Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3
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ABSTRACT |
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Intestinal glucose uptake (GUi) from blood
increased when blood flow (BF) was increased. The increase in BF could
elevate shear stress. Therefore, we hypothesize that shear
stress-induced release of autacoids mediates the increase in
GUi. A surgically separated
segment of small intestine was perfused in situ with the use of an
arterial circuit in anesthetized cats. Arterial and portal blood
samples were taken simultaneously for assessment of
GUi. Adenosine was used to elevate
intestinal BF. The GUi increased by 45.0 ± 18.3 from 25.3 ± 3.8 µmol · min1 · 100 g tissue
1 when the BF
increased about four times. It was not a direct effect of adenosine
because GUi was not altered if the
flow was held constant. This increase was blocked by a cyclooxygenase
inhibitor, indomethacin, but not by nitric oxide synthase blocker
NG-nitro-L-arginine
methyl ester. Furthermore, prostaglandin
F2
(PGF2
) but not
PGE2 or
PGI2 reversed the blockade of the increase in GUi after indomethacin
during elevated blood flow, whereas they had no influence on basal
uptake. The results suggest that shear stress-induced release of
PGF2
mediated the increase in
GUi when blood flow was elevated.
shear stress; superior mesenteric artery; nitric oxide; indomethacin; prostaglandin E2
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INTRODUCTION |
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ALTHOUGH THE GUT SERVES to regulate the absorption of glucose and other nutrients, few studies have addressed how the intestine regulates its own energy metabolism. Substances such as glutamine (26) and some digested products including glucose (21) are important energy sources for intestinal tissues. Increasing evidence suggests that the intestine is not only important for glucose absorption; it may also be important in the disposal of glucose in basal and postingestive states. Abumrad et al. (1) reported that the gut utilized up to 25% of net hepatic glucose output in basal states and up to 15% of the glucose load in the postabsorptive state in conscious dogs. The intestinal mucosa was found to be a quantitatively important site of action of metformin, an antihyperglycemic agent, to increase glucose utilization (2).
The mechanism that controls intestinal glucose uptake and metabolism is not known. Kellett et al. (14) indicated that normal intestinal glucose metabolism is not insulin concentration dependent, although the presence of insulin seems necessary. Xie and Lautt (27) found that insulin has no effect on net glucose balance in extrahepatic splanchnic tissues, mainly the gut, and that a hepatic insulin-sensitizing substance released by the liver similarly did not affect the gut. These results are consistent with a previous report that hyperglycemia and hyperinsulinemia had no effect on extrahepatic splanchnic tissue glucose uptake (9).
We recently reported (13) that the inhibitory metabolic actions of adenosine (Ado) on intestinal oxygen consumption were antagonized by shear stress-induced nitric oxide (NO), an effect that was seen only when blood flow was allowed to increase. As an index of preparation status we also monitored glucose uptake at several time points. Glucose uptake appeared to increase in the presence of vasodilation but only when blood flow was allowed to rise. Based on this preliminary observation, a hypothesis that increased intestinal glucose uptake is mediated by shear stress-induced release of autacoids, such as NO or prostaglandins, during high-flow perfusion was formulated and tested in this study.
The results demonstrated that intestinal glucose uptake increased when
blood flow was raised. The increased intestinal glucose uptake was
blocked by a cyclooxygenase inhibitor, indomethacin, but not by the NO
synthase blocker
NG-nitro-L-arginine
methyl ester (L-NAME) at a dose
(2.5 mg/kg) previously shown to block intestinal shear stress induction
of NO release (19). In addition, the blockade of increased intestinal glucose uptake by indomethacin could be reversed by prostaglandin F2
(PGF2
), suggesting that shear
stress-induced release of PGF2
mediated the increase in intestinal glucose uptake when blood flow was elevated.
