Towards identifying optimal doses for alpha-2 adrenergic modulation of colonic and rectal motor and...

Towards identifying optimal doses for alpha-2 adrenergicmodulation of colonic and rectal motor and sensory function

A. MALCOLM*, M. CAMILLERI*, L. KOST*, D. D. BURTON*, S. L. FETT & ALAN R. ZINSMEISTER *Gastroenterology Research Unit, and Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, USA

Accepted for publication 14 December 1999

INTRODUCTION

Disorders of colorectal motor and sensory function are

thought to contribute to the symptoms of various

gastrointestinal diseases including functional bowel

disorders.1 Heightened sensitivity has been demonstrat-

ed in irritable bowel syndrome and reduced colonic

motility has been demonstrated in idiopathic constipa-

tion, pseudo-obstruction, neurological conditions such

as spinal cord injury, multiple sclerosis and Parkinson's

disease.1±6 Increased high amplitude colonic contrac-

tions are observed postprandially in irritable bowel

syndrome with predominant diarrhoea.7

Current therapy for these conditions is suboptimal;

future advances require mechanistic studies of the

neuromuscular apparatus of the colon. The adrenergic

nervous system provides extrinsic inhibitory control of

gut motility; visceral afferents synapse with dorsal horn

neurones and descending adrenergic and serotonergic

®bers in the spinal cord modulate dorsal horn neurones

which are the second order neurones in the 3-neurone

pathway mediating visceral sensation.8

Correction of colorectal motor or sensory dysfunction

may improve symptoms if selective therapies modulate

SUMMARY

Rationale: Visceral sensation and motility are important

in functional gut disorders and are partly controlled by

adrenergic innervation.

Objectives: To characterize the a2-adrenergic control of

motor and sensory function of descending colon and

rectum.

Methods: In 32 healthy volunteers, we assessed com-

pliance, fasting and postprandial tone, and sensations of

gas, urgency and pain during phasic distentions. Each

subject received one agent at clinically approved doses:

clonidine (0.05, 0.1, 0.2 or 0.3 mg p.o.); or the a2

antagonist yohimbine (0.0125 mg, 0.05 mg, 0.125 mg

or 0.2 mg intravenously and infusion over 2.5 h).

Results: Clonidine increased colonic and rectal compli-

ance, and reduced tone, pain, gas sensation and rectal

urgency. Clonidine showed large pairwise differences in

sensation and motility between 0.05 and 0.1 mg doses,

which did not interfere with the colon's motor response

to feeding. Conversely, yohimbine dose-dependently

altered the compliance curve, increased tone and

sensations of gas, pain and urgency. Drug effects in

the colon were more marked at low distensions;

a2 modulation of rectal sensation was observed at all

levels of distension.

Conclusions: a2-adrenergic mechanisms modulate colo-

rectal sensations and motility; at doses as low as

0.05 mg, clonidine reduced colorectal sensation while

the tone response to feeding was preserved. These

studies provide insight into the potential use of a2

agents in disease states.

Correspondence to: Dr M. Camilleri, Gastroenterology Research Unit, Al-

fred 2±435, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905,

USA.E-mail: [email protected]

Aliment Pharmacol Ther 2000; 14: 783±793.

Ó 2000 Blackwell Science Ltd 783

functions without deleterious effects on others. We have

previously demonstrated that, among a variety of

adrenergic agents active on receptor subtypes, the

a2-adrenergic agents, administered at maximal

approved doses, affect colonic and rectal motor and

sensory function.9, 10 Thus, clonidine, an a2-adrenergic

agonist, induces colonic and rectal relaxation and

reduces conscious perception of balloon distention in

the colon and rectum.9, 10 On the other hand, yohim-

bine, an a2-adrenergic antagonist, has been shown to

cause contraction of the rectum and to increase the

perception of balloon distention in the rectum.10

In this study, our aims were to characterize dose-

related effects of clonidine and yohimbine on colonic

and rectal motor and sensory function in healthy

human volunteers; this goal was intended to indicate

the optimal doses of each of the drugs to be used in

future studies in disease states. A second speci®c goal

was to evaluate the doses of clonidine that relieve pain

or gas perception during experimental distentions, while

preserving the ability of the colon to contract or

increase tone following meal ingestion.

