© 1996 American Heart Association, Inc.
Articles |
Intestinal Absorption of Sodium and Nitric OxideDependent Vasodilation Interact to Dominate Resting Vascular Resistance
From the Department of Physiology and Biophysics, Indiana University Medical School, Indianapolis.
Correspondence to Dr Glenn Bohlen, Department of Physiology and Biophysics, Indiana University Medical School, 635 Barnhill Dr, Indianapolis, IN 46202.
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Abstract |
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Abstract The villi of the small intestine maintain a hypertonic interstitium at all times, and the submucosal glands constantly secrete ions and accompanying water into the lumen. Generation of the 400- to 600-mOsm interstitial fluid in the villus and secretion by glands may require a large expenditure of energy and, consequently, have major effects on intestinal vascular regulation to supply oxygen and nutrients. Blood flow and oxygen consumption were measured in the ileum of anesthetized rats during natural resting conditions with physiological sodium chloride in the bathing fluid and during isosmotic replacement of sodium chloride with mannitol. Microvascular pressures and blood flow were used to determine the changes in resistance of the major arterioles and the terminal vasculature. When mannitol replaced sodium chloride in contact with the villi, intestinal blood flow decreased to 58.6±2.8% of control, and oxygen consumption was 54.2±3.4% of control. Resistance of the major arterioles increased 101.7±9.9%, and that of the terminal vasculature increased 40.4±6.2%. The increased resistance appeared to be caused by suppression of a nitric oxide mechanism. Local application of 10-4 mol/L NG-nitro-L-arginine methyl ester caused about the same reduction in flow and increases in regional vascular resistance as during replacement of sodium but did not alter the oxygen consumption. These data indicate that about half of the intestinal metabolic rate during natural resting conditions is devoted to sodium secretion/absorption. Large resistance vessels are dilated to maintain a high blood flow through release of nitric oxide. We propose that dilation of the terminal vasculature in the metabolically active tissues increased flow velocity sufficiently in the major resistance vessels to cause a flow-mediated release of nitric oxide.
Key Words: intestine • blood flow • oxygen use • nitric oxide • sodium • absorption
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Even when the intestine is not absorbing food, the intestinal mucosa is in a constant state of active transport of ions. Ions are reabsorbed from luminal secretions, and the formation of secretions in the submucosa requires the active transport of ions. Exactly what energy costs are incurred by these transport processes and the impact on vascular function to supply the required oxygen are unknown. However, there is circumstantial evidence that the metabolic cost for ion secretion/reabsorption is high. In seven mammalian species studied to date,1 2 including humans,3 an osmotic gradient of 100 to 200 mOsm above isotonicity is maintained along the villus shaft at rest. To offer a simple perspective, maintenance of a 100-mOsm gradient in osmolarity across a perfectly semipermeable membrane would be equivalent to the generation of a gradient of
2000 mm Hg or a force
of 2.6 kg/cm2. It has been suggested that this hyperosmotic
condition is maintained primarily by countercurrent exchange and
multiplication of a small amount of absorbed sodium; if this is the
case, then the energy cost may be
minimal.1 2 3 However, if
countercurrent exchange and multiplication are relatively inefficient
in the villus, as recent studies of oxygen exchange
suggest,4 then the hypertonic status is likely primarily
created by the active absorption of sodium, which would require a large
amount of metabolic energy. In addition, a high
metabolic rate in the villus is supported by the
independent observations that the natural mucosal blood flow when
sodium ions are in the lumen is highest in the intestinal wall (
50 to
100 mL/min per 100 g tissue
[wet]),5 6 7 and yet villus
tissue oxygen tensions8 9 are seldom >15 mm Hg. Jodal et al10 have proposed that some fraction of the intestinal glandular secretions is reabsorbed by the villi. In view of the fact that the small intestine absorbs the vast majority of pancreatic, hepatic, and gastric secretions during the process of digestion, it seems very reasonable that locally secreted sodium ions, the dominant cation of secretions, would also be quickly reabsorbed into the villus. The present study tested the hypothesis that this secretion/absorption circuit is a metabolically expensive process and accounts for a large fraction of the intestinal tissue oxygen consumption during the natural state between meals. In testing this hypothesis, we found that the metabolic process has profound effects on the regulation of intestinal microvascular function in that blood flow is dramatically decreased when sodium absorption is suppressed by isosmotic replacement of luminal sodium chloride with mannitol. The cause of the decline in blood flow is proposed to be through suppression of a nitric oxide–dependent process. We suspected a nitric oxide–dependent process, because large arterioles demonstrated a relatively greater increase in vascular resistance than did the smaller arterioles. Such an event is consistent with suppression of the flow-mediated release of nitric oxide in larger arterioles when mucosal events depress mucosal blood flow and, of course, the reverse, ie, amplification of flow increases in the mucosal layer by flow-mediated dilation of the larger arterioles.