Medical Systems, Wallingford, CT), Finapres sphygmomanometry (Ohmeda, Madison, WI), and electrocardiogram (Tektronix, Beaverton, OR), respectively. The blood pressure measurements were also confirmed by standard manual sphygmomanometry at regular intervals during the study.Colonic Motor Function
A multilumen polyethylene balloon barostat-manometric assembly incorporating several manometric point sensors was placed into the prepared colon as described in previous studies (11, 12). Tonic and phasic contractile activity of the colon were measured as in previous studies (3, 32) using an infinitely compliant 10-cm-long balloon with a maximum volume of 600 ml (Hefty Baggies, Mobil Chemical, Pittsford, NY) linked to an electronic barostat (Distender Series II, G & J Electronics, Toronto, Ontario, Canada) which has a rigid piston. The manometric portion comprised six water-perfused (0.4 ml/min) pneumohydraulic sensors, three in descending (sensor numbers 1-3) and three in sigmoid colon (sensor numbers 4-6); manometric sensors were 5 cm apart. The first and second sensors were 5 cm orad and caudad to the balloon, respectively. The balloon was positioned in the upper descending colon with the aid of flexible sigmoidoscopy and fluoroscopy. The intraballoon pressure at which respiratory excursions were regularly recorded as changes in barostat volume was defined as the "minimum distending pressure." The "operating pressure" was set 2 mmHg above the minimum distending pressure (median pressure 10 mmHg, range 6-14 mmHg). Intraballoon volumes and manometric pressure changes in response to wall contractions and relaxations were monitored continuously throughout the study. A pneumobelt was applied around the abdominal wall at the level of the lower costal margin to help exclude artifact during movement and coughing.Colonic Compliance
Colonic compliance was assessed as the volume response to 4-mmHg increments in intraballoon pressures at 60-s intervals from 0 to 36 mmHg. The intrinsic compliance of the rigid piston in the barostat used for this study is nearly zero. Two compliance curves were performed, since intrasubject visceral compliance may differ after an initial distension sequence and is more consistent after an initial distension, as previously shown in the stomach (2) and rectum (17). During the first compliance curve, intraballoon pressure was increased in 4-mmHg increments at 60-s intervals from 0 to 36 mmHg. After a 15-min equilibration period, a second colonic compliance curve was performed.Colonic Sensation
As described previously (12), colonic distension was performed as rapid, intermittent "phasic" increases in intraballoon pressure in four steps of 8, 16, 24, and 32 mmHg greater than the operating pressure. The order of distensions was randomized; each phasic pressure increment was maintained for 1 min, with a 1-min interval when the intraballoon pressure was reduced to operating pressure. For rating sensory perception, the participants were asked to mark two separate 100-mm visual analog scales for abdominal pain and feeling of gas at a standardized time, 20 s after the distension had commenced. The 100-mm-long visual analog scales were anchored at the ends by the descriptions "unnoticeable" and "unbearable." During assessment of sensation, verbal interaction between the subject and investigator was kept to an absolute minimum. This approach was previously shown to be responsive to variations in stimulus intensity and to psychosensory modulation of symptoms (12).The balloon volume during the initial part of each 1-min distension varies over time as the colonic segment accommodates initially to the pressure load. Therefore, the intraballoon volume was averaged over a 30-s period, beginning at 20 s after the distension had commenced. Levels of arousal and stress were determined immediately before assessment of colonic sensation, i.e., after drug administration. This was performed because a previous study in healthy participants (12) showed that the level of arousal significantly influences the perception of colonic distension. Thus two 100-mm linear analog scales marked "tired-energetic" and "active-drowsy" were used to assess levels of arousal, whereas levels of stress were assessed using similar scales marked "peaceful-tense" and "worried-relaxed" (12).
Colonic Response to a Meal
As in previous studies (11), colonic tone and motility were assessed for 20 min before and 90 min after consuming a chocolate milkshake containing 1,000 kcal (35% carbohydrate, 53% fat, and 12% protein).Experimental Design
All subjects were admitted to the General Clinical Research Center at St. Mary's Hospital on the evening before the study for bowel preparation, comprising 1.5-2 liters of polyethylene glycol 3350 and electrolyte solution (OCL; Abbott Laboratories, Chicago, IL). This was drunk until the fecal effluent became a clear liquid. All volunteers signed informed consent forms and had a screening electrocardiogram to exclude significant rhythm disturbances or ischemia. Women of child-bearing potential underwent a plasma
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Thirty minutes after setting the operating pressure, fasting colonic tone was measured for 40 min: 20 min before and 20 min after drug administration. This recording of fasting colonic tone was followed by measurement of colonic compliance, sensation, and the response to a standard meal.