MATERIALS AND METHODS

Healthy volunteers

Thirty-two healthy volunteers, aged 19±44 years (14

males, 18 females; mean age 29 years), were recruited

by public advertisement. None had undergone previous

gastrointestinal surgery; all had negative responses on

the Bowel Disease Questionnaire and normal responses

on the Hospital Anxiety and Depression Inventory, and

a normal clinical and physical examination and

electrocardiogram (EKG).11, 12 Women of childbearing

potential were required to have a negative pregnancy

test. The protocol was approved by the Mayo Institu-

tional Review Board, and written informed consent was

given in all cases.

Experimental design

All subjects were admitted to the General Clinical

Research Center on the evening prior to the study for

bowel cleansing with 2 L of polyethylene glycol and

electrolyte solution (OCL, Abbott Laboratories, Chicago,

IL) and overnight fast. Left-sided colonoscopy was

performed without sedation; a 4-meter Te¯on-coated

guidewire (Microvasive, Hobbs Medical, Stafford

Springs, CT) was placed with its tip at the splenic

¯exure and the colon was de¯ated as the colonoscope

was withdrawn. The colonic tube assembly was intro-

duced into the colon over the guidewire and positioned

under ¯uoroscopic control with the polyethylene bal-

loon (9-cm long cylinder with a maximum volume of

600 mL [Hefty Baggies, Mobil Chemical Company,

Pittsford, NY]) in the mid-descending colon. A second

balloon was then inserted into the rectum. Respiratory

excursions were continually recorded from a pneumo-

graph belt positioned around the lower chest. Blood

pressure was recorded at 30-min intervals during the

entire study. Patients lay in the right lateral position

during the study to avoid pressure on the descending

colon and rectum from surrounding organs.

After a `dummy' distention (ramp to 20 mmHg with

steps of 4 mmHg, 30 s), which has previously been

shown to enhance reproducibility of colorectal compli-

ance tests, the barostat operating pressures were set

(2 mmHg above the point at which respiratory variation

was noted).13 The entire experimental protocol is sum-

marized in Figure 1. After a 30-min wait, the levels of

sensory perception and compliance were measured,

followed by fasting tone (30-min period). The drug was

then administered, and post-drug tone (30 min), compli-

ance and perception were reassessed. Tone was assessed

for 30 min pre-meal and 1 h following a 1000 kcal

liquid, high-fat (50%) meal. Sensation and compliance

were again measured 1 h after the meal was ingested.

Colonic and rectal motor function

Tone of the colon was measured as in previous

studies.14

Figure 1. Experimental protocol.

784 A. MALCOLM et al.

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 783±793

Testing colonic and rectal compliance

Colonic and rectal compliance were assessed as the

volume response to 2 mmHg increments in intraballoon

pressures at 30-s intervals from 0 to 24 mmHg above

operating pressure. The rigid piston barostat used in this

study (Distender Series II, G & J Electronics, Toronto,

Canada) has almost zero intrinsic compliance.

Testing colonic and rectal sensation

Subjects received a standardized information sheet prior

to sensation testing; thereafter there was minimal inter-

action between subject and investigator. Sensation was

assessed by responses recorded on a visual analogue scale

during rapid phasic distentions of 8, 16 and 24 mmHg

above operating pressure performed in a randomized

order. Each distention lasted 60 s and was followed by a

rest period at the operating pressure, also lasting 60 s.

Ratings of sensory perception were assessed at a

standardized time, 30 s after the onset of the distention.

The subject was asked to record perception on three

100 mm visual analogue scales for the feeling of gas and

pain during colonic distensions, and for urgency, gas and

pain during rectal distensions. The visual analogue

scales were anchored at each end by the descriptions

`none' and `worst possible'. This approach to measuring

visceral perception has previously been shown to be

responsive to variations in stimulus, psychosensory

state, and pharmacological modulation.9, 10, 15

Clonidine and yohimbine administration

Clonidine was administered p.o. because it is > 99%

bioavailable, Tmax is around 60 min, and plasma

levels are high for at least 4 h after p.o. ingestion.

Yohimbine was administered as i.v. bolus and infu-

sion in order to maintain a constant plasma level,

because intravenous yohimbine has a short half life

(3±5 min). The doses used are over a range where

effect has been seen in previous studies, and in

addition an investigational drug permit was obtained

from the United States Food and Drug Administration

to also use yohimbine at a dose just above that which

has been used in previous gastrointestinal physiolog-

ical studies in order to obtain wider dose response

data. Table 1 shows the number of subjects in each

treatment arm and the doses of clonidine and

yohimbine given.