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METHODS |
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Surgical preparation. Fifteen cats (either gender, 3.7 ± 0.1 kg) in three groups were fasted for 18 h (overnight) but allowed free access to water. The animals were anesthetized with pentobarbital sodium (32.5 mg/kg ip). Anesthesia was maintained by continuous infusion (~0.5 ml/min, 0.78 mg/ml of pentobarbital sodium in saline) through a brachial venous cannulation. Supplemental anesthetics (6.5 mg) and fluid (10% Dextran 40 intravenous solution mixed with equal volume of saline) were also given when required. Body temperature was monitored and maintained at 37.0 ± 0.5°C with the use of a thermally controlled surgical table (model 72, Yellow Springs Instruments, Yellow Springs, OH). The respiration was mechanically assisted (Harvard Apparatus, Millis, MA). Systemic arterial and central venous pressures were monitored by left carotid arterial and right femoral venous cannulation, respectively. All pressures were monitored by pressure transducers (Gould and Statham, Gould, Oxnard, CA) that had been set to zero at the level of the central vena cava.
After a midline incision of the abdomen, the spleen and large intestine, including ascending, transverse, and part of the descending colon, were surgically removed. The inferior mesenteric artery and vein were ligated, and the upper end of the intestinal segment was ligated at the duodenum. The superior mesenteric nerve plexus was surgically denervated. The superior mesenteric artery (SMA) was ligated and cannulated. A pump-controlled vascular circuit (Masterflex, Cole Parmer Instrument, Barrington, IL) that acquired blood from the abdominal aorta by a double aortic cannulation perfused the small intestine through the SMA cannula (13). The animals were heparinized (200 IU/kg) before the vascular circuit was established. The pump rate was controlled to generate a circuit pressure that was similar to systemic pressure. Two venous catheter units (24G, Optiva, Johnson & Johnson Medical, Arlington, TX) were placed into the portal vein for monitoring portal venous pressure and for blood sampling. The flow rate was measured with a flow-through electromagnetic flow probe (EP608, Carolina Medical Electronics, King, NC) that was incorporated into the circuit. Calibration of the flow probe was carried out at the end of each experiment, and the SMA pressure was obtained after correction of circuit pressure for resistance in the circuit (20). The pressures and flow rates were recorded on a dynograph recorder (R611, Sensor Medics, Anaheim, CA). After the surgery, the animals were allowed to stabilize for at least 1 h. At the end of each experiment, the defined intestinal segment was removed from the carcass, and the intestinal contents were cleaned out to obtain a wet tissue weight. The Animal Care Committee at the University of Manitoba approved all procedures.The influence of blood flow on intestinal glucose uptake.
To increase intestinal blood flow, the vasodilator Ado was infused into
the SMA through an infusion line in the circuit at a dose (0.4 mg · kg body
wt1 · min
1)
previously shown (20) to produce maximal dilation
(n = 7). A constant SMA perfusion
pressure was maintained, with the use of the pump to increase blood
flow during the drug infusion. Blood samples for measuring blood
glucose, lactate, and oxygen content were taken from the circuit and
portal vein simultaneously at 5 min before the infusion, as control,
and after 5 min of the infusion when blood flow and oxygen consumption
effects are stable (13). Ado was also infused into the SMA while the
blood flow was maintained constant to prevent a rise in shear stress.
The involvement of NO in intestinal glucose uptake. The shear rate in the superior mesenteric vascular bed is increased because of the increase in blood flow when a vasodilator is infused during constant-pressure perfusion. To study the involvement of NO, the animals in the first group (n = 7) were treated with L-NAME (2.5 mg/kg iv, infused over 10 min), a potent nonselective NO synthase blocker. Ado infusions were repeated 10 min after the completion of L-NAME administration. The intestinal glucose uptake in basal state and during raised blood flow were compared before and after NO synthase blockade.
The influence of indomethacin on intestinal glucose uptake.
To investigate the role of prostanoids in control of intestinal glucose
uptake, the uptake during raised blood flow by Ado infusion (0.4 mg · kg body
wt1 · min
1)
was compared before and after the inhibition of cyclooxygenase by
indomethacin (5 mg/kg iv bolus infusion over 10 min) in the second
group of animals (n = 5). Ado infusion
during constant-pressure perfusion was performed before and 30 min
after indomethacin administration.