Data Analysis
Colonic compliance. In analyzing the compliance curve, we averaged the barostat balloon volume over a 30-s interval. Therefore, there are two data points for each pressure increment lasting 60 s. The volume-pressure relationship obtained during a pressure ramp is often nonlinear. Therefore, a linear model may not detect differences between different segments of the compliance curve. Other investigators have used several mathematical functions, including a cubic polynomial model to "fit" the nonlinear shape (25). We examined several alternative nonlinear models and found the best fit was provided by a power exponential model, in which the volume (Vol) at any given pressure (P) is defined as
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Colonic motor parameters. Phasic manometric pressure activity and changes in both pressure and volume of the barostat balloon were sampled as analog signals at 8 Hz and converted to digital signals before entry into a computer. As in previous studies, movement and respiratory artifact were filtered out using a modified VAX LAB filtering program (Ref. 11; Digital Equipment, Boston, MA). Thereafter, all data were analyzed by a customized computer program (11) that assessed phasic contractions and changes in the volume within the barostatically controlled balloon. On-line continuous recordings of all other parameters were similarly collected independent of the investigator.
For the manometric record, the waveform was initially smoothed using a high-frequency filter to remove instrumentation artifact. Thereafter, all contractions with a pressure change >10 mmHg amplitude above baseline, duration from 1.5 to 60 s, and an interpeak interval of >1.5 s were selected. These parameters are based on previous data showing that >98% of all colonic myoelectric activity has a frequency range of 1-11 minStatistical Analysis
Colonic tone and phasic activity were analyzed by similar methods. An overall comparison among groups for the various summary data values [e.g. colonic tone (baseline barostat volume), average motility index] was performed using an analysis of covariance adjusting for the predrug fasting values. For example, an analysis of covariance with the predrug mean fasting volume as a covariate was used to analyze the colonic response to the meal, which was expressed as the change between an average 20-min premeal value and a 90-min average value after the meal. In addition, five specific pairwise comparisons, between placebo and each of the four drugs, and between clonidine and yohimbine, were examined. Because saline and yohimbine were the only agents administered as a bolus followed by an infusion, a separate pairwise comparison between placebo and yohimbine was examined for a bolus vs. infusion effect using predrug values as a covariate.The analysis of sensation scores (pain and gas) over the multiple distending pressures [0 (i.e., operating pressure), 8, 16, 24, and 32 mmHg] was based on a mixed model analysis of variance with drug group and actual barostat volume as effect variables, and with gender, anxiety, depression, tension, and energy scores as covariates. An unstructured variance-covariance matrix was used to account for correlations among responses within the same subject at the multiple distending pressures.
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RESULTS |
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Patient Characteristics
Demographic features, anxiety and depression ratings, as well as stress and arousal scores are summarized in Table 1. Scores for energy and tension, which were measured after drug administration, tended to be lower in volunteers who received clonidine. Because of an error in the computerized data transfer process, we lost all data from the first patient randomized to clonidine. Technical problems precluded an assessment of predrug fasting colonic volume in one volunteer randomized to ritodrine and of colonic compliance, sensation, and the meal response in 4 of the 40 volunteers (2 received placebo, 1 each received yohimbine and phenylephrine).
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Drug Effects on Hemodynamic Parameters
As indicated in Table 2, all drugs produced noticeable and statistically significant effects on mean arterial blood pressure and/or heart rate. In six volunteers who received either phenylephrine or ritodrine, the infusion rate was reduced to maintain the heart rate within the predesignated safety limits, i.e., at a heart rate >45 min
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Effect of Drug on Fasting Colonic Tone and Phasic Activity
An overall drug effect on fasting colonic tone was observed (P = 0.02). Clonidine reduced fasting colonic tone (P = 0.016) compared with saline (Figs. 4 and 5). Clonidine and yohimbine had significantly different (P = 0.001) effects on colonic tone. Similar drug effects on fasting phasic motor activity were observed in the descending (Fig. 6A) and sigmoid (Fig. 6B) colon. In particular, clonidine decreased while yohimbine increased fasting phasic contractile activity in the descending and sigmoid colon.