Data analysis

Colonic and rectal motor parameters. Barostat balloon

volume and pressure activity for colon and rectum

were sampled as analogue signals at 8 Hz and

converted to digital signal before being recorded on a

computer. A modi®ed VAX LAB ®ltering program

(Digital Equipment Corporation, Boston, MA) was used

to record and identify phasic activity. Phasic volume

peaks recorded by the barostat balloon occur at a

frequency of < 3 per minute;14 therefore, waveform

frequencies of > 6 cpm were ®ltered out by a computer

program to separate baseline balloon volume from

phasic volume events. Colonic and rectal tone are

assessed by the level of colonic or rectal barostat

balloon baseline volume.

Colonic and rectal compliance. The volume±pressure

relationships de®ning colonic or rectal compliance are

Table 1. Participant characteristics

Drug Dose

Gender

number (M:F) Age Anxiety* Depression*

Clonidine 0.05 mg 3 1:2 31.0 � 4.9 2.7 � )1.2 2.7 � )1.2

Clonidine 0.1 mg 5 1:4 27.8 � 3.7 3.8 � )1.0 0.8 � )0.4

Clonidine 0.2 mg 5 2:3 25.8 � 2.7 1.1 � )0.5 0.4 � )0.2

Clonidine 0.3 mg 3 2:1 23.7 � 2.7 2.7 � )1.2 2.0 � )1.5

Yohimbine 0.0125 mg 3 1:2 36.7 � 4.9 2.7 � )0.3 1.0 � )0.6

Yohimbine 0.05 mg 5 3:2 27.4 � 3.0 4.8 � )0.7 3.2 � )0.8

Yohimbine 0.125 mg 5 3:2 30.8 � 4.2 3.2 � )1.3 2.0 � )0.8

Yohimbine 0.2 mg 3 1:2 31.0 � 6.5 4.3 � )0.9 3.0 � )0.6

Data are mean + S.E.M.

* Anxiety and depression ratings based on Hospital Anxiety and Depression Scale, where

scores < 7, 8±10 and > 10 represent normality, indeterminate and de®nite anxiety or

depression, respectively.

a2 -ADRENERGIC CONTROL OF HUMAN COLON 785


nonlinear and were analysed as in previous studies

using a power exponential model:9

Pvol � R� expfÿ�k� rP�bg

where rP is reciprocal pressure (1/pressure), Pvol is the

proportionate volume (vol/Vmax, Vmax is the maximum

volume in the compliance assessment) and R is the

estimated minimal proportionate volume. The summary

parameters estimated for this model of compliance,

k (slope) and b (overall shape of the curve), were used to

calculate Pr1/2, the pressure producing half maximum

volume on the pressure±volume curve.

Colonic and rectal sensation. Sensation scores for gas,

urgency and pain were analysed separately; an addi-

tional analyses used the aggregate (mean) of pain and

gas sensation scores in the colon and an aggregate

(mean) sensation of gas, urgency and pain scores for

analysis of rectal sensation.

Statistical analysis

We examined the pre-drug differences in tone, com-

pliance and sensation among the four dosage groups

for each drug using the Kruskal±Wallis test. Overall

drug effects were assessed by comparing pre-drug and

post-drug values using the Wilcoxon signed rank test.

In order to adjust for minor differences in baseline

response values, we adjusted for pre-drug values (and,

in the analysis of tone, for body mass index) by

incorporating these as covariates in the analysis of

dose level effects on post-drug and post-meal measure-

ments using an analysis of covariance. The analysis of

sensation scores was based on a (mixed-model)

repeated measures analysis incorporating pre-drug

sensation score, volumes corresponding to each speci®c

distention level, and the corresponding pressure and

order of distention. To facilitate individual pairwise

comparisons among dosage groups, the (adjusted for

baseline values) mean (and 95% con®dence intervals)

was computed for tone and sensation scores. The (least

squares estimated) mean values of the compliance

parameters (adjusted for baseline values) were used to

construct mean dosage group compliance curves to

graphically summarize drug effects on colonic and

rectal compliance. In situations where overall dose

effects were detected, the Tukey adjustment for mul-

tiple pairwise comparisons amongst speci®c doses was

used.

