School of Rehabilitation Therapy and Department of Physiology, Queen's University, Kingston, Ontario, Canada K7L 3N6
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ABSTRACT |
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The effects of
endothelin-1 (ET-1) infusion on blood flow
(G) and
O2 uptake
(
O2G)
were examined in the small intestine of anesthetized dogs
(n = 10). Arterial and venous flows of
a gut segment were isolated, and the segment was perfused at constant pressure. Arterial and gut venous blood samples were taken, gut perfusion pressure and
G were
measured, and O2 extraction ratio (OERG) and
O2G
were calculated. ET-1 was infused (0.118 µg · kg
1 · min
1
ia) throughout the experiment. In group
1 (n = 5),
ETA receptors were blocked using
BQ-123 (0.143 mg · kg
1 · min
1
ia) followed by blockade of ETB
receptors with BQ-788 (0.145 mg · kg
1 · min
1
ia). The order of ETA and
ETB receptor blockade was reversed in group 2 (n = 5). In group
1, the decrease in
G observed
with ET-1 infusion was partially reversed with BQ-123; no further
change occurred after BQ-788 administration. In group
2, addition of BQ-788 to the infusate
further decreased
G, whereas
addition of BQ-123 returned
G to a value
not different from that with ET-1 infusion alone. These data indicated
that ET-1-induced vasoconstriction in the gut was mediated via
ETA receptors and that this
constriction was buffered by activation of
ETB receptors.
O2G
decreased in proportion to the decrease in
G with ET-1,
decreased further with ET-1 plus
ETB receptor blockade
(group 2), and increased in proportion to the
increases in
G
with ETA receptor blockade (both
groups). No changes in OERG
occurred during ETA and
ETB receptor antagonism in either
group. This study is the first to demonstrate that a flow-limited
decrease in gut
O2G
occurred with infusion of ET-1 in gut vasculature. An intriguing and
novel finding was that, during O2
limitation, OERG was only 50% of
that normally associated with ischemia in this tissue.
oxygen uptake; flow limitation; oxygen extraction
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INTRODUCTION |
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THE EXPECTED VASCULAR response to infusion of endothelin-1 (ET-1) is a transient dilation that occurs over 30-60 s followed by a prolonged constriction; the maximal constrictor response is normally observed by 15 min but varies somewhat between tissues (19, 28, 33). The vasoconstrictor action of ET-1 is primarily mediated through activation of ETA receptors (8, 23, 27, 32, 33) and, in some cases, also ETB receptors located on vascular smooth muscle cells (2, 14, 19, 32). In addition, activation of ETB receptors located on endothelial cells by ET-1 (25) results in the release of the vasodilator substances prostacyclin and/or nitric oxide (NO) (25).
The gut circulation appears to be more susceptible to the
vasoconstrictor actions of ET-1 than other peripheral vascular beds. Specifically, the gut vasoconstrictor response to ET-1 is more intense
than that observed for iliac flow in anesthetized monkeys (6), renal
and carotid flows in anesthetized cats (21), and flow in all
nongastrointestinal tissues in the anesthetized rat (17). This
sensitivity of the gut vasculature to ET-1 may be of considerable
importance in light of the fact that
1) ET-1 levels are elevated in a
number of instances, including chronic hypoxia (4, 10), a variety of
surgical interventions (11, 12, 30), and sepsis (22), and
2) this tissue has a high resting O2 uptake (20-25
ml · kg1 · min
1) that is normally
met by a high blood flow rate (300-500
ml · kg
1 · min
1)
(7, 9, 24, 29). If blood flow is reduced to the point that gut
O2 delivery falls below critical
values (30-40
ml · kg
1 · min
1),
O2 uptake will be compromised
(24).
To date, no studies have examined the possible metabolic consequences of an ET-1-induced increase in gut vascular resistance and the accompanying reduction in gut blood flow. We have developed an isolated perfused in vivo canine gut loop preparation to examine simultaneously the effects of ET-1 on both blood flow and O2 uptake in canine small intestine. On the basis of the highly sensitive response of the gut vasculature to ET-1, we hypothesized that ET-1 infusion at concentrations within the moderate range of the dose-response curve (32, 34) would result in a vasoconstriction that would reduce both gut blood flow and gut O2 uptake.