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Because the overall comparison evaluated mainly the effects of a 20-min yohimbine infusion, we performed a separate pairwise comparison of bolus effects. The yohimbine bolus significantly reduced balloon volume, from 80.4 ± 12 to 68.2 ± 14.3 (SE) ml (P = 0.05), reflecting an increase in colonic tone when compared with saline bolus (predrug, 75.3 ± 8.4 ml; bolus, 72.1 ± 9 ml, P = NS). Moreover, we observed interindividual differences in the pattern of the tone response to yohimbine. Thus, in one volunteer, colonic tone increased dramatically during the bolus, with a recovery toward baseline during the infusion (Fig. 4). In four volunteers, the increase in tone during the bolus infusion was sustained or increased further during the infusion, whereas yohimbine did not affect colonic tone in one volunteer.
Fasting colonic tone and phasic activity were not altered by phenylephrine or ritodrine.
Effect of Adrenergic Agents on Colonic Compliance
For the compliance curves, the goodness of fit using a power exponential model (median r2 = 99.2%), defined by the parameters
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Effect of a Meal on Colonic Tone and Phasic Responses With Adrenergic Agents
The mean postprandial reduction in barostat balloon volume (consistent with increased colonic tone) for placebo was 40.8 ± 7.9% (SE). After adjusting for predrug values of balloon volume, these drugs did not significantly alter the tonic or phasic response to a meal when compared with placebo (Table 5). Phenylephrine and clonidine enhanced the magnitude of the phasic contractile to the meal response in the descending and sigmoid colon, respectively.
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Effect of Adrenergic Agents on Perception of Colonic Distension
For placebo, the median pain and gas scores were proportional to pressure applied during balloon distension (Fig. 7, A and B). Of the potential covariates assessed [that is, gender, and median sensation scores (VAS) for anxiety, depression, stress, and arousal], only the anxiety score was a significant covariate in the analysis of abdominal pain sensation. None of these covariates was significant for the feeling of gas. Clonidine significantly reduced, whereas yohimbine increased VAS scores for abdominal pain, but no significant drug effects on the feeling of gas during balloon distension were detected.
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DISCUSSION |
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This is the first study to comprehensively assess adrenergic modulation
of colonic motor and sensory function and compliance in healthy human
volunteers. Our data demonstrate that the
2-agonist clonidine reduces
fasting colonic tone and phasic activity, increases colonic compliance,
and markedly attenuates the perception of pain, but not gas during
colonic balloon distension. The marked hemodynamic and colonic effects
of clonidine indicate that, as predicted from the high bioavailability
and pharmacokinetic properties, the oral formulation was adequate for
the purposes of this study.
The 2-antagonist yohimbine
increased fasting colonic tone and enhanced colonic perception of pain,
but not gas. These drugs did not modify the overall colonic motor
(tonic and phasic) response to a meal. Finally, the
1-agonist phenylephrine and the
2-agonist ritodrine at the
doses used in this study (which were maximal permissible doses in
humans) did not affect colonic motor function, compliance, or
sensation.
The opposing effects of clonidine and yohimbine on fasting colonic tone
and sensation suggest that these effects are mediated via adrenergic
2-receptors. It is conceivable
that either central and/or peripheral imidazoline receptors
mediate some of the effects of clonidine, which has an imidazoline ring
structure (19). It is unlikely that the effects of yohimbine are
mediated via imidazoline receptors, since the
imidazoline-to-
2-affinity ratio for this compound is <1:100 (33). Similarly, studies in mice indicate
that the agonist properties of clonidine at adrenergic
1- and
H2 histaminergic receptors are
minimal, and they do not participate in the antidiarrheal effects of
clonidine (7). Yohimbine is predominantly an
2-antagonist; the
non-
2-effects of yohimbine at
adrenergic
1-, dopamine, and
serotonin receptors probably do not contribute significantly to its
effects at the dose employed in this study (15). Because both clonidine
and yohimbine cross the blood-brain barrier, we cannot distinguish between central or peripherally mediated effects; previous animal studies using the peripherally active
2-agonist ST-91, which does not
cross the blood-brain barrier (36), or intracerebroventricular clonidine (7) suggest that the gastrointestinal motor effects of
2-agonists are partly
peripherally mediated.