RESULTS

Patient characteristics

Demographic features and hospital anxiety and de-

pression ratings are summarized in Table 1. Post-drug

data could not be fully evaluated in three patients for

technical reasons (blocked pressure port in the baro-

stat, leak in the barostat balloon, or a kinked tube).

These three subjects were receiving yohimbine at

doses of 0.05 mg (n � 1), 0.125 mg (n � 1) and

0.2 mg (n � 1). Prior to the studies, the participants

who had been randomized to the yohimbine group

had higher depression scores (P � 0.03, 2-sample t-

test) and somewhat higher anxiety scores (P � 0.07,

2-sample t-test) compared to the participants in the

clonidine group; however, none of the scores were in

the range associated with clinically signi®cant affective

disorder.

Effects of a2-adrenergic agents on colonic and rectal tone

Clonidine (Figure 2). There were no differences in the

pre-drug balloon volumes (tone) among the different

dosage levels of clonidine. Post-drug, there was an

overall relaxation of colonic tone (P < 0.01) relative to

pre-drug (Wilcoxon signed rank test). Meal ingestion

resulted in a reduction in volume relative to pre-meal.

Clonidine relaxed rectal tone (P < 0.01, Wilcoxon

signed rank test) during fasting. The meal induced a

reduction in balloon volumes (increase in tone) in the

colon and rectum (P < 0.01 for both sites, Wilcoxon

signed rank test).

After adjusting for the pre-drug volume and body mass

index, as a means to compensate for differences in

colonic and rectal dimensions (since these were signi®-

cant covariates), there was a signi®cant overall dose-

related effect (P < 0.05) on the colon's tone (increase in

volume) following administration of the drug. The

largest pairwise difference in volumes for the colon

was between the 0.05 mg (mean 79 mL, 95% con®d-

ence interval 64, 97) and 0.1 mg (mean 124 mL, 95%

con®dence interval 107, 145) doses (P < 0.05, Tukey

adjustment).

Yohimbine (Figure 2). There were no differences in the

pre-drug balloon volumes among the different dosage

levels of yohimbine. Overall, yohimbine resulted in

signi®cantly lower colonic and rectal balloon volumes



(increased tone) in the post-drug vs. pre-drug fasting

and post-meal vs. pre-meal periods (all P < 0.01,

Wilcoxon signed rank test). After adjusting for the

pre-drug volume (a signi®cant covariate), we observed a

tendency for dose-related effects on the post-drug

volume in the colon (P � 0.06).

Figure 2. Overall effects of several doses of clonidine and yohim-

bine on colonic and rectal tone. Note that clonidine increases

balloon volumes post-drug and pre-meal, consistent with reduced

tone; the meal results in an increase in tone (reduction in balloon

volume) in the colon and rectum. Conversely, yohimbine reduces

balloon volume, and meal ingestion results in a further reduction,

consistent with increased tone. Data show mean �95% con®dence

intervals; overall (doses), the post-drug and post-meal effects of

both drugs are statistically signi®cant.

Figure 3. Dose-related effects of clonidine on colonic compliance

post-drug (left) and post-meal (right). In the range tested, there

was a signi®cant difference between effects of 0.05 and 0.1 mg

clonidine on colonic compliance; no overall dose responsiveness

was noted post-drug or post-meal. Data show least square means,

incorporating pre-drug compliance curve parameter estimates at

each dose level.



Effects of a2-adrenergic agents on colonic

and rectal compliance

The ®t of the power exponential model across all studies

resulted in a median R2 of 0.992 (with 10th and 90th

percentiles of 0.972 and 0.999, respectively). No pre-

drug differences in compliance were detected in the

dosage levels for the two drugs.

Clonidine (Figure 3). Clonidine induced an overall

increase in colonic and rectal compliance as shown by

decreased j and Pr1/2. Speci®cally, clonidine had an

overall post- vs. pre-drug (pre-drug Pr1/2 � 16.1;

post-drug Pr1/2 � 11.6; P < 0.01) effect on rectal

compliance, but no dose effect was detected. The only

dose-related effect of clonidine identi®ed was a signi®-

cant dose effect on Pr1/2 estimates in the colon after the

meal (P < 0.05), adjusting for pre-drug compliance and

body mass index.

