Role of hepatic
- and
-adrenergic receptor stimulation
on hepatic glucose production during heavy exercise
Robert H.
Coker,
Mahesh G.
Krishna,
D. Brooks
Lacy,
Deanna P.
Bracy, and
David H.
Wasserman
Department of Molecular Physiology and Biophysics and Diabetes
Research and Training Center, Vanderbilt University School of Medicine,
Nashville, Tennessee 37232
 |
ABSTRACT |
The role of catecholamines in the control of
hepatic glucose production was studied during heavy exercise in dogs,
using a technique to selectively block hepatic
- and
-adrenergic
receptors. Surgery was done >16 days before the study, at which time
catheters were implanted in the carotid artery, portal vein, and
hepatic vein for sampling and the portal vein and vena cava for
infusions. In addition, flow probes were implanted on the portal vein
and hepatic artery. Each study consisted of a 100-min equilibration, a
30-min basal, a 20-min heavy exercise (~85% of maximum heart rate), a 30-min recovery, and a 30-min adrenergic blockade
test period. Either saline (control; n = 7) or
(phentolamine)- and
(propranolol)-adrenergic blockers
(Blk; n = 6) were infused in the
portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE)
were infused in the portal vein during the blockade test period to
create supraphysiological levels at the liver. Isotope ([3-3H]glucose)
dilution and arteriovenous differences were used to assess hepatic
function. Arterial Epi, NE, glucagon, and insulin levels were similar
during exercise in both groups. Endogenous glucose production
(Ra) rose similarly during
exercise to 7.9 ± 1.2 and 7.5 ± 2.0 mg · kg
1 · min
1
in control and Blk groups at time = 20 min. Net hepatic glucose output
also rose to a similar rate in control and Blk groups with exercise.
During the blockade test period, arterial plasma glucose and
Ra rose to 164 ± 5 mg/dl and
12.0 ± 1.4 mg · kg
1 · min
1,
respectively, but were essentially unchanged in Blk. The attenuated response to catecholamine infusion in Blk substantiates the
effectiveness of the hepatic adrenergic blockade. In conclusion, these
results show that direct hepatic adrenergic stimulation does not
participate in the increase in Ra,
even during the exaggerated sympathetic response to heavy exercise.
catecholamine; adrenergic blockade; endogenous glucose production
 |
INTRODUCTION |
MOST INVESTIGATIONS into the regulation of hepatic
function during exercise have addressed mechanisms that are operative
at moderate intensities (~50% maximum oxygen uptake). Under these conditions, hepatic glucose production
(Ra) is controlled by the exercise-induced changes in plasma glucagon and insulin (25). Glucoregulation during heavy exercise may be much different. It has
been postulated that catecholamines are the primary regulators of the
increase in Ra during heavy
exercise. This is based on the fact that during heavy exercise,
catecholamines may increase 10- to 15-fold, while arterial glucagon may
increase, remain the same, or even decrease, and arterial insulin
levels may be unchanged (6, 16). Although this correlation analysis is
consistent with the possibility that catecholamines may be important
during heavy exercise, studies attempting to establish causality have been uniformly negative. Attenuation of sympathetic nerve activity to
the liver and adrenal medulla, using anesthesia of the celiac ganglion,
does not affect Ra during
high-intensity exercise (~75% maximum oxygen uptake) (11). A second
study showed that liver transplant patients (presumably free of hepatic
innervation) have a normal glucose production response to
high-intensity exercise (~82% maximum oxygen uptake) (12). Finally,
-adrenergic blockade actually results in an exaggerated increase in
Ra during exercise at 100%
maximum oxygen uptake in healthy subjects (24). These studies were
informative and added greatly to our knowledge but were complicated by
the use of a patient population or by the nonspecific effects of the
methods used to study catecholamine action.