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Male Wistar rats (Harlan Sprague Dawley, Inc, Indianapolis, Ind) in the weight range of 400 to 550 g were anesthetized with sodium thiopental (200 mg/kg) given subcutaneously in four locations over the thighs and lower back.11 Supplemental injections of 20% of the original dosage were given (subcutaneously) if corneal blink reflexes returned. The trachea was cannulated, and the right femoral artery was cannulated to allow measurement of mean arterial pressure and administration of physiological fluids (0.5 mL/100 g per hour). The small intestine was exposed by a midline incision, and the ileum,
10
cm upstream from the appendix-ileal junction, was used for all
studies. The muscle submucosal or mucosal surface of the bowel was
prepared for observation with a standard technique.12 The
mucus layer over the mucosal surface was initially removed by gently
flushing with physiological saline during the
surgical procedures. During the experiment, the mucosal surface was
bathed by a rapidly flowing suffusion medium (4 to 5 mL/min over an
1-cm2 tissue surface) to wash away mucus as it was
secreted both from the villus surface and glandular tissue. The
suffusion solution was equilibrated with 5% O2/5%
CO2/90% N2, and delivery lines
were protected from equilibration with the atmosphere until the fluid
entered the tissue support device. All fluids were warmed to 37°C
before entering the support device, which was warmed independently to
37°C. After completion of surgery, the animal's body temperature was
maintained by contact with the stainless steel tissue support.
Esophageal temperature was measured to verify that the animal had a
core temperature of 37°C to 38°C, and supplemental heat was
provided under the body if needed. All solutions, including those that
contained mannitol, L-NAME (Sigma Chemical Co), or both substances,
also contained 10-7 g/mL isoproterenol (Sigma) and 20 mg/L
phenytoin (Parke-Davis) to suppress intestinal motility. Even with
these potentially dilatory agents present, blood flow in the
preparations would increase 2.5-fold, as has been previously
found,12 in response to 10-4 mol/L
adenosine applied topically to the muscle submucosal side of
the bowel. In five animals, the small intestine was not opened, except for small thermal cautery incisions at both ends of the exteriorized bowel. A small cannula was inserted into each incision to flush all debris from the bowel lumen. These preparations were used to test the hemodynamic effects of isosmotic replacement of the bulk of sodium chloride with mannitol on only the exterior surface of the bowel. This test was necessary because the muscle layer side of the bowel was exposed to the sodium-depleted mannitol solution passing over the mucosa. We were concerned that the mannitol solution might cause vascular responses independent of those resulting from changing mucosal sodium absorption.
To maintain the pH of the final mannitol medium, the 2.1 g sodium
bicarbonate used in each liter of normal medium was retained; however,
the overall sodium content was reduced by 90%. A pulsed Doppler
flow probe (Tritronics Medical Instruments) was placed on the single
artery to the isolated section of bowel, and relative changes in the
Doppler shift were used to monitor blood flow changes. To prevent
changes in arterial diameter within the flow probe, the
ultrasound scanning gel placed in the flow probe around the artery
contained 10-3 mol/L sodium nitroprusside.
In preparations used for in vivo microscopy, the formation of nitric
oxide was suppressed by adding 10-4 mol/L L-NAME to all
bathing media. The L-NAME was exposed to the tissue for a minimum of 30
minutes before recording vascular and metabolic
effects during the resting state. Topically applied L-NAME has been
shown to suppress vasodilation of intestinal arterioles to locally
applied acetylcholine.13 Because there is some possibility
that L-NAME acts as a muscarinic blocker unless first frozen in
solution,14 all stock solutions were prepared in advance
and kept frozen until needed. Application of L-NAME to the 5- to
7-cm length of bowel did not affect the mean arterial
pressure, which was essentially the same at the beginning and end of
the experiment.
In the in vivo microscopy studies, relative changes in blood flow were calculated from simultaneous measurements of inner lumen diameter and the red blood cell velocity, as measured with the dual slit cross-correlation method (Instrumentation for Physiology and Medicine), of the largest arterioles. Since all data are presented as the ratio of flow during a perturbation relative to that during the natural resting state, no correction factor for translating centerline to average red blood cell velocity was used, because the factor would appear in both the numerator and denominator of the calculated ratio.