The effects of prostaglandins on intestinal glucose uptake.
For further confirmation of the results obtained in the previous
protocol and to identify the role of different prostaglandins in
control of intestinal glucose uptake, the effects of prostaglandins (intra-SMA infusion) were tested in the second group of animals and
compared before and after the inhibition of cyclooxygenase. The effects
on intestinal glucose uptake of
PGF2 and
PGE2 (and
PGI2 in some animals) infusion
(41.2 ng · kg body
wt
1 · min
1
for all) alone or with Ado during constant-pressure (elevated flow)
perfusion were tested before and after the administration of
indomethacin. PGF2
was also
infused with Ado (0.4 mg · kg body
wt
1 · min
1)
during constant-flow perfusion in two animals. One extra dose (8.2 ng · kg body
wt
1 · min
1)
of PGF2
was also tested with
Ado infusion after indomethacin. The order of testing was randomly
assigned before and after indomethacin. The two different
PGF2
doses after indomethacin
were tested sequentially but ordered randomly. The infusion lasted for
10 min in this case, and the dose was changed by switching infusion rate after samples were taken at 5 min for the first dose.
The influence of increased shear stress in the liver.
To study the influence of the liver on intestinal glucose uptake in
response to increased blood flow, a special surgical procedure was
performed in two animals to bypass portal blood from the liver and
shunt it directly into the central vena cava. A loop with a T connector
was placed in the central vena cava by double cannulation. The portal
vein was cannulated and connected to the central venous loop.
Intestinal glucose uptake in the two animals was studied during
increased SMA blood flow by infusion of Ado (0.4 mg · kg body
wt1 · min
1).
Assays and data analysis. For each sample, blood (<0.5 ml) was withdrawn simultaneously from the circuit and portal venous catheter. Blood glucose and lactate concentration were analyzed with glucose and lactate analyzers (Sports Industrial Analyzer, Yellow Springs Instruments). Total CO2 production was calculated from the PCO2 and pH that were measured with a blood gas analyzer (system 1302, Instrumentation Laboratory, Lexington, MA). Glucose uptake by the intestine was assessed with the use of the product of arterial-venous concentration difference and the blood flow, yielding a result in units of micromoles per minute per 100 g tissue. All data in this study are expressed as means ± SE. Paired Student's t-test or ANOVA was used for detection of any difference. P < 0.05 was chosen as the criterion for significance to reject the null hypothesis. The computer programs GraphPad Prism and Microsoft Excel were used to compute the statistics.
Drugs and chemicals.
Ado, L-NAME, indomethacin, and
PGF2 were purchased from Sigma
(St. Louis, MO). PGE2 was
purchased from Upjohn (Kalamazoo, MI). Ado and
L-NAME were dissolved in saline
before each experiment. The prostaglandins were dissolved in 95%
ethanol at 1 mg/ml concentration as a stock solution, which was stored
as small aliquots at
20°C. Fresh solutions were made by
dilution of the stock solution to desired concentrations with saline in
each experiment. One tube of stock solution was used at a time, and all
prostaglandin solutions were protected from light with aluminum foil.
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RESULTS |
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Basal metabolic and hemodynamic conditions.
Basal conditions of the animals were stabilized within 2 h after the
surgery. On stabilization, for the first and second group of animals
basal arterial glucose concentrations were 98.1 ± 6.5 and 101.9 ± 2.7 mg/dl (5.44 ± 0.36 and 5.65 ± 0.15 mmol/l),
respectively, and the SMA perfusion pressures were 114.9 ± 7.6 and
105.3 ± 3.1 mmHg at flow rates of 37.6 ± 8.1 and
35.5 ± 2.0 ml · min1 · 100 g tissue
1. The basal
conditions of these two groups were not significantly different. The
third group of two animals had similar basal hemodynamic and metabolic conditions.