The aim of this study was to examine the effect of the catecholamines
on Ra during heavy exercise, using
a selective hepatic adrenergic receptor blockade technique that
produces only minimal extrahepatic effects. This method utilizes the
infusions of the
- and
-adrenergic blockers, phentolamine and
propranolol, respectively, into the hepatic portal vein of chronically
catheterized and instrumented conscious dogs exercising at a high
intensity.
 |
METHODS |
Animals and surgical procedures.
Experiments were performed on a total of 13 overnight-fasted mongrel
dogs (mean wt 21.5 ± 0.5 kg) of either sex that had been fed a
standard diet (Pedigree beef dinner and Wayne Lab Blox; 51%
carbohydrate, 31% protein, 11% fat, and 7% fiber based on dry wt).
The dogs were housed in a facility that met American Association for
the Accreditation of Laboratory Animal Care guidelines, and the
protocols were approved by the Vanderbilt University Animal Care
Subcommittee. At least 16 days before each experiment, a laparotomy was
performed under general anesthesia (0.04 mg/kg atropine and 15 mg/kg
pentobarbital sodium presurgery; 1.0% isoflurane inhalation anesthetic during surgery). An incision in the neck region
allowed the isolation of the carotid artery, into which a Silastic
catheter (0.04 in. ID) was inserted and advanced to the aortic arch for
sampling and hemodynamic measurements during experiments. Silastic
catheters (0.03 in. ID) were inserted into the vena cava for infusion
of indocyanine green and
[3-3H]glucose. Last, a
Silastic catheter (0.03 in. ID) was inserted into the splenic vein and
positioned so that the catheter tip rested just beyond the point where
the splenic and portal veins coalesce. This catheter was used for the
intraportal infusions of phentolamine and propranolol and the infusion
of catecholamines during the final period of the experiment. Catheters
were inserted into the portal vein and hepatic vein for blood sampling
purposes. Ultrasonic transit time flow probes were fitted and secured
to the portal vein and hepatic artery (Transonic Systems, Ithaca, NY).
The knotted catheter ends and Transonic probe leads were stored in a
subcutaneous pocket in the abdominal region (except for the carotid
artery catheter, which was stored in a pocket under the skin of the
neck) so that the complete closure of the skin incisions was possible.
At 7 days after surgery, dogs were acclimatized to running on a
motorized treadmill, with the intensity of the exercise progressively increased. Each animal underwent a treadmill test to determine the work
rate at which ~85% of maximum heart rate was achieved. Dogs were not
exercised 48 h before the experiment. Maximum heart rate was assumed to
equal 270 beats/min, based on the work of Musch et al. (18) and Ordway
et al. (20). Blood samples were drawn 3 days before the experiment to
determine the leukocyte count and the hematocrit of the animal. Only
animals with 1) a leukocyte count
below 18,000/mm3,
2) a hematocrit above 36%,
3) a good appetite (consumption of daily food ration), and 4) normal
stools were used.
All studies were conducted in dogs after an 18-h fast. The free
catheter ends and flow probe leads were accessed through small skin
incisions made under local anesthesia (2% lidocaine; Astra Pharmaceutical Products, Worcester, MA) in the abdominal and neck regions on the morning of the experiment. Catheters were then aspirated
and flushed with saline. The exposed catheters were connected to
Silastic tubing, which was secured to the back of the dog with
quick-drying glue.
Experimental procedures.
Experiments consisted of a tracer and dye equilibration period
(
130 to
30 min), basal period (
30 to 0 min), heavy
exercise period (0 to 20 min), recovery period (20 to 50 min), and
catecholamine infusion period (50 to 80 min). A primed (50 µCi)
infusion (0.30 µCi/min) of
[3-3H]glucose was
initiated at time (t) =
130
min and continued throughout the study. The tracer infusion rate was
increased by 2.5-fold during the heavy exercise period to minimize
changes in glucose specific activity in the non-steady state. After
completion of the exercise period, the
[3-3H]glucose infusion
rate was returned to the basal rate, at which point it remained for the
remainder of the study. A constant-rate indocyanine green infusion (0.1 mg · m
2 · min
1)
was also started at t =
130 min
and continued throughout the study. Indocyanine green was used as a
backup method of blood flow measurement if the Doppler probes did not
provide a clear signal and as confirmation of hepatic vein catheter
placement. There was no Doppler flow probe failure in these studies.