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METHODS |
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Mongrel dogs (23.9 ± 1.2 kg) were anesthetized with pentobarbital sodium (32 mg/kg iv), paralyzed with succinylcholine chloride (30 mg im and 0.1 mg/min iv), and ventilated to maintain arterial PCO2 at ~30 mmHg. A Swan-Ganz catheter was inserted into the right jugular vein and advanced to the pulmonary artery for thermodilution cardiac output determinations (Baxter, COM-2) and withdrawal of mixed venous blood samples. A catheter was placed in the brachial artery for measurement of mean arterial blood pressure and to obtain arterial blood samples.
A previously described isolated gut loop preparation was modified to control arterial perfusion (9, 24). Briefly, a midline abdominal incision was made, and a section of small intestine (ileum or jejunum; 26 ± 1 g average wt) subserved by a vascular arcade was exteriorized. The animals were heparinized (1,000 U/kg), and then a two-channel cannula was placed in the vein draining the gut segment. One channel contained an electromagnetic flow probe (Narco) for measurement of venous outflow, whereas the second allowed for in situ zero calibration of the flow probe without occlusion of venous outflow. Venous outflow was returned to the animal via a reservoir attached to a catheter in the right femoral vein. The distal end of a two-channel catheter was placed in the artery serving the vascular arcade while the proximal end was inserted into the right femoral artery. This allowed for autoperfusion of the gut segment through one channel or pump perfusion via the second channel in which an in-line peristaltic pump was located. Venous outflow from the gut segment was isolated to the vein draining the segment by tightening ties around the gut tissue at either end of the area served by the vascular arcade. At one end of the segment, an incision was made into the gut tissue, and a temperature probe was inserted into the lumen to monitor temperature of the exteriorized segment. A heat lamp was used to maintain the gut temperature constant during the experiment. Gut perfusion pressure was measured by a pressure transducer attached to a T branch in the arterial cannula just before insertion into the gut arcade artery. Gut perfusion pressure under autoperfused conditions was determined, the gut was pump perfused, and perfusion pressure was maintained within 5% of control values via an electrical feedback system for the remainder of the experiment. To determine if pump perfusion of the gut segment resulted in edema, dry-to-wet weight ratios were determined in the pump-perfused segment and in an autoperfused, nontreated gut segment in one group of animals. The average values for the dry-to-wet weight ratios were not different between the pump-perfused segments (0.29 ± 0.01) and the autoperfused segments (0.32 ± 0.02).
Once surgical and technical preparations were complete, a 30-min period
was allowed for cardiovascular and metabolic parameters to stabilize.
In preliminary experiments, we found that infusion of 0.1 mg · kg1 · min
1
ia ET-1 into the canine gut segment vasculature caused an intense vasoconstriction that abolished blood flow. Similarly, Ralevic and
Burnstock (26) observed that ET-1 concentrations in excess of
10
9 M caused severe
vasoconstriction that increased perfusion pressure by 120 mmHg in an in
vitro-perfused rat mesentery preparation. In the 10 animals used in the
current experiments, initial control measures were obtained and then
ET-1 was infused sequentially at two different concentrations (0.060 ± 0.001 and 0.118 ± 0.005 µg · kg
1 · min
1
ia, respectively) into the gut segment; measurements were taken at 20 min of infusion for each concentration (Table
1). These concentrations of ET-1 were
chosen because they evoked physiological increases in gut vascular
resistance of 32 and 72%, respectively (Table 1); the magnitude of
these changes in gut vascular resistance was similar to that reported
by others (1, 32, 34). The protocol was continued with an ongoing
infusion of ET-1 at the higher concentration. In group
1, BQ-123
[cyclo-(D-Trp-D-Asp-Pro-D-Val-Leu); 0.143 ± 0.010 mg · kg
1 · min
1
ia], a selective ETA
receptor antagonist (14), was added to the infusate, and measurements
were obtained at 30 min postinfusion. BQ-788
[N-cis-2,6-dimethylpiperidinocarbonyl-L-
-methyl-Leu-D-1-(methoxy-carbonyl)-Trp-D-Nle; 0.145 ± 0.014 mg · kg (gut
wt)
1 · min
1
ia], a selective ETB
receptor antagonist (15), was then added to the infusate, and
measurements were obtained at 30 min postinfusion of BQ-123 + BQ-788.
In group 2, the protocol was identical
to that followed in group 1 except
that BQ-788 was given first, followed by infusion of BQ-123. Others
have reported that the concentrations of BQ-123 and BQ-788 must be
1,000-fold greater than the concentration of ET-1 to produce effective
antagonism of the vascular effects of this peptide (25, 33).
