Adrenergic modulation of human colonic motor
and sensory function
ADIL E. BHARUCHA,1 MICHAEL CAMILLERI,1
ALAN R. ZINSMEISTER,2 AND RUSSELL B. HANSON1
1Gastroenterology Research Unit and 2Section of Biostatistics, Mayo Clinic,
Rochester, Minnesota 55905
Bharucha, Adil E., Michael Camilleri, Alan R. Zins-
meister, and Russell B. Hanson. Adrenergic modulation of
human colonic motor and sensory function. Am. J. Physiol.
273 (Gastrointest. Liver Physiol. 36): G997–G1006, 1997.—
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 cloni-
dine, 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 disten-
sions delivered in random order. Clonidine reduced and
yohimbine increased fasting, but not postprandial tone, by
63.2 6 22.3% and 24.8 6 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 in-
creased colonic perception of pain but not gas sensation
during distension. Phenylephrine and ritodrine did not influ-
ence colonic motor or sensory function in the present studies.
Thus a2-receptors modulate fasting colonic tone and compli-
ance and alter perception of pain but not gas during mechani-
cal stimulation of the colon.
colonic tone; sensation; compliance
SYMPATHETIC STIMULATION is one of the putative mecha-
nisms of paralytic ileus and even isolated colonic pseudo-
obstruction (13). Conversely, pharmacological sympa-
thetic blockade increases colonic motility in animals
(14), and some patients with diabetic autonomic neu-
ropathy have diarrhea that is attributable to loss of the
‘‘sympathetic brake.’’ Clonidine, an a2-agonist, can ame-
liorate diabetic diarrhea (10); the precise mechanisms
for this beneficial clinical response are unclear.
a2-Agonists probably slow gut transit by enhancing
a2-mediated fluid and electrolyte absorption (30) and by
inhibiting fasting and postprandial small intestinal
contractile activity (35, 36). However, the effects of a2-
and other adrenergic receptors on gut neuromuscular
function in vivo require further elucidation. For ex-
ample, the effects of pharmacological modulation of a2-
and other adrenergic receptor subtypes on colonic
motor and sensory function in humans are unknown. In
addition to the effects of a2-agents, the a1- and b2-
receptors may also contribute to the overall effects of
the sympathetic brake, since the a1-agonist phenyleph-
rine and the b2-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, fast-
ing 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 co-
lonic meal response in primates (6).
The role of the adrenergic nervous system in media-
tion or modulation of colonic sensation in humans is
unclear. a2-Receptors are found along nociceptive path-
ways 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 (a2-agonist), yohimbine (a2-
antagonist), phenylephrine (a1-agonist), and ritodrine
(b2-agonist) on colonic motility, compliance, and sensa-
tion in healthy human volunteers. We have not yet
studied the b2-system with an antagonist, since a
selective b2-antagonist is unavailable for human stud-
ies.
MATERIALS AND METHODS
Healthy Volunteers
Forty healthy volunteers, aged 18–45 yr (mean 6 SE, 29 6
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 cholecystec-
tomy). None was taking medications with the exception of
acetaminophen or oral contraceptives. A clinical interview
and physical examination were performed to exclude signifi-
cant 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 partici-
pants 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 medica-
tion. 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 medica-
tion or placebo, either intravenous or oral. As control or
0193-1857/97 $5.00 Copyright
r
1997 the American Physiological Society G997

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 demon-
strated 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 administra-
tion to humans in the United States; however, the bioavailabil-
ity 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. Cardio-
vascular 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. Yohim-
bine was administered as an initial 0.125-mg/kg intravenous
bolus over 5 min followed by an infusion at 0.06 mg·kg21 ·h21.
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 a1-agonist, causes peripheral venoconstric-
tion, an increase in blood pressure, and reflex bradycardia. An
initial dose of 0.4 µg·kg21 ·min21 given intravenously was
titrated upward in 0.4 µg·kg21 ·min21 increments at 10-min
intervals until the systolic blood pressure increased by 20
mmHg, or until a maximum infusion rate of 2.5 µg·kg21·min21
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 hypoten-
sion in conditions such as hypovolemic or septic shock (21).
Ritodrine. Ritodrine (Abbott, Abbott Park, IL), a selective
b2-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 recom-
mended for inhibiting uterine contractions in preterm labor,
that is, 150–350 µg/min (22).
The effects of phenylephrine and ritodrine on fasting
colonic motor function were measured for 20 min after the
target systolic blood pressure and heart rate, respectively,
were achieved.
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 descend-
ing colon with the aid of flexible sigmoidoscopy and fluoros-
copy. The intraballoon pressure at which respiratory excur-
sions 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 inter-
vals 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 vis-
ceral compliance may differ after an initial distension se-
quence 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 in-
creased 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 per-
formed as rapid, intermittent ‘‘phasic’’ increases in intra-
balloon pressure in four steps of 8, 16, 24, and 32 mmHg
greater than the operating pressure. The order of distensions
G998 ADRENERGIC EFFECTS IN HUMAN COLON