Two protocols were performed (Fig.
1). In the blockade
protocol, the
- and
-adrenergic receptor blockers, phentolamine
and propranolol, were infused intraportally from
t =
50 to 80 min at rates of 2 and 1 µg · kg
1 · min
1,
respectively. To test the effectiveness of the blockade, norepinephrine and epinephrine were infused at rates of 0.40 and 0.20 µg · kg
1 · min
1,
respectively, from t = 50 to 80 min.
In the control protocol, animals were handled and prepared identically
except that vehicle alone (saline and ascorbate) was infused. Heart
rates were monitored by a transducer connected to the carotid arterial
catheter.

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Fig. 1.
Heavy exercise protocol utilizing hepatic adrenergic blockade and
control groups. * Epinephrine and norepinephrine were infused
into the portal vein at rates of 0.20 and 0.40 µg · kg 1 · min 1,
respectively. ** Isotope infusion was increased 2.5-fold during
exercise [time (t) = 0-20
min]. *** Phentolamine and propranolol were infused into
the portal vein at rates of 2 and 1 µg · kg 1 · min 1,
respectively, from t = 50 to 80 min.
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Blood sample collection and processing.
Arterial blood samples were drawn every 5 min during the basal period
and at 1- and 2.5-min intervals during the first 5 and the last 15 min
of heavy exercise, respectively. Arterial blood samples were drawn
every 5 min during the recovery and blockade test periods. Portal vein
and hepatic vein blood samples were drawn every 10 min during the basal
period, every 5 min during the exercise period, at 10 and 30 min of the
recovery period, and every 10 min during the blockade test period.
Plasma glucose concentrations were determined by the glucose oxidase
method, using a Beckman Glucose Analyzer (Beckman Instruments, Fullerton, CA). For the determination of plasma glucose radioactivity, samples were deproteinized with barium hydroxide and zinc sulfate and
centrifuged. The supernatant was then evaporated to remove 3H2O
and reconstituted in 1 ml water and 10 ml scintillation fluid [Ecolite (+); ICN Biomedicals, Irvine, CA]. Radioactivity
was determined on a Beckman liquid scintillation counter. Blood samples were deproteinized (0.5 ml blood in 1.5 ml of 4% perchloric acid), and
whole blood lactate, alanine, and glycerol concentrations were
determined, using standard enzymatic methods (13), on a Monarch 2000 Centrifugal Analyzer (Lexington, MA). Free fatty acids (FFA) were
measured with the use of the Wako FFA C test kit (Wako Chemicals,
Richmond, VA) on the centrifugal analyzer. Immunoreactive insulin was
measured, using a double-antibody procedure (interassay coefficient of
variation of 16%) (17). Immunoreactive glucagon (3,500 mol wt) was
measured in plasma samples containing 500 kallikrein inhibitory units
(KIU)/ml Trasylol (FBA Pharmaceuticals, New York, NY),
using a double-antibody system modified from the method developed by
Morgan and Lazarow (17) for insulin. Plasma samples for norepinephrine
and epinephrine were collected into tubes containing ethylene
glycol-bis(
-aminoethyl
ether)-N,N,N',N'-tetraacetic acid and glutathione, centrifuged at 4°C, and stored at
70°C for subsequent analysis, using high-performance liquid
chromatography. Catecholamine concentrations were calculated based on
linear regression, using dihydroxybenzylamine as an internal standard.
With the use of this method, the coefficients of variation were 5 and
7% for norepinephrine and epinephrine, respectively. Plasma cortisol was measured with the Clinical Assays Gamma Coat radioimmunoassay kit
(Travenol-Gene Tech Diagnostics, Cambridge, MA) with an interassay coefficient of variation of 6%.