The opposing effects of clonidine and yohimbine on fasting colonic tone
are consistent with the recognized ability of
2-adrenergic receptor agonists
to inhibit acetylcholine release from neurons in the myenteric plexus
and from the parasympathetic pelvic plexus, thereby inhibiting
gastrointestinal motility (14). Thus
2-antagonists enhance baseline
colonic motility in cats (14). In contrast, the
2-agonists (either clonidine or
ST-91) inhibit defecation in mice (7), reduce baseline colonic
contractile activity in primates (26), and inhibit small intestinal and
colonic transit in human volunteers (30).
Several reasons may account for the interindividual variability in the
effects of yohimbine on fasting colonic tone. Plasma levels of
yohimbine and, consequently, norepinephrine are higher during a
yohimbine bolus than during a subsequent infusion (18). Interindividual
variations in baseline sympathetic tone may influence the response to
yohimbine. Indeed, the hemodynamic response to yohimbine is greater in
humans with a history of anxiety, depression, or other psychopathology
(16). Finally, Gillis et al. (14) observed that the increase in colonic
motility after nonspecific sympathetic blockade lasted for only 6 min,
indicating the possibility of tachyphylaxis. It is conceivable that
acetylcholine released from myenteric cholinergic neurons in response
to an 2-antagonist feeds back
to inhibit neuronal acetylcholine release, which in turn limits the
duration of enhanced contractility (14).
Clonidine did not attenuate the tonic or phasic colonic meal response,
suggesting that a physiological stimulus can overwhelm the inhibitory
effects of clonidine on fasting motor activity. Furthermore, it seems
unlikely that a reduction in
2-mediated sympathetic input,
as suggested by Dapoigny et al. (6), is the sole or major mechanism for
the colonic meal response. It is also conceivable that the failure of
clonidine to influence the meal response may have resulted from a
decline in plasma clonidine levels over the 2-h period that elapsed
between measurement of fasting and postprandial colonic tone. However,
we consider this unlikely, since systolic blood pressure remained
significantly lower than baseline throughout the postprandial period.
Our studies provide interesting insights on colonic compliance in humans. With the use of an infinitely compliant polyethylene balloon and a rigid barostat cylinder, the colonic pressure-volume curve is approximated by an exponential function. The barostat used in this study obviated the need to correct for the intrinsic compliance of a latex balloon which is nonlinear, or for the compliance of the rubber "bellows-type" barostat. The vast majority of papers have previously summarized gastric, colonic, and rectal pressure-volume relationships using either a linear or cubic polynomial function (11, 25). An exponential function provided the best fit to the actual data points in our study and, in contrast to the linear functions, can distinguish between the effects of placebo and clonidine on colonic compliance. An exponential function provides an opportunity to differentiate the initial component from the latter portions of the compliance curve. Also, in contrast to a linear function, the exponential function indicates that, within defined limits of pressure loads that apply in the in vivo setting, colonic volume reaches a near maximum and does not increase despite increases in balloon pressure.
Mertz et al. (23) suggested that "active" compliance,
representing muscular tone, and relaxation primarily contribute to the
pressure-volume relationship during the initial portion of the curve.
In contrast, the latter part of the curve at higher balloon pressures
reflects the viscoelastic properties of connective tissue and muscle,
i.e., "passive" compliance, which provides the primary resistance
to stretch. According to this hypothesis, pharmacological agents would
be anticipated to alter the initial but not the latter portion of the
compliance curve. The latter portion may be more clearly influenced by
fibrosis or inflammation, which change the colon's viscoelasticity.
The exponential model indicates that clonidine does not alter the
overall shape of the curve (or ), but does alter
, or
instantaneous slope of volume expressed against 1/pressure. A close
perusal of colonic compliance curves, as depicted in Fig.
3A, demonstrates an initial flat
portion, a transition to a steeper segment at an "inflection
point," and a flatter segment at the highest pressures tested.
Therefore, we selected the parameters
P10,
Phalf, and
Vmax to represent the initial,
middle, and latter portions of the compliance curve, respectively.
Although the P10 indicates a
leftward shift in the compliance curve (see Fig.
3B), it is important to note that
the instantaneous slope of the curve (
) is also significantly
altered by clonidine. Thus clonidine changes compliance both at low
pressures ("active compliance") and along the whole range of
pressures tested, possibly reflecting viscoelastic properties of the
colon. In contrast, clonidine did not change the maximum balloon volume
recorded during imposed pressures of 36 mmHg. This parameter,
Vmax, is similar for all agents,
suggesting that drug-related differences in active compliance are
unlikely to influence pressure-volume relationships at the highest
pressures tested.