Yohimbine (Figure 4 [colon] and Figure 5 [rectum]).

Overall, yohimbine did not change compliance charac-

teristics, however we observed subtle dose-related

changes in the initial shape of the compliance curve

(b value) in the colon post-drug (P � 0.02) and in the

rectum post-drug (P � 0.05) and post-meal (P < 0.01).

Effects of a2-adrenergic agents on colonic

and rectal sensation

Clonidine (Tables 2 [overall] and 3 [dose-related effects]).

There were no differences in the pre-drug sensation

scores among the different dosage levels of clonidine. In

the colon, there were lower gas and aggregate gas and

pain scores post-clonidine in response to distention

with 8 mmHg (P < 0.01), but not at higher distention

levels. After adjusting for pre-drug sensation score,

volume, pressure, and order of distention, there was an

overall dose effect in the colon (Table 3) for aggregate

gas and pain post-drug (P � 0.01) and post-meal

(P � 0.04).

Figure 4. Dose-related effects of yohimbine on colonic compliance

post-drug (left) and post-meal (right). There were signi®cant dose-

related effects of yohimbine on the estimated b parameters of the

compliance curves (P � 0.02), but not on j or Pr1/2 parameters.

The ®gure shows curves constructed from least square means,

incorporating the pre-drug compliance curve parameter estimates

at each dose level.



In the rectum, pooling dose groups, clonidine signi®-

cantly decreased (Table 2) aggregate scores of gas,

urgency, and pain at all levels of distention (P < 0.05 for

8 and 24 mmHg; P < 0.01 at 16 mmHg). A borderline

signi®cant dose-related effect of clonidine was observed

in the rectum (Table 3) during the post-drug period for

gas scores (P � 0.06), but not for urgency or pain.

Yohimbine (Tables 4 [overall] and 5 [dose-related effects]).

Sensation scores during pre-drug assessment were

similar among the different yohimbine dosage groups

except for pain scores in the colon at 8 mmHg

distention (P � 0.03, unadjusted for multiple compar-

isons). Overall, the changes in colon sensation (pre vs.

post, Table 4) at each distention level indicated consis-

tently higher scores post-drug for both pain and gas,

and the aggregate (average score). Similar results

(Table 4) were observed in the rectum for gas, urgency,

pain, and the aggregate (average score). The speci®c

signi®cant changes are noted in Table 4.

After adjusting for the signi®cant covariates (pre-drug

sensation scores, the individual volumes corresponding

to each speci®c distention level, the speci®c pressure,

and the order of distention), we observed signi®cant

dose-related increases in colonic sensation of gas

(P < 0.01), pain (P < 0.01), and the aggregate (aver-

age score [P � 0.06] with yohimbine). These were

especially evident in the post-meal period (P < 0.01 for

gas, P < 0.005 for pain, P < 0.005 for average gas and

pain, respectively). Higher doses of yohimbine tended to

increase the sensation scores (Table 5) in both the colon

and the rectum, in particular post-drug and post-meal

rectal urgency.

DISCUSSION

This study shows that the a2-adrenergic system alters

motor and sensory function of the human colon and

rectum in healthy individuals. These studies also

indicate threshold levels for the dose-related effects on

some of the motor and sensory functions of the colon

and rectum. With clonidine, it appears that a signi®cant

dose-related pairwise difference is observed between the

0.05 and 0.1 mg doses. These dose-related effects of

clonidine on perception scores are not associated with

major differences in the relaxation of the colon, nor on

the ability of the colon to increase tone postprandially.

Therefore, we would consider a dose of 0.05 mg optimal

for ongoing studies of clonidine, given this dose has the

lesser potential to cause haemodynamic side-effects in

patients.