Materials.
[3-3H]glucose was
obtained from NEN (Boston, MA). Glucagon and
125I-labeled glucagon were
obtained from Novo Research Institute (Copenhagen, Denmark). Standard
insulin and 125I-labeled insulin
were obtained from Linco Research (St. Louis, MO). Indocyanine green
was purchased from Hynson, Westcott, and Dunning (Baltimore, MD).
Enzymes and coenzymes for metabolite analyses were obtained from
Boehringer Mannheim Biochemicals and Sigma Chemical.
Calculations.
Net hepatic lactate balance (NHLB), net hepatic alanine uptake (NHAU),
and net hepatic glucose output (NHGO) were determined according to the
formula HAF × ([A]
[H]) + PVF × ([P]
[H]), such that
[A], [P], and [H] are the arterial,
portal vein, and hepatic vein substrate concentrations, and HAF and PVF
are the hepatic artery and portal vein blood flows. Hematocrits were
measured at each multiple catheter sampling point to correct for
changes in red cell volume. The sign was reversed for the calculation of NHGO so that net output would be a positive number. Endogenous Ra was calculated, using the
two-compartment approach described by Mari (14). Changes in specific
activity were minimized during the exercise period by increasing the
infusion rate of
[3-3H]glucose by
2.5-fold to increase the accuracy of the
Ra calculation (19).
Statistical analysis.
Superanova (Abacus Concepts, Berkeley, CA) software installed on a
Macintosh Power PC was used to perform statistical analysis. Statistical comparisons between groups and over time were made, using
analysis of variance designed to account for repeated measures. Time
points were specifically examined for significance, using contrasts
solved by univariate repeated measures. Statistics are reported in the
corresponding table or figure legend for each variable. Data are
presented as means ± SE for seven control and six hepatic
adrenergic blockade dogs. Statistical significance was defined as
P < 0.05.
 |
RESULTS |
Arterial epinephrine and norepinephrine
concentrations.
Catecholamine values for five of the seven control experiments have
been published previously (4). Plasma epinephrine rose (P < 0.05) in control experiments
from 165 ± 41 to 530 ± 100 pg/ml at 20 min of exercise. In the
blockade group epinephrine levels were not different
(P > 0.05) from controls, increasing
from 207 ± 27 to 495 ± 85 pg/ml at 20 min of exercise (Fig.
2). Plasma norepinephrine increased
(P < 0.05) from 416 ± 96 to
1,093 ± 182 pg/ml at 20 min of exercise in control experiments and
from 365 ± 68 to 1,109 ± 258 pg/ml at 20 min of exercise in the
blockade group (Fig. 2). There was no difference in the exercise
response between groups. No significant differences were noted in
plasma epinephrine or norepinephrine between the groups during recovery or the blockade test period.

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Fig. 2.
Arterial plasma epinephrine (A) and
norepinephrine (B) during basal,
exercise, recovery, and blockade test periods. Values are significantly
increased for both hormones from basal at
t = 5, 10, 15, and 20 min of exercise.
Data are means ± SE; n = 7 dogs
for control and n = 6 dogs for
blockade.
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Arterial insulin, glucagon, and cortisol
concentrations.
No significant differences in plasma insulin were noted between the two
groups throughout the basal, exercise, or recovery periods. However,
plasma insulin was significantly higher in the control group compared
with the blockade group because of hyperglycemia during the blockade
test period (Fig. 3). Plasma glucagon rose similarly in both groups during exercise and was not significantly different between groups throughout the remainder of the experiment (Fig. 3). Plasma cortisol was higher in the blockade group compared with the control group during the basal period
(P < 0.05). Otherwise, there was no
significant difference between protocols (Table
1).

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Fig. 3.