Microvascular pressures were measured with the servo-null technique (Instrumentation for Physiology and Medicine) using 2 mol/L NaCl–filled glass micropipettes sharpened to an outer diameter of 3 to 5 µm at the end of the 20° to 25° beveled tip. The arterioles chosen for pressure measurements were 2A, which not only distribute blood longitudinally in the intestine but also serve as collateral vessels between adjacent 1A, the large radial arterioles of the bowel wall. The point chosen for pressure measurement along the 2A was approximately midway between the adjacent 1A. At this point in the vasculature, the microvascular pressure is about half of the perfusion pressure, ie, the systemic arterial pressure minus portal venous pressure, indicating about equal upstream and downstream resistances on either side of this point.
The systemic arterial pressure and microvascular pressure in 2A and the percentage of control blood flow measurements were used to calculate the relative resistance of all arterioles upstream from the 2A; the downstream resistance was based on the relative flow and pressure drop from 2A to mesenteric veins. The upstream resistance segment is referred to as the distribution arteriolar resistance but also includes the resistance of the arterial resistance vessels. The downstream segment, which includes the terminal arteriolar, capillary, and venular vessels, is referred to as the terminal vascular resistance. The outflow pressure of the intestinal venous system was assumed to be 10 mm Hg at all times because (1) this is the typical mesenteric venous pressure in adult rats15 and (2) the perturbations used affected, at most, 10% of the bowel vasculature, and as such the mesenteric venous pressure should not be appreciably altered. Calculation of each segmental resistance index was as follows:
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where PSYS is systemic arterial pressure, P2A is microvascular pressure in 2A, and %Flow is percentage of control blood flow measurements. These indices of resistance were used to calculate the relative changes in segmental resistance elicited by the various experimental perturbations. The percentage of the total vascular resistance in each segment was calculated by the pressure drop across that segment divided by the difference between the systemic arterial pressure and the estimated portal pressure of 10 mm Hg.
The percent saturation of hemoglobin was measured in submucosal arterioles, the second-order venules, and the vessels of the villi using an image-analysis adaptation16 of the video line scan method developed by Pittman and Duling.17 18 Light wavelengths in the 500- to 555-nm range were used for measurements in the larger vessels, and wavelengths in the 400- to 450-nm range were used for measurements in the small vessels of the villi.4 In all cases, two adjacent lengths of the same vessel were used for measurement, and the results were averaged. The measurements were accepted only if the two measurements were within 2% saturation units. Technical details, limitations, and in vivo verification of these complex measurements in this laboratory have been previously reported.16
Relative changes in oxygen consumption were calculated from the measured changes in arteriolar to venular difference in percent saturation of hemoglobin and the blood flow. Arteriolar percent saturation was measured in the first 100 µm of the first side branch of the large arteriole (1A) in which flow was measured. The 1A was not used because the optical density of the large arteriole was generally too high for reliable measurement of hemoglobin saturation at light wavelengths of 500 to 560 nm. The venular percent saturation was measured in the second-order venules draining the region of bowel in which blood flow was measured.
The protocol for the experiment was initiated after 30- to 60-minute
stabilization of the preparation. Measurements for all variables to
be tested in a given experiment were then obtained during natural
resting conditions, which are 140 mmol/L NaCl in the bathing media
over the mucosa. The suffusion solution was changed to one containing
mannitol, and all measurements were repeated after a 30-minute
stabilization period. The suffusion solution was then switched to a
solution containing L-NAME, and the data were collected after a
30-minute exposure to saline or mannitol solutions containing L-NAME.
Although most of the vascular responses were fully developed in 10 to
15 minutes of exposure to a given solution, 30 minutes was allowed to
ensure that the vascular and metabolic responses
represented were those at sustained conditions.
Approximately 15 to 20 minutes was required for full expression of the
responses to L-NAME. In most experiments, either blood flow and
microvascular pressure measurements or blood flow and percent
saturation measurements were the primary emphasis. However, in four
experiments, every measurement at each perturbation step was made, and
these data will be reported separately because these experiments
required 1-hour "steps" for the protocols rather than 30
to
40 minutes.
Data were processed and index calculations were performed using Lotus 123 for Windows (Lotus Development Corp). Statistical analyses were performed using CSS:Statistica (Statsoft). Two-way ANOVA (mannitol and L-NAME) were performed, and least-significant-difference tests were used to evaluate specific group comparisons.