Clonidine lowered gas and pain sensation in the colon

at low levels of distension during fasting and postpran-

Figure 5. Dose-related effects of yohimbine on rectal compliance

post-drug (left) and post-meal (right). Yohimbine dose-relatedly

altered the b parameter of the rectal compliance curves post-drug

(P � 0.05) and post-meal (P < 0.01). There were no effects on jor Pr1/2. Data show least square means, incorporating the pre-

drug compliance curve parameter estimates at each dose level.



dially. These data expand on the previous observations

from our lab showing that 0.3 mg clonidine p.o.

reduced pain sensation during colonic distention, but

failed to signi®cantly alter gas sensation.9 The current

experiments explored a broader range of distentions and

a wider dosage range. The current data suggest that the

sensory effect of clonidine is not restricted to pain since

clonidine dose-dependently reduced aggregate colonic

sensation. Moreover, clonidine reduced rectal sensations

of urgency, gas and pain at all levels of rectal disten-

sion. These observations con®rm the importance of

a2-adrenergic mechanisms in the control of colorectal

sensation and suggest a potential role for clonidine in

the treatment of hypersensitivity or hypercontractile

states in the colorectum, such as in patients with

diarrhoea-predominant irritable bowel syndrome or

colonic autonomic neuropathy. These conditions are,

respectively, associated with rectal hypersensitivity and

with increased prevalence of high amplitude propagated

colonic contractions in the post-meal period which

induce rectal urgency and diarrhoea.3, 7

The effects of yohimbine, which induced higher gas

and pain scores in the colon, and gas, pain and

urgency scores in the rectum during all three levels of

8 mmHg 16 mmHg 24 mmHg

Colon

Gas 1.5 (0.5, 2.4)** 0.2 ()0.3, 0.8) )0.1 ()0.8, 0.6)

Pain 0.3 (0.0, 0.6) 0.2 ()0.6, 0.9) 0.5 ()0.3, 1.2)

Aggregate (gas and pain) 0.9 (0.3, 1.4)** 0.2 ()0.3, 0.7) 0.2 ()0.2, 0.6)

Rectum

Gas 0.9 ()0.5, 2.4) 0.8 (0.0, 1.7) 0.4 ()0.5, 1.3)

Urgency 0.8 (0.0, 1.6) 1.2 (0.5, 1.9)** 0.5 ()0.4, 1.4) Pain 0.3 ()0.1, 0.7) 0.7 ()0.1, 1.5) 0.8 ()0.3, 1.8)

Aggregate (gas, urgency, pain) 0.7 (0.0, 1.4)* 0.9 (0.3, 1.5)** 0.6 ()0.1, 1.2)*

* P < 0.05; ** P < 0.01; P < 0.1, from Wilcoxon signed rank test (pre-drug vs. post-drug),

unadjusted for multiple comparisons. Positive values indicate clonidine reduced sensation

scores.

Table 2. Overall effect of clonidine on

change in sensation (VAS, cm) in colon and

rectum during isobaric distentions. Mean

differences (pre-post-drug) and (95% con-

®dence interval)

Table 3. Dose-related effect of clonidine on sensation (VAS, cm) in colon and rectum (mean, 95% con®dence interval)

0.05 mg 0.1 mg 0.2 mg 0.3 mg

Post-drug effect of clonidine on sensation during fasting

Colon

Gas 1.9 (1, 2.8) 1.6 (0.9, 2.4) 1.5 (0.7, 2.2) 0.5 (0, 1.4)

Pain 0.2 (0, 0.6) 0.3 (0, 0.7) 0.5 (0.1, 0.8) 0.3 (0, 0.8)

Aggregate (gas and pain)* 1.6 (1.1, 2.2) 1.0 (0.5, 1.4) 0.8 (0.4, 1.2) 0.2 (0, 0.7)

Rectum

Gas 2.7 (1.6, 3.8) 1.3 (0.4, 2.1) 2.2 (1.3, 3.1) 1.1 (0, 2.2)

Urgency 4.9 (3.8, 6.0) 4.4 (3.5, 5.2) 4.8 (4.0, 5.6) 3.8 (2.7, 4.9)

Pain 0.7 (0.3, 1.0) 0.8 (0.5, 1.1) 0.5 (0.2, 0.9) 0.6 (0.2, 0.9)

Aggregate (gas, urgency, pain) 2.9 (2.2, 3.7) 2.2 (1.6, 2.7) 2.3 (1.7, 2.8) 2.0 (1.2, 2.7)

Post-meal effect of clonidine on sensation

Colon

Gas 0.9 (0, 2.1) 2.0 (1.0, 3.0) 1.6 (0.6, 2.5) 0.2 (0, 1.4)

Pain 0.4 (0, 0.7) 0.3 (0, 0.6) 0.3 (0, 0.6) 0.3 (0, 0.7)