Arterial plasma insulin (A) and
glucagon (B) during basal, exercise,
recovery, and blockade test periods. Data are means ± SE;
n = 7 dogs for control and
n = 6 dogs for blockade.
* P < 0.05 difference between
the 2 groups.
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Arterial glucose concentration and
kinetics.
Arterial plasma glucose was similar in both control and blockade groups
during the basal, exercise, and recovery periods. During the blockade
test period, arterial plasma glucose was greater (P < 0.05) in the control group
(164 ± 5 mg/dl at t = 60 min) than the blockade group (126 ± 4 mg/dl at
t = 60 min; Fig.
4). NHGO was also similar in both groups
during the basal, exercise, and recovery periods. During the blockade
test period, NHGO was greater (P < 0.05) in the control group (8.5 ± 3.3 mg · kg
1 · min
1
at t = 60 min) compared with the
blockade group (3.0 ± 0.9 mg · kg
1 · min
1
at t = 60 min; Fig. 4).
Ra rose similarly from 3.1 ± 0.2 and 3.0 ± 0.2 mg · kg
1 · min
1
during the basal period to 7.9 ± 1.2 and 7.5 ± 2.0 mg · kg
1 · min
1
at 20 min of exercise in the control and blockade groups, respectively. Ra was also similar during the
recovery periods. However, Ra was higher (P < 0.05) during the
blockade test period in the control group (10.9 ± 1.2 mg · kg
1 · min
1
at t = 60 min) compared with the
blockade group (4.1 ± 0.3 mg · kg
1 · min
1
at t = 60 min; Fig.
5).

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Fig. 4.
Arterial plasma glucose (A) and net
hepatic glucose output (B) during
basal, exercise, recovery, and blockade test periods. Data are means ± SE. Arterial glucose: n = 7 dogs
for control and n = 6 dogs for
blockade. Net hepatic glucose output:
n = 7 dogs for control and
n = 5 dogs for blockade.
* P < 0.05 difference between
the 2 groups.
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Fig. 5.
Endogenous glucose production
(Ra) during basal, exercise,
recovery, and blockade test periods. Data are means ± SE;
n = 7 dogs for control and
n = 6 dogs for blockade.
* P < 0.05 difference between
the 2 groups.
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Arterial lactate concentrations and
NHLB.
Mean basal arterial lactate was less in the control group (478 ± 58 µmol/l) than in the blockade group (674 ± 150 µmol/l). Arterial lactate rose to a significantly greater level in
the control group (1,315 ± 75 µmol/l at
t = 20 min) than the blockade group
(881 ± 84 µmol/l at t = 20 min)
during the exercise period. Arterial lactate remained elevated
(P < 0.05) in the control group during the recovery period. Arterial levels during the blockade test
period were not different between the two groups (Fig.
6). NHLB in both control and blockade
groups shifted similarly from net uptake during the basal period to net
output during exercise. NHLB was similar during the recovery and
blockade test periods in the control and blockade groups (Fig. 6).

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Fig. 6.
Arterial blood lactate (A) and net
hepatic lactate balance (B) during
basal, exercise, recovery, and blockade test periods. Data are means ± SE. Arterial lactate: n = 7 dogs
for control and n = 6 dogs for
blockade. Net hepatic lactate balance:
n = 7 dogs for control and
n = 5 dogs for blockade.
* P < 0.05 difference between
the 2 groups.
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Arterial alanine concentrations and
NHAU.
Arterial alanine was higher in the control group at
t =
30 min and during the
recovery period (P < 0.05). No
significant differences were present during the blockade test
period between the two groups (Fig. 7).
NHAU was less (P < 0.05)
in the control group (1.4 ± 0.3 µmol · kg
1 · min
1
at t = 20 min) than the blockade group
(3.6 ± 0.7 µmol · kg
1 · min
1
at t = 20 min) during exercise. No
significant differences in NHAU were seen during the recovery or
blockade test periods (Fig. 7).

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Fig. 7.