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Results |
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The isotonic mannitol solution, when applied only to the exterior of the small intestine and mesenteric tissue, had no appreciable effect on the blood flow, as measured with a pulsed Doppler flow probe system in five rats. Standard physiological medium or mannitol solution (equilibrated with 5% O2/5% CO2/90% N2) was applied to the intestine for 30 minutes each, and this sequence was repeated three times in each animal. The averaged percentage of control blood flow during mannitol exposure was 99.4±1.9%.
For 1A in which flow was measured, the average percentages of control
diameter and red blood cell velocity during mannitol exposure to the
mucosal layer were 91.7±1.3% and 70.3±2.4% of control,
respectively, and during L-NAME in physiological
saline, 85.4±2.0% and 59.8±4.3%, respectively. The percentage of
control wall shear rate (8xvelocity/diameter) was 77.0±3.4% for
mucosal mannitol exposure and 70.7±6.0% for L-NAME in
physiological solution. The calculated percentages
of control blood flow for each of the experimental conditions are
presented in Fig 1
. When luminal sodium
absorption was reduced with mannitol and nitric oxide formation was
suppressed with L-NAME, blood flow was reduced to 58.6±2.8% and
50.1±3.8% of the natural resting state, respectively. In the presence
of L-NAME, replacement of sodium chloride with an isosmolar amount of
mannitol caused a further reduction in blood flow to 27.5±3.1% of
resting natural flow.
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for rest vs NAME status; @P
The fractions of total vascular resistance in the distribution
arterioles, which includes small arteries and other vessels proximal to
2A,19 and the terminal vasculature, which includes small
arterioles, capillary beds, and venules in the three layers of the
bowel wall, are shown in the left panel of Fig 2. The
microvascular pressure in 2A was 60.5±3.3 mm Hg at a mean
arterial pressure of 101.4±2.7 mm Hg during natural
conditions, and during mannitol suffusion, the pressure was 52.2±3.5
mm Hg at a mean arterial pressure of 99.6±2.8 mm Hg.
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Under natural conditions, resistances of the distribution arterioles
and terminal vasculature are about equal, as shown in the left panel of
Fig 2
. When mannitol is present, there is a shift in the
resistance
distribution to a higher proportion of the total resistance in the
distribution vasculature; consequently, a lower fraction of the total
resistance is attributed to the terminal vasculature. This shift in the
distribution of the total resistance is due to the much larger increase
in resistance of the distribution arterioles (101.7±9.9%) compared
with that of the terminal vasculature (40.4±5.1%) during mannitol
suffusion (Fig 2, right panel).
In four animals not included in the data set for Fig 2, we
were able to
obtain microvascular pressure, percent saturation, and flow data for
natural solution, mannitol solution, L-NAME in
physiological solution, and L-NAME in mannitol
solution. The increased complexity of measurements approximately
doubled the time required to complete each step of the protocol. Note
in the left panel of Fig 3 that the percentage changes
in distribution arteriole and terminal vessel resistances during
mannitol are virtually identical to the responses found in other
animals (Fig 2, right panel). The percentages of control blood
flows
(Fig 1 and right panel of Fig 3) during exposure
of the mucosa to
mannitol and L-NAME with NaCl present are also equivalent to those
in the other animals studied. L-NAME alone increased distribution
arteriole and terminal vessel resistances more than the mannitol
solution did (Fig 3, left panel). However, the pattern of
increased
resistance caused both by mannitol over the mucosa and global
application of L-NAME was similar in that the increase in distribution
arteriolar resistance was 2.5 times the increase in terminal vessel
resistance. Suffusion with mannitol and L-NAME caused an additional
decrease in blood flow compared with that produced by L-NAME alone (Fig
3, right panel) and a further increase in resistance of both
the
distribution arterioles and terminal vessels (Fig 3, left
panel).
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The venular hemoglobin saturations and AV saturation differences during
the various experimental conditions are shown in Fig 4,
and the calculated changes in oxygen consumption are presented
in Fig 5. In every animal, the hemoglobin saturation in
2A was >90% during spontaneous ventilation. Mannitol had remarkably
little effect on either venous outflow hemoglobin saturation or the AV
oxygen difference (Fig 4), but the oxygen consumption was
decreased by
50% (Fig 5). The decrease in oxygen use during mannitol
exposure
was accommodated by decreasing blood flow while maintaining a normal
oxygen extraction. In comparison, L-NAME in
physiological buffer, which decreased blood flow
somewhat more (50.1±3.4% of control) than did mannitol solution
(58.6±2.8% of control) (Fig 1 and right panel of Fig
3), had no
significant effect on oxygen usage (Fig 5). To compensate for
the
decreased blood flow, venular hemoglobin saturation decreased as the AV
saturation difference nearly doubled (from 21.5% to 40.7%) (Fig
4).