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At each measurement period, arterial, mixed venous, and gut venous
blood samples were taken and whole body and gut perfusion pressure, gut
blood flow, and cardiac output were determined. All blood samples were
analyzed for
PO2,
PCO2, and
pH using a Radiometer BMS MKII, and these values were corrected to the
temperature of the dog at the time of sampling.
O2 concentration was determined in
all samples using an Instrumentation Laboratories 482 Co-Oximeter. The
O2 concentration values were
adjusted for the amount of O2 in
solution using the factor 0.03 ml
O2 · dl1 · mmHg
(PO2)
1.
Whole body and gut O2 uptake were
determined using the Fick equation, whereas whole body and gut vascular
resistance and O2 extraction ratio
were calculated using standard equations.
All data are reported as means ± SE. Because the treatments were identical for all animals during the control period and ET-1 infusions and the data were not different between the two groups at these times, the data are reported for a total of 10 animals for each of these periods. The effects of ETA and ETB receptor blockade were determined within each group (n = 5), with the blocked values being compared with the control and ET-1 values of the five animals within each specific group using a single repeated measures ANOVA (n = 5). Post hoc multiple comparisons of differences between means were achieved by paired t-test analysis within each group of 5 animals with the critical value for significance (P < 0.10) adjusted using the Bonferroni correction (P < 0.017) (31).
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RESULTS |
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The gut blood flow responses are shown in Fig.
1A. Gut
blood flow decreased significantly from the control value in all 10 animals with infusion of ET-1. In group
1, gut blood flow then increased above the value
observed during ET-1 infusion alone with the addition of BQ-123 to the
infusate but remained significantly less than the initial control
values. No further effect on gut blood flow was observed with the
addition of BQ-788. In group 2, gut
blood flow decreased with the addition of BQ-788 to the infusate; the
mean value was significantly less than that observed both during the
control period and ET-1 infusion alone. When BQ-123 was added to the
infusate, gut blood flow increased significantly above that observed
with BQ-788 but remained less than that observed during the control
period.
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The values for gut vascular resistance are shown in Fig. 1B. Gut vascular resistance increased significantly from the control value with infusion of ET-1. In group 1, after addition of BQ-123 to the infusate, the mean value for gut vascular resistance was not different from that observed during the control period; infusion of BQ-788 had no further effect on gut vascular resistance. In group 2, addition of BQ-788 to the infusate resulted in a significant rise in gut vascular resistance above that observed with ET-1 infusion alone. Addition of BQ-123 to the infusate resulted in a significant decrease in gut vascular resistance to a level not different from that observed during infusion of ET-1 alone. However, this value was significantly greater than that observed during the control period.
The values for gut O2 uptake are
shown in Fig.
2A. Gut
O2 uptake decreased significantly
from the control value of 19.2 ± 0.7 to 13.1 ± 1.0 ml · kg1 · min
1
with infusion of ET-1. In group 1,
after infusion of BQ-123, the value for gut
O2 uptake was not different from
that observed during the control period. Subsequent infusion of BQ-788
resulted in a significant fall in gut
O2 uptake below the control value. In group 2, infusion of BQ-788
resulted in a further decrease in gut
O2 uptake from that observed with
ET-1 infusion alone. During infusion of BQ-123, the value for gut
O2 uptake rose significantly to a
level that was not different from that observed during ET-1 infusion
alone but remained significantly less than the control value.
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The values for gut O2 extraction ratio are shown in Fig. 2B. Gut O2 extraction increased significantly from a value of 0.34 ± 0.03 in the control period to that of 0.41 ± 0.05 with ET-1 infusion. However, the small increase in O2 extraction was not sufficient to offset the decrease in gut O2 uptake (Fig. 2A). The values for gut O2 extraction were not different from those observed during the control period when ETA and ETB receptor blockade were induced during ET-1 infusion.
During the last segment of the experiment, the ETA and ETB receptors were blocked in both groups. The values for gut blood flow, resistance, O2 uptake, and O2 extraction ratio were not different between the two groups under these conditions.
The values for whole body hemodynamic and metabolic variables and blood
gas data are listed in Table 2. There was
no expectation that the local infusion of ET-1, BQ-123, or BQ-788 into
the gut segment would have an effect on whole body metabolic or
cardiovascular parameters. This proved to be the case. As normally seen
over time during barbiturate anesthesia in dogs, cardiac output
decreased and total peripheral resistance increased; no changes in mean arterial pressure or whole body O2
uptake were observed during the experiment (13). Arterial
PO2,
PCO2, and
pH remained stable during the experiment. The values for gut venous
PO2 reflected the
O2 extraction responses of the
gut.