Arterial blood alanine (A) and
hepatic alanine uptake (B) during
basal, exercise, recovery, and blockade test periods. Data are means ± SE. Arterial alanine: n = 7 dogs
for control and n = 6 dogs for
blockade. Hepatic alanine uptake: n = 7 dogs for control and n = 5 dogs for
blockade. * P < 0.05 difference between the 2 groups.
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Arterial FFA and glycerol
concentrations.
Arterial FFA was significantly higher in the blockade group at
t = 20 min during the
exercise period. Otherwise, both FFA and glycerol levels responded
similarly in the two groups (Table 1).
Heart rate and blood flow.
Heart rate increased by 118 ± 7 and 121 ± 3 beats/min at 20 min
of exercise in the control and blockade groups, respectively (Fig.
8). Heart rate did not increase during the
blockade test period in either group, indicating that splanchnic escape
of the catecholamines was minimal. Blood flow measurements for five of the seven control experiments have been published previously (4). Hepatic artery blood flow was less (P < 0.05) in the control group (5 ± 1 ml · kg
1 · min
1)
compared with the blockade group (11 ± 1 ml · kg
1 · min
1)
during the basal period. Hepatic artery blood flow was also less
(P < 0.05) during the recovery
period in the control group. However, there was no significant
difference in hepatic artery blood flow between the two groups during
the exercise and blockade test periods (Table
2). In contrast, portal vein blood flow was higher (P < 0.05) in the control
group compared with the blockade group during exercise and
the blockade test period (Table 2). Total hepatic blood flow was not
significantly different between the two groups during the course of the
experiment.

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Fig. 8.
Heart rate during basal, exercise, recovery, and blockade test periods.
Data are means ± SE; n = 7 dogs
for control and n = 6 dogs for
blockade.
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 |
DISCUSSION |
The results of this study demonstrate that the exercise-induced
increment in Ra is not critically
dependent on adrenergic receptor stimulation during heavy exercise. The
use of frequent sampling, arteriovenous difference techniques, and
improved tracer methods coupled with local delivery of
- and
-adrenergic blockers to the liver permitted a more precise
assessment of the role of catecholamines during exercise. These
findings in the dog support studies conducted in humans that failed to
show an effect of catecholamines on
Ra during heavy exercise (11, 12,
24). The attenuation of sympathetic nerve activity to the liver and
adrenal medulla, using celiac ganglion blockade during heavy exercise
(~75% maximum oxygen uptake), did not affect
Ra (11). In addition, liver
transplant patients who are free of hepatic innervation have a normal
Ra response to heavy exercise
(~82% maximum oxygen uptake) (12). Last, systemic infusion of a
-adrenergic blocker, propranolol, does not attenuate the rise in
Ra during exercise at 100% of
maximum oxygen uptake
(
O2 max) (24). The interpretation
of these previous studies was complicated by the use of a patient population or by the nonspecific nature of the methods used to prevent
hepatic adrenergic stimulation. The present study provides strong
support for the assertion that catecholamine actions mediated through
hepatic adrenergic receptors do not play an essential role in mediating
the increase in Ra during heavy
exercise. This conclusion is supported by a study in the
adrenalectomized rat that showed that the breakdown of hepatic glycogen
during high-intensity exercise was independent of epinephrine
replacement (15).
Previous studies have shown that the fall in insulin and the increase
in glucagon are the major determinants of the increase in
Ra during moderate exercise (25).
In the present study, heavy exercise resulted in similar arterial
glucagon and insulin levels in both the control and blockade groups. It
is important to recognize that the glucagon levels in the portal vein
to which the liver is mainly exposed increase considerably more than
those in the artery (26). It is noteworthy, however, that
Ra still increases during cycling
in humans in whom systemic glucagon and insulin were clamped at basal
levels, using the pancreatic clamp technique (23). These investigators
deduced indirectly from these studies that catecholamines must be
important. This conclusion contrasts with results obtained when they
tried to assess catecholamine action directly, using
-adrenergic
blockade during heavy exercise.