The influence of SMA blood flow on intestinal glucose uptake.
The infusion of Ado increased the SMA blood flow by 111.9 ± 14.3 from 31.6 ± 7.5 ml · min1 · 100 g tissue
1
(P < 0.0005, n = 7, Fig.
1), whereas the perfusion pressure was maintained [123.9 ± 5.5 vs. 120.0 ± 3.8 mmHg for control,
not significant (NS)]. The glucose uptake across the intestine
increased by 45.0 ± 18.3 from 25.3 ± 3.8 µmol · min
1 · 100 g tissue
1
(P < 0.05, Fig. 1). The total
production of CO2 and lactate
balance across the intestine were not changed
(CO2: 45.1 ± 25.4 vs. 37.4 ± 12.3 µmol · min
1 · 100 g tissue
1 for control, NS;
lactate: 19.0 ± 8.1 vs. 18.0 ± 4.9 µmol · min
1 · 100 g tissue
1 for control, NS).
Ado was also infused while holding the SMA blood flow constant. The SMA
perfusion pressure was reduced by 68.5 ± 11.3 from 114.9 ± 7.6 mmHg (P < 0.001, n = 7) during Ado infusion, whereas
the flow rate was unchanged (36.4 ± 7.7 vs. 37.0 ± 7.5 ml · min
1 · 100 g tissue
1, NS). Glucose
uptake in the constant-flow situation, however, was not altered (22.0 ± 3.9 vs. 19.3 ± 4.3 µmol · min
1 · 100 g tissue
1 for control, NS,
Fig. 1).
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The influence of NO synthase blockade on intestinal glucose uptake.
To assess the possible involvement of NO in the regulation of
intestinal glucose uptake during constant-pressure perfusion in which
shear stress was elevated,
L-NAME (2.5 mg/kg) was used to
block endogenous NO production.
L-NAME significantly increased the SMA perfusion pressure from 116.8 ± 3.6 to 178.1 ± 7.8 mmHg (P < 0.0005, n = 7), whereas the blood flow was not
changed (32.8 ± 8.0 before vs. 30.7 ± 8.0 ml · min1 · 100 g tissue
1
after L-NAME, NS). The basal
glucose uptake across the intestine was not altered by
L-NAME. After the administration
of L-NAME, the intestinal
glucose uptake was increased by 52.0 ± 10.2 from 20.2 ± 4.5 µmol · min
1 · 100 g tissue
1
(P < 0.005, n = 7, Fig. 1) when the blood flow was
increased by 112.8 ± 15.2 ml · min
1 · 100 g tissue
1
(P < 0.0005) during Ado infusion.
The increase in blood flow was controlled as close as possible before
L-NAME. The increases in the
intestinal glucose uptake during increased blood flow were the same
before and after L-NAME
(increased by 45.0 ± 18.3 before vs. 52 ± 10.2 µmol · min
1 · 100 g tissue
1 after
L-NAME, NS). Similar to the
response before L-NAME, Ado infusion during constant-flow perfusion did not change intestinal glucose uptake (22.8 ± 5.3 vs. 28.8 ± 5.3 µmol · min
1 · 100 g tissue
1 for control after
L-NAME, NS). Thus the blockade
of NO formation had no influence on the basal or blood flow-induced
increase in intestinal glucose uptake.
The influence of indomethacin on intestinal glucose uptake.
In another group of animals (n = 5), a
cyclooxygenase inhibitor, indomethacin, was used to block the
production of prostanoids during increased blood flow. Before
indomethacin, the intestinal glucose uptake was increased by 41.0 ± 4.4 from 18.8 ± 4.1 µmol · min1 · 100 g tissue
1
(P < 0.001) by infusion of Ado
during constant-pressure perfusion, which increased SMA blood flow by
145.9 ± 9.8 from 35.5 ± 2.0 ml · min
1 · 100 g tissue
1
(P < 0.0001, Fig.