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DISCUSSION |
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This is the first study to examine the metabolic consequence of ET-1-induced flow reduction in the small intestine in vivo. As others have reported, we also found that ET-1-induced vasoconstriction was mediated solely through ETA receptors and that ETB receptor activation buffered the magnitude of ETA receptor-mediated vasoconstriction. The new and important findings in our study were that O2 uptake fell in proportion to the fall in blood flow during ET-1 administration and that little, if any, compensatory increase in gut O2 extraction occurred to offset this flow limitation. The latter observation is in striking contrast to the response normally observed in this tissue during local or whole body stagnant hypoxia.
In group 1 as gut vascular resistance increased during ET-1 infusion, gut O2 uptake and blood flow decreased 32 and 37%, respectively, during ET-1 administration. When gut blood flow returned to control levels during ETA receptor blockade, so did gut O2 uptake. A similar pattern emerged in group 2; as gut blood flow decreased further (64%) with ETB receptor blockade, gut O2 uptake also decreased (62%). Subsequent ETA receptor blockade resulted in small but significant increases in both blood flow and gut O2 uptake, but both values remained significantly less than those observed in the control period. Gut O2 uptake during infusion of ET-1 in both groups and during infusion of ET-1 and BQ-788 in group 2 appeared to be flow limited. It was surprising that little, if any, compensatory increase in gut O2 extraction occurred to offset this flow limitation. The average values for gut O2 extraction ratio ranged from a minimum of 0.34 during control to a maximum value of 0.41 during ET-1 infusion. Previous studies using the same in situ canine gut loop preparation have established that the gut relies heavily on compensatory O2 extraction responses during periods of reduced O2 supply (9) such that under conditions of low flow, gut O2 extraction increased to values ranging from 0.60 to 0.70 (7, 29). Peak and/or critical values for O2 extraction in this gut preparation during ischemia have been reported to reach 0.80 (24). It is not unreasonable to postulate that the failure of the gut to increase O2 extraction during ET-1 infusion and ETA and ETB receptor blockade was the result of redistribution of gut blood flow away from exchange vessels. Another possibility is that ET-1 administration may have reduced gut O2 demand through a direct action on cellular metabolism. The latter seems unlikely in light of in vitro studies that have demonstrated that ET-1 causes contraction of guinea pig ileal longitudinal smooth muscle via activation of ETB receptors located on the longitudinal smooth muscle cells (3, 13, 20, 35). This direct inotropic action of ET-1, if present in situ, would be expected to result in an increase rather than a decrease in gut metabolism and O2 demand.
We have obtained preliminary data that may provide some insight into
the mechanism responsible for the failure of gut
O2 extraction to increase in the
face of reduced O2 delivery
following infusion of ET-1. Using intravital videomicroscopy, we
observed mesenteric arterial (diameter of ~20 µm) microvascular
responses during ET-1 infusion (0.1 µg · kg1 · min
1
iv) in anesthetized rats (n = 3). No
changes in vessel diameter were observed; however, mean red blood cell
velocity and blood flow were significantly reduced at 20 min of ET-1
infusion, and stasis occurred by 25 min of ET-1 infusion (Table
3). The mesenteric vessels employed in
these experiments were similar in size to third-order arterioles in the
submucosal layer. These preliminary findings suggest that ET-1 infusion
may result in microvascular plugging independent of changes in vessel
diameter, which would significantly reduce the number of capillaries
receiving nutritive flow with a resultant decrease in
O2 extraction. Further experiments must be performed to confirm these initial findings.
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Our vascular findings that infusion of ET-1 into the gut vasculature at
concentrations of ~0.06 and 0.12 µg · kg1 · min
1
increased gut vascular resistance 32 and 72%, respectively, were in
general agreement with values of 33% (32) and 100% (26) reported by
others during infusion of ET-1 at similar concentrations in the
perfused rat mesentery. Furthermore, whole body infusion of ET-1 (10 pmol · kg
1 · min
1)
in anesthetized rats increased small intestine vascular resistance fivefold (1). Finally, bolus intravenous administration of ET-1 of 0.1 µg/kg in anesthetized monkeys did not affect mesenteric blood flow,
whereas higher concentrations of 0.3, 1.0 and 3.0 µg/kg resulted in
decreases in mesenteric blood flow of 20, 40, and 60%, respectively
(6).