The potential for the catecholamines to stimulate
Ra is dependent on their levels at
the liver. This is determined by catecholamine delivery via the
circulation and/or sympathetic nerve activity (norepinephrine).
The gut extracts ~50% of the plasma catecholamine concentration
delivered to it by the blood during rest and heavy exercise (4). This
results in portal vein levels that are ~50% of the arterial
epinephrine levels. Plasma norepinephrine concentration in the portal
vein remains comparable to arterial levels, despite gut norepinephrine
extraction, because of sympathetic innervation of the gut and spillover
of norepinephrine into the portal vein. In addition, marked increases
in hepatic norepinephrine spillover during heavy exercise show that
sympathetic drive to the liver is increased (4). Even though
norepinephrine levels at the liver are higher than epinephrine levels,
the effectiveness of norepinephrine in stimulating
Ra is 30-fold less than that of epinephrine in the dog (5). Thus the reason that adrenergic stimulation
is less effective in stimulating
Ra during heavy exercise than has
previously been postulated (16) is that arterial epinephrine levels
overestimate those at the liver and norepinephrine is less effective
compared with epinephrine in stimulating
Ra.
The hepatic adrenergic blockade was designed to achieve completeness
and selectivity. That the hepatic adrenergic blockade was virtually
complete was shown by the attenuation of the rise in
Ra in the blockade group during
the portal vein infusion of catecholamines.
Ra increased approximately
threefold during the catecholamine infusion in the control group. In
contrast, Ra was unchanged in the
blockade group during the catecholamine infusion period. Other
differences in the blockade and control groups (circulating glucose and
insulin) are probably secondary to the higher
Ra during the blockade test in
controls. That the hepatic adrenergic receptor blockade was largely
selective to the liver was demonstrated by similar glycerol and FFA
responses during exercise in the present study. Local sympathetic
nervous activity elicits fat mobilization (10), whereas the blockade of
sympathetic nerves attenuates glycerol and FFA responses to heavy
exercise (11). In addition, catecholamines have marked effects on
pancreatic hormone secretion. The similar glucagon and insulin
responses in both groups further support that the extrahepatic effects
of the portal vein adrenergic blocker infusion are small. Peripheral
-adrenergic receptor blockade of the pancreas would increase insulin
secretion, whereas
-adrenergic blockade would decrease insulin
secretion (21, 22). In addition, an
- and/or
-adrenergic
blockade would be expected to attenuate the increase in glucagon during
exercise (22). Thus the local delivery of adrenergic blockers to the
liver did not seem to affect pancreatic hormone secretion. The local
nature of the hepatic blockade is also seen by the equal heart rate
responses to exercise in both groups, since blockade of
-adrenergic
receptors by propranolol has been shown to decrease heart rate during
exercise by 60% (1). Portal vein administration of adrenergic blockers
localizes their action to the liver, and their efficient extraction by
the liver reduces their systemic effects (9). In addition, the local irrigation of the liver with adrenergic blockers allows the infusion rate to be markedly reduced over that utilized during peripheral infusion. Therefore, it is likely that only small amounts of the adrenergic blockers are available to extrahepatic tissues.
Although the hepatic adrenergic blockade was far more selective than
could be obtained by using conventional approaches, there was still
evidence that there may be systemic effects of the blockers. During
heavy exercise, arterial lactate was higher in the control group than
the blockade group. Because net hepatic balance of lactate was similar
in both groups, lactate formation must be reduced or lactate clearance
must be greater in the blockade group at an extrahepatic site.
2-Adrenergic receptors mediate
the epinephrine-stimulated increase in glycogenolysis and, by doing so,
stimulate muscle lactate release (7). It may be that enough propranolol
is escaping from the splanchnic bed to attenuate this response.