The opposing effects of clonidine and yohimbine on balloon
distension-induced pain, but not gas sensation, were impressive. These
effects may result from a combination of drug effects on colonic tone
and/or nociceptive pathways. Clonidine reduced colonic tone and
sensation, whereas yohimbine increased colonic tone and sensation.
Similarly, colonic sensitivity also increases after a meal when tone is
generally increased (9). It has been hypothesized that alterations in
viscous tone alter sensitivity by altering the set point or threshold
of receptors in the gut wall (24). However, if the sensory effects of
clonidine and yohimbine were predominantly mediated by alterations in
tone, one would anticipate similar effects on gas and pain sensation,
since visceral receptors for noxious and nonnoxious sensation are
probably situated at similar levels in the gut wall. Therefore, our
data do not support a sensory effect mediated solely through changes in
tone but suggest a specific effect on afferent pathways. However, this
hypothesis deserves further study with in-depth dose-response studies
of 2-agents on colonic
sensation, motility, and tone.
There are several a priori reasons to support an effect of
2-agents on pain pathways
independent of changes in tone.
2-Receptors are situated at
multiple locations along the nociceptive pathway in the spinal cord,
brain stem, and forebrain (37); the antinociceptive properties of
clonidine in humans with somatic pain are well recognized (4).
Volunteers who received clonidine in our study tended to have lower VAS
scores for arousal and stress, suggesting an effect on the central
nervous system. However, clonidine did not induce sleep, and all
subjects receiving clonidine were awake throughout the studies. Further
experiments are required to determine whether central opioid receptors
might be involved in mediating the antinociceptive effects of clonidine
during colonic distension.
Neither phenylephrine nor ritodrine significantly altered colonic motor
or sensory function using a dose range modified according to recorded
hemodynamic parameters. Our findings are consistent with
observations in primates where the higher doses of phenylephrine >50 µg/kg were required to reduce colonic contractile frequency (26). Because of the risks of hemodynamically adverse consequences, we
were unable to use a higher dose in healthy subjects. It is possible
that higher doses that cannot be safely used in humans could alter
colonic tone and/or sensation. Although postsynaptic 2-receptors are found in the
cat colon (8), ritodrine did not modify colonic tone or sensation at
the dose that is known to relax uterine smooth muscle in humans (22).
Our experiments did not assess the effects of modulating
1-receptors that are found in
the cat colon (8) and inhibit primate colonic contractile activity
(26). The selective
1-antagonist metoprolol
increases sigmoid colonic pressure activity, and the effects of
selective
1-receptor modulation
on colonic physiology deserve further study (1).
In summary, these observations on colonic motor and sensory effects of
adrenergic agents suggest that
2-agents should be studied
further, including evaluation of their effects on transit and
sensation. Eventually, they may be useful additions to our therapeutic
armamentarium for patients with alterations in colonic motor and
sensory function such as irritable bowel syndrome.
2-Antagonists have been
successfully employed to date for managing paralytic ileus
[narcotic bowel syndrome (27)]. These and other potential indications, such as in the treatment of megacolon, require further study. Further studies are also needed to clarify the role of imidazoline receptors, the contributions of central vs. peripheral
2-receptors, and the role of
1-,
1-, and
3-receptors in modulating colonic motor and sensory function.
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ACKNOWLEDGEMENTS |
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We thank Dr. George Lawson and Ed Mansfield for assisting in the preparation of the intravenous solution of yohimbine and stability studies; Peggy Helwig, Julie Wiste, and George Thomforde for technical support; and Cindy Stanislav for typing and preparing the manuscript.
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FOOTNOTES |
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This study was supported in part by National Institutes of Health General Clinical Research Center Grant 00585 in support of the Physiology Laboratory and Patient Care Cores and by the Samsung Colonic Motility Research Fund at Mayo Foundation.
This work has been presented at the Annual Meeting of the American Gastroenterological Association in May 1996 (Gastroenterology 110: A633, 1996) and at the Biennial Meeting of the American Motility Society in September 1996 (Dig. Dis. Sci. 41: A16, 1996).
Address for reprint requests: M. Camilleri, Mayo Clinic, Gastroenterology Research Unit, 200 First St. SW, Rochester, MN 55905.
Received 16 January 1997; accepted in final form 15 July 1997.
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