2). The blockade of cyclooxygenase by
indomethacin did not change basal intestinal glucose uptake (14.1 ± 5.1 before vs. 17.5 ± 6.8 µmol · min
1 · 100 g tissue
1 after
indomethacin, NS), whereas the basal SMA blood flow was slightly
increased after indomethacin (P < 0.05, by ANOVA). Ado infusion during constant-pressure perfusion
increased SMA blood flow by 152.5 ± 23.5 from 52.0 ± 8.3 ml · min
1 · 100 g tissue
1
(P < 0.005). However, the intestinal
glucose uptake after indomethacin was not increased (23.6 ± 11.3 vs. 17.5 ± 6.8 µmol · min
1 · 100 g tissue
1 for control, NS,
Fig. 2).
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The role of different prostaglandins in control of intestinal
glucose uptake.
The infusion of PGE2 into the SMA
decreased the SMA perfusion pressure by 29.0 ± 4.3 from 112.0 ± 4.2 mmHg (P < 0.005, n = 5) while the blood flow was held
steady (40.1 ± 6.0 vs. 35.3 ± 5.1 ml · min1 · 100 g tissue
1 for control, NS).
Infusion of PGF2
at a dose of
41.2 ng · kg body
wt
1 · min
1
caused a slight and transient increase in the SMA perfusion pressure followed by a sustained small decrease in the perfusion pressure by
15.5 ± 3.8 from 104.3 ± 2.5 mmHg
(P < 0.05), whereas the blood flow
was not changed (32.6 ± 5.9 vs. 32.6 ± 5.8 ml · min
1 · 100 g tissue
1 for control, NS).
After the administration of indomethacin,
PGE2 decreased perfusion pressure
by 40.9 ± 3.6 from 100.1 ± 4.1 mmHg (P < 0.0005, n = 5), whereas the blood flow was not
changed (60.1 ± 9.4 vs. 59.3 ± 9.2 ml · min
1 · 100 g tissue
1 for control, NS).
The infusion of PGF2
at the
same dose after indomethacin did not change perfusion pressure (90.4 ± 3.4 vs. 95.3 ± 1.0 mmHg for control, NS). However, neither
the infusion of PGE2 nor of
PGF2
, before and after the
administration of indomethacin, changed intestinal glucose uptake in
the constant-flow condition, as shown in Fig.
3.
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Intestinal glucose uptake in liver-bypassed animals.
In two animals, the portal venous blood flow was surgically shunted to
the central vena cava. The intestinal glucose uptake increased by 24.0 and 89.0 µmol · min1 · 100 g tissue
1 when the blood
flow was increased by 80.1 and 172.3 ml · min
1 · 100 g tissue
1 in response to
Ado in the two animals, respectively.
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DISCUSSION |
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Intestinal glucose uptake from blood increased dramatically when the
blood flow increased. Since shear rate was elevated during increased
blood flow, we further tested the hypothesis that shear stress-induced
release of NO or prostaglandins mediated the increase of intestinal
glucose uptake. Indomethacin, a cyclooxygenase inhibitor that blocks
the production of prostanoids, eliminated the increase in glucose
uptake that was elicited by increased blood flow, suggesting that shear
stress-induced release of prostaglandins was involved in mediating
increased glucose uptake in the intestine.
PGF2, at a dose that produced
only a small vascular response, reversed the inhibitory effect of
indomethacin on increased intestinal glucose uptake induced by
increased blood flow; in contrast,
PGE2 and
PGI2 had no effect on the glucose
uptake. The data suggest that
PGF2
was responsible for
mediating the increase in intestinal glucose uptake when shear stress
was elevated. The involvement of another shear stress-induced autacoid,
NO, was ruled out because the blockade of NO synthase did not affect
the glucose uptake. In addition, the prostaglandins and NO were not
involved in the control of basal intestinal glucose uptake because the
blockade of cyclooxygenase or NO synthase did not change the basal
glucose uptake. An unusual aspect of the results was that
PGF2
only increased glucose
uptake when blood flow was increased. To our knowledge, this is the
first time that a blood flow-elicited increase in intestinal glucose
uptake has been reported and that the mechanism of shear stress-induced
release of PGF2
was suggested.