Our data indicated that ET-1-induced vasoconstriction in the gut
vasculature was mediated through
ETA receptors. This conclusion was
based on the findings that gut vascular resistance returned to levels
that were not significantly different from control and gut blood flow
also returned to control values when
ETA receptor blockade was
superimposed during ET-1 infusion. Furthermore, subsequent ETB receptor blockade did not
alter gut blood flow or gut vascular resistance. If the constrictor
actions of ET-1 had been partially mediated by
ETB receptors, then further
changes in both gut blood flow and vascular resistance would have been
expected with ETB receptor
blockade. Our results were consistent with those of Warner et al. (32),
in which the maximal increase in perfusion pressure following
administration of ET-1 (109
M) in the in vitro-perfused rat mesentery bed was reduced ~70% by
ETA receptor blockade with BQ-123,
whereas no further decrease in perfusion pressure was observed with
ETA and
ETB blockade with PD-142893. In
contrast, Allcock et al. (1) were unable to demonstrate any effect of
ETA receptor blockade with BQ-123
or ETA and
ETB receptor blockade with
PD-145065 on ET-1-induced vasoconstriction in the small intestine of
anesthetized rats. However, in the latter study, the rats were
pretreated with hexamethonium and ET-1 (10 pmol · kg
1 · min
1) was administered
systemically, two factors that may have accounted for the differences
between the studies. Our findings and those of Warner et al. (32)
clearly demonstrated that ETB
receptor blockade caused no further attenuation of ET-1-mediated
constriction in the mesenteric vasculature and suggested that
ETA receptor activation was the
primary mechanism of ET-1-induced vasoconstriction in the mesenteric circulation.
The current study also established that there was a substantial contribution of ETB receptor activation to vascular tone in canine small intestine during ET-1 administration. In group 2, gut vascular resistance, which increased significantly during ET-1 administration, increased an additional 62% with ETB receptor blockade (BQ-788), an effect similar to that reported by Allcock et al. (1) for vascular resistance in the rat small intestine. These data indicate that the vasoconstrictor response of the small intestine to ET-1 is substantially modulated by the simultaneous activation of ETB receptors. The mechanism underlying the magnitude of this buffering capacity is not clear but may be due to the loss of release of dilator substances such as NO or a reduced clearance rate of ET-1 (25). The latter seems most probable because the dilator response may be of short duration (16). ETB receptors are the primary method by which ET-1 is cleared from the system (25), and blockade of these receptors may reduce the clearance rate and therefore enhance the constrictor action of ET-1.
Our findings have demonstrated that the modest increase in vascular resistance that occurred during ET-1 administration resulted in gut ischemia that caused a substantial limitation in gut O2 uptake. These findings may have direct clinical implications for those situations that promote the release of endogenous ET-1. Plasma ET-1 levels have been shown to double during chronic hypoxia (4, 10), increase 2- to 7-fold during surgeries including small bowel transplantation, abdominal aortic aneurysm resection, and coronary artery bypass grafting (11, 12, 30), increase 8-fold with chronic peritonitis (5), and increase 15-fold with septic shock (22). Furthermore, teVelthuis et al. (30) demonstrated that the increase in plasma ET-1 levels during coronary artery bypass surgery was associated with increased circulating endotoxin concentrations. It is possible that the prolonged duration of reduced gut oxygenation as a result of ET-1-induced gut ischemia may contribute to mucosal dysfunction in these conditions.
In conclusion, the findings of the current study demonstrate first that ET-1-induced constriction in the canine small intestine is mediated solely by ETA receptors and second that this constrictor response is substantially modulated by ETB receptor activation. Finally, this study is the first to demonstrate that a flow-limited decrease in gut O2 uptake occurred with infusion of ET-1 in gut vasculature. An intriguing and novel finding was that, during the period of O2 limitation, O2 extraction ratio was only 50% of that normally associated with ischemia in this tissue.
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ACKNOWLEDGEMENTS |
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We thank Monica R. Prasad for participation in data collection and analysis during the course of the experiments.
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FOOTNOTES |
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These experiments were supported by funds from the Medical Research Council of Canada.
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: C. E. King-VanVlack, School of Rehabilitation Therapy, Queen's Univ., Kingston, ON, Canada K7L 3N6 (E-mail: kingce{at}post.queensu.ca).
Received 19 June 1998; accepted in final form 22 January 1999.
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