Aggregate (gas and pain)* 0.3 (0, 1.0) 1.4 (0.9, 2.0) 0.8 (0.3, 1.4) 0.3 (0, 1.1)

Rectum

Gas 2.6 (1.5, 3.7) 1.2 (0.4, 2.1) 1.5 (0.6, 2.3) 1.1 (0, 2.3)

Urgency 5.3 (3.6, 7.0) 4.9 (3.6, 6.3) 4.2 (2.9, 5.5) 4.5 (2.8, 6.3)

Pain 0.5 (0, 1.0) 0.6 (0.1, 1.1) 0.6 (0.1, 1.1) 0.5 (0, 1.0)


* P < 0.05; P < 0.1; overall test for dose effects from repeated measures analysis (see text).



distention, also argue strongly for the role of the

a2-adrenergic system in control of colorectal sensation.

The therapeutic potential of a2-adrenergic antagonists

in increasing colonic tone is probably greater than the

observed effects on sensation. The results of the

compliance curve changes with yohimbine are consis-

tent with the increases in baseline tone, since the bparameter, a measure of the initial shape of the

pressure±volume curve, was altered, not the (k slope)

or Pr1/2. The latter appears to re¯ect the elastic

properties of the smooth muscle hollow organs and

these are unaltered by yohimbine. These effects of

yohimbine on tone need to be further evaluated in the

context of acute or chronic colonic pseudo-obstruction

or megacolon. Yohimbine could also be used poten-

tially as a pharmacological model for colorectal

hypersensitivity. Given the dose±response relationship

seen and the lack of haemodynamic side-effects, the

Table 5. Dose-related effect of yohimbine on sensation (VAS, cm) in colon and rectum (mean, 95% con®dence interval)

0.0125 mg 0.05 mg 0.125 mg 0.2 mg

Effect of yohimbine on sensation during fasting

Colon

Gas** 2.3 (1.7, 3.0) 3.5 (3.0, 4.0) 3.1 (2.7, 3.6) 4.2 (3.6, 4.8)

Pain** 0.8 (0.1, 1.6) 1.0 (0.4, 1.6) 2.8 (2.2, 3.4) 1.8 (1.1, 2.6)

Aggregate (gas + pain) 1.8 (1.0, 2.5) 2.3 (1.8, 2.8) 2.9 (2.4, 3.5) 2.9 (2.2, 3.5)

Rectum

Gas 2.9 (0.4, 5.5) 4.1 (2.2, 6.0) 3.0 (1.2, 4.9) 4.6 (2.2, 7.0)

Urgency** 5.9 (5.3, 6.6) 7.4 (6.9, 7.9) 6.8 (6.3, 7.3) 6.9 (6.3, 7.5)

Pain* 1.1 (0, 2.6) 2.8 (1.6, 3.9) 2.2 (1.1, 3.4) 4.5 (3.1, 6.0)


Effect of yohimbine on sensation postprandially

Colon

Gas** 0.9 (0, 2.8) 4.7 (3.0, 6.4) 2.5 (1.0, 4.0) 6.8 (4.4, 9.1)

Pain** 0 (0, 1.4) 2.3 (1.1, 3.5) 1.5 (0.3, 2.6) 5.7 (3.7, 7.7)

Aggregate (gas and pain)** 1.2 (0, 2.8) 3.3 (1.9, 4.6) 1.7 (0.5, 3.0) 6.4 (4.4, 8.3)

Rectum

Gas 3.2 (0, 6.6) 4.2 (1.5, 6.8) 3.4 (0.8, 6.0) 5.3 (1.9, 8.6)

Urgency* 3.9 (2.2, 5.6) 7.5 (6.2, 8.8) 6.8 (5.6, 8.1) 6.9 (5.4, 8.5)

Pain 1.0 (0, 2.2) 1.8 (0.9, 2.7) 2.6 (1.8, 3.5) 2.7 (1.6, 3.9)


*P < 0.05; **P < 0.01; P < 0.1, Overall test for dose effects from the repeated measures analysis (see text).