Methodology consideration. In this study, we surgically separated a segment of small intestine in situ, which was perfused by an arterial circuit through the SMA. This setup provided a model that would be least affected by changes in systemic and hemodynamic reflexes. The surgical procedures, including the removal of the spleen and large intestine and ligation at the duodenum, were to ensure that the portal blood was exclusively from the defined portion of intestine. A sample line in the circuit and a portal catheter provided routes to access arterial and portal blood samples simultaneously.
A pump was incorporated into the circuit to allow the SMA blood flow to be adjusted. However, it was necessary to use a vasodilator to increase the SMA blood flow substantially without the need to produce a massive increase in the perfusion pressure. Ado is a potent vasodilator and has been suggested to mediate postprandial and reactive hyperemia in the intestine (24). To assess the direct effect of Ado on glucose uptake in the intestine, we administered the same dose of Ado during both constant-flow and constant-pressure perfusion. In contrast to constant-pressure perfusion, Ado did not change basal glucose uptake during constant-flow perfusion, suggesting that there was no direct effect of Ado on intestinal glucose balance.The influence of blood flow on intestinal glucose uptake. We demonstrated that the intestinal glucose uptake from blood increased dramatically when the SMA blood flow was increased. The active role of the gut in glucose disposal in basal and absorptive states reported by Abumrad et al. (1) suggested that, in addition to basal utilization of up to 25% of hepatic glucose output by the gut in dogs, the glucose uptake was increased after ingestion; the change in intestinal blood flow was, unfortunately, not reported. The gastrointestinal blood flow is normally increased during ingestion. However, the absorption of glucose from the intestinal lumen makes it difficult to assess the net glucose utilization by the intestine. Direct glucose absorption from the lumen in roughage-fed ruminants is negligible. Bergman et al. (4) demonstrated that the gut of sheep used about 16% of hepatic output of glucose in a "continuously fed" model. Blood flow was not reported.
Data from other studies also implied that there is a relationship between increased intestinal blood flow and glucose uptake. Fernández-López et al. (10) reported that the gut consumes a considerable portion of glucose load in rats, in which the portal blood flow increased two- to threefold. In that study, the portal glucose concentration was actually decreased, whereas the portal blood flow increased more than twofold when a small amount of glucose (0.1 mmol) was gavaged. Intestinal glucose uptake was elevated when blood flow increased during septic shock (15), although the authors concluded that the elevated glucose uptake was not dependent on increased blood flow because somatostatin reduced the blood flow but did not reduce glucose uptake in the gut. However, somatostatin did not bring the intestinal blood flow to its control level, and somatostatin-induced vasoconstriction could possibly increase shear stress in that situation.The influence of shear stress on intestinal glucose uptake. We previously discussed (13) that when blood flow increases during constant-pressure perfusion the shear rate increases at areas not actively dilated, including the capillary endothelium. Shear stress stimulates the release from the endothelial cells of autacoids, including NO, prostaglandins, and endothelium-derived hyperpolarizing factor (5). These substances may have direct or indirect effects on the intestinal glucose uptake and metabolism. We showed that the release of NO was increased when blood flow was increased (13). In the present study, we used L-NAME to block NO synthase to reduce shear stress-induced release of NO. The dose (2.5 mg/kg) used in the study was previously demonstrated to be sufficient to block NO production (13, 20). The increase in SMA pressure after L-NAME in this study further confirmed the successful blockade. However, neither the basal nor increased intestinal glucose uptake was altered by NO synthase blockade, suggesting that NO was not primarily involved in the control of intestinal glucose uptake.