NHAU fell during heavy exercise in controls. This decrease may be due
to a potent stimulation of hepatic glycogenolysis and glycolytic flux
during short-term (27), high-intensity exercise. This could decrease
NHAU by causing an opposing increase in alanine efflux from the liver.
Evidence for an increase in hepatic glycolytic flux is seen by the
parallel increase in net hepatic lactate output. It is unlikely that
NHAU is decreased because of a direct stimulation of the A transport
system, which mediates hepatic membrane alanine transport, since
glucagon, its major endocrine agonist (2), is increased. A surprising
finding was that hepatic adrenergic blockade prevented the fall in NHAU
during heavy exercise. This implies that the fall in NHAU is mediated,
in some way, by hepatic adrenergic stimulation. It is hard to relate
this effect of adrenergic stimulation to an overall effect on hepatic
glycogenolysis and glycolysis, since net hepatic glucose and lactate
output responses were still intact. Regardless, it is unlikely that the
greater NHAU in the blockade group could have had a major effect on
Ra by providing more substrate for
the gluconeogenic pathway. This is because the increase in
Ra during short-term exercise is
due to an increase in hepatic glycogenolysis (25), and the additional carbon due to the differences in NHAU is small relative to the increment in Ra.
Another interesting finding was the increased basal arterial cortisol
response in the blockade group compared with the control group. This
difference was not present during exercise. The stimulatory effect of
intraportal blocker administration on basal cortisol levels suggests
that hepatic afferents may play a role in the regulation of cortisol
secretion. It is unlikely that this increase in cortisol had a
significant impact on the interpretation of this short study, since
cortisol must remain elevated for a longer duration to have metabolic
effects (8). Even if increased cortisol levels were studied over an
extended time period, the relative importance would probably be minor,
since the hormone serves to enhance the capacity for gluconeogenesis
and glycogen synthesis, neither of which operates at high rates during
heavy exercise. In addition to basal cortisol levels, blood flow
distribution was also altered by intraportal blocker administration.
Although the total hepatic blood flow was the same in the two groups,
portal vein blood flow made up 82 and 63% of the total blood flow in the control and blockade groups, respectively. It is conceivable that
the increased blood flow in the hepatic artery may be due to
phentolamine entering the systemic circulation and the adrenergic blockade of
-receptors, which cause vasoconstriction. The decrease in portal vein blood flow may be compensatory for the increase in
hepatic artery blood flow. It is important to recognize that the
exercise-induced blood flow responses were similar in the two groups.
The metabolic effects of this redistribution in blood flow, if any,
will require further investigation.
The present study utilizes rapid arterial sampling, arteriovenous
difference techniques, improved tracer methodology, and a selective
hepatic adrenergic receptor blockade to determine the role of the
catecholamines in control of hepatic glucose output during heavy
exercise. The effectiveness of the hepatic adrenergic blockade was
illustrated by the demonstration that the blockade eliminated the
increases in Ra and NHGO resulting
from a combined norepinephrine and epinephrine challenge. Minimal
extrahepatic effects of the adrenergic blockade are supported by the
similar insulin, glucagon, glycerol, FFA, and heart rate responses to heavy exercise in control and adrenergic blockade groups. In
conclusion, under conditions in which glucagon, insulin, and plasma
glucose levels are equal, the Ra
and NHGO responses to heavy exercise are unaffected by hepatic
adrenergic receptor blockade. This demonstrates that the catecholamines
do not play an essential role in mediating the increase in
Ra during heavy exercise.
 |
ACKNOWLEDGEMENTS |
We are grateful to Pamela Venson, Eric Allen, Wanda Snead, Robert
Allison, and Thomas Becker for excellent technical assistance.
 |
FOOTNOTES |
This work was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Grant R01-DK-50277.
Address for reprint requests: R. H. Coker, Dept. of Molecular
Physiology and Biophysics, Vanderbilt Univ. School of Medicine,
Nashville, TN 37232.
Received 11 March 1997; accepted in final form 7 July 1997.
 |
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