Table 4. Overall effect of yohimbine on

change in sensation (VAS, cm) in colon and

rectum during isobaric distentions

Mean differences (pre-post-drug) and (95% con®dence interval)

8 mmHg 16 mmHg 24 mmHg

Colon

Gas )0.5 ()1.1, 0.2) )1.4 ()2.3, )0.5)** )1.0 ()1.9, )0.1) Pain )0.6 ()1.3, 0.1) )0.8 ()1.6, 0.1)* )0.8 ()1.5, 0.0)*

Aggregate

(gas and pain)

)0.6 ()1.1, 0.0)* )1.1 ()1.7, )0.5)** )0.9 ()1.4, )0.3)**

Rectum

Gas )1.1 ()2.2, 0.0) )0.2 ()1.3, 0.9) )1.6 ()2.7, )0.5)**

Urgency )1.0 ()1.7, )0.3)** )0.4 ()1.1, 0.3) )0.7 ()1.2, )0.3)**

Pain )0.6 ()1.2, 0.0)* )1.9 ()3.0, )0.9)** )1.4 ()2.3, )0.5)**

Aggregate

(gas, urgency, pain)

)0.9 ()1.4, )0.4)** )0.8 ()1.2, )0.4)** )1.2 ()1.8, )0.6)**

*P < 0.05; **P < 0.01; P < 0.1, from Wilcoxon signed rank test (pre-drug vs. post-drug),

unadjusted for multiple comparisons. Negative values indicate yohimbine aggravated

(increased) score of sensation.



higher doses of yohimbine may be considered in future

studies.

The current studies do not provide suf®cient detail to

de®ne the ED50 for clonidine or yohimbine's effects on

colonic or rectal motor and sensory functions or

induction of megacolon or pseudo-obstruction in view

of the normal meal response. It is unclear whether the

differences in clonidine's effects on descending colonic

and rectal tone imply differences in a2-adrenergic

control of the two regions. Since yohimbine's dose-

related effects were very similar in the two regions, the

hypothesis of differential regional control by a2-adren-

ergic neurones seems unlikely.

The increase in sensory perception with increasing

dose of yohimbine suggests that, at levels that would

increase colonic tone, it is likely that yohimbine would

increase perception of colonic stimuli. Nevertheless, it is

conceivable that yohimbine might have a therapeutic

potential, as in acute post-operative ileus or acute

colonic pseudo-obstruction, when reversal of colonic

relaxation or distention is clinically indicated. Such a

pharmacologic approach could be advantageous, since

it may avoid the need for colonic decompression by

colonoscopy. The increase in rectal sensation observed

with yohimbine is also worthy of further study in

conditions associated with rectal sensory de®cits such as

in patients with diabetes mellitus and faecal incontin-

ence unassociated with external anal sphincter dener-

vation.16, 17

In fact, the effects of a2-adrenergic agents on colonic

motor and sensory function need to be further explored

in the context of neurological disorders which may

affect extrinsic afferent and efferent supply to the colon

and rectum. Such diseases include Parkinsonism

[especially those variants associated with autonomic

dysfunction such as Parkinson's plus or multiple

system atrophy (Shy±Drager's syndrome)], multiple

sclerosis, and diabetic autonomic neuropathy.18±20

The role of sympathetic adrenergic dysfunction in

non-neurologic disorders is currently unclear, though

other authors have suggested that sympathetic dys-

function is associated with diarrhoea-predominant

irritable bowel syndrome or slow transit constipa-

tion.21, 22

In summary, these in-depth studies indicate a poten-

tially important, hitherto disregarded and clinically

unexploited mechanism which may signi®cantly alter

the functions of the human colon and rectum. Our

data argue strongly for the continuation of the in-

depth study of the a2-adrenergic mechanism, its role in

colorectal diseases, and its potential as a modulator of

colorectal sensory and motor functions. Such studies

may lead to signi®cant advances in therapy with

agents that are already approved for use in humans

and that have known and generally acceptable toxicity

pro®les.

ACKNOWLEDGEMENTS

Dr Malcolm was funded by the Mayo-Janssen Advanced

Fellowship in GI Motility; Dr Camilleri is funded by NIH

grants 1RO1-DK54681±01 and 1K24±02638±01. This

study was also supported in part by NIH General

Clinical Research Center grant #RR00585 (Physiology

Core).

We thank Mrs. Cindy Stanislav for typing this

manuscript.

This work was presented at the Annual Meeting of the

American Gastroenterological Association in May,

1997 (Gastroenterology 1997; 112: A780).

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