Prostaglandins are arachidonic acid metabolites of cyclooxygenase. Increase in shear stress may stimulate the endothelium to release prostaglandins (5, 6, 22), which in turn may have direct or indirect effects on intestinal glucose uptake. In order to reduce the release of prostaglandins when shear stress was elevated, indomethacin, a cyclooxygenase inhibitor, was used. The slight increase in SMA blood flow after indomethacin suggested that the basal prostaglandin(s) produced mainly vasoconstriction in cats. The basal intestinal glucose uptake was not affected by indomethacin, suggesting that the prostaglandin(s) was not involved in the control of basal glucose uptake in the intestine. The increased glucose uptake during raised blood flow was totally blocked in the presence of indomethacin. These results supported our hypothesis that elevated shear stress plays a key role in the control of intestinal glucose uptake, and further suggested that it was shear stress-induced release of prostaglandin that mediated this event. The increase in SMA blood flow directly resulted in an increase in the portal blood flow, which may have elevated shear stress in the liver as well. Elevated shear stress in the liver could trigger a hepatic event that had influence on intestinal glucose uptake through hormone circulation or nerve reflexes. Although the superior mesenteric plexus was denervated, an enterohepatic reflex could pass through the posterior hepatic plexus (16), which distributes along the portal vein and bile duct, or hepatic vagal branches (17). In two animals, we surgically diverted portal venous blood from the liver to the central vena cava, which avoided exposure of the liver to raised portal blood flow. The intestinal glucose uptake was stimulated as well when the SMA flow was increased in this group. The data ruled out the possibility that the liver regulated intestinal glucose uptake in response to elevated portal flow, and provided further evidence that the site of increased shear stress responsible for the regulation of glucose uptake was in the intestine.The effect of PGF2.
PGI2,
PGE2 and
PGF2
are released from the
endothelial cells in response to shear stress (5, 6, 22).
PGE2 and PGI2 had no influence on glucose
uptake in our study. PGF2
stimulated glucose metabolism in rat uterus (12).
PGF2
is believed to be a
vasoconstrictor that causes increase in the SMA pressure (18) or
decrease in the blood flow (23). However, PGF2
at the dose used in the
present study, which was about 12 times lower than that used in dogs
(23) and much lower than that in the cat study (18), produced only a
minor and transient increase in the SMA pressure followed by a
sustained small vasodilation. In our study, the indomethacin-inhibited
increase in intestinal glucose uptake was reversed by
PGF2
in a dose-dependent manner but not by PGE2 and
PGI2 at a similar molar dose. Our
data suggest that PGF2
is the
specific prostaglandin that is responsible for mediating shear
stress-induced increase in intestinal glucose uptake.
Unresolved issues.
It seems that the increased shear stress or blood flow per se was a
necessary or permissive factor, because the infusion of PGF2 under normal blood flow
did not alter the glucose uptake. An example of permissive control of
prostaglandin effects has been previously reported. 17-
Estradiol
was necessary for PGF2
and
PGE1 to have their effect on
uterus glucose metabolism, although the hormone per se did not have any
effect on glucose metabolism (12). Ado did not serve in this role
because the infusion of PGF2
with Ado during constant-flow perfusion did not change the glucose
uptake. Shear stress-induced release of other endothelium-derived factor(s) could possibly serve as a permissive factor for
PGF2
action. It was reported
that NO had a permissive effect on endothelial arachidonic acid
metabolism and the arteriole dilation caused by the metabolite(s) (3).
This possibility, however, was ruled out by our observation that
L-NAME did not block the
increased intestinal glucose uptake.
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ACKNOWLEDGEMENTS |
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We thank Dallas J. Legare for excellent technical assistance and Karen Sanders for preparation of the manuscript.
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FOOTNOTES |
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This project was supported by the Manitoba Heart and Stroke Foundation and The Medical Research Council of Canada. C. Han received a Canadian Hypertension Society-Pfizer-Medical Research Council of Canada studentship.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: W. W. Lautt, 753 McDermot Ave., Dept. of Pharmacology and Therapeutics, Faculty of Medicine, Univ. of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3 (E-mail: wlautt{at}cc.umanitoba.ca).
Received 30 November 1998; accepted in final form 21 April 1999.
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