Mannitol and L-NAME together decreased oxygen usage more than did
mannitol alone (54.2% vs 42.3% of control) (Fig 5).
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The percent saturation of hemoglobin was also measured in the main
villus arteriole as it reached the villus tip and in one of two
collecting venules as the blood was about to leave the villus base.
These results are shown in Fig 6. The primary purpose of
these measurements was to determine whether a substantial change in
intravascular oxygen content occurred in the villus microvasculature as
a result of decreased villus absorption of sodium during suffusion with
mannitol solution. As shown by the data in Fig 6, neither
arteriolar
nor venular percent saturation of hemoglobin appreciably changed during
suffusion with mannitol.
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Discussion |
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Under conditions in which suffusion of the intestinal mucosal surface both displaced the mucus layer to allow free access to the absorptive surface and replaced the naturally secreted fluid, we were able to demonstrate that the normal secretion/reabsorption of the sodium ion has profound effects on intestinal metabolism and the microvascular regulation of blood flow. These observations, presented in Figs 1
and 5, confirm our
hypothesis that the
secretion of sodium, presumably by the glands, and absorption in the
villus are metabolically expensive processes during natural
resting conditions and account for about half of the oxygen consumption
in the rat intestine when motility is suppressed by isoproterenol. The
basic idea, as originally proposed by Hallback et al,20 is
that secreted sodium ions are reabsorbed by the villus and are
therefore available to repeat the secretion/absorption cycle. The
overall process contributes to the interstitial villus
hyperosmolarity by providing the major osmolites, sodium and anions, as
verified both by ion-selective electrode
measurements21 and by the loss of interstitial
hyperosmolarity if luminal sodium is isosmotically
replaced.22
As mentioned in the introduction, osmotic gradients represent a
large amount of potential energy, and an active process must initially
store this energy. Countercurrent exchange systems, although quite
capable of redistributing energy as heat or concentration gradients, do
not generate energy, and unless an external energy source is
maintained, the gradient fails because of diffusional and convective
losses. Hallback et al22 have shown that removal of sodium
from the bowel lumen essentially abolishes the hypertonic
interstitial environment during the natural resting state.
Therefore, villus hyperosmolarity is dependent on mucosal active
absorption of sodium. The present data on oxygen consumption (Fig
5) demonstrate for the first time that the maintenance of
villus hyperosmolarity by recirculating sodium ions is the major
metabolic activity of the rat intestine under conditions of
very little motility due to application of isoproterenol. As the rat
intestinal villi develop hyperosmolar conditions quite similar to those
of cats, gerbils, guinea pigs, rabbits, and
humans,1 3 22
the present data set has implications for the intestinal vascular
physiology of many mammals during the natural resting state.
Lowering the intestinal oxygen consumption by limiting the
secretion/absorption circuit for sodium was associated with an 50%
decrease in blood flow (Fig 1). Although vessels throughout the
bowel
microvasculature were involved in the reduction of blood flow when
mannitol replaced sodium, the increase in the resistance of the
distribution arterioles was 2.5 times greater than in the terminal
vasculature (Figs 2 and 3). The major arterioles
and small arteries
preceding the mucosa and deep submucosa were constricted by what we
believe to be a form of mechanical communication between small and
larger microvessels, flow-mediated vasodilation. We propose that
terminal arteriolar resistance initially increases when the
metabolism is decreased in the mucosa and glandular portion
of the submucosa by the removal of sodium secretion and absorption. The
vascular effect is then amplified as the velocity of blood in the
intestinal small arteries and larger arterioles is decreased and the
flow-mediated release of nitric oxide is suppressed. Under these
conditions, a tonically active vasodilatory stimulus for the major
resistance vessels is removed,23 which allows the
constrictor stimuli to dramatically increase vascular resistance and
lower blood flow (Figs 1, 2, and
3).
The first step in analysis of this hypothesis was to
substantially inhibit nitric oxide formation without appreciably
altering the metabolic status of the bowel. This step was
essential because three prior
studies24 25 26 of the rat
small intestine have shown that L-NAME decreases blood flow by 30% to
50%; such a reduction in blood flow could potentially limit oxygen
usage because of ischemia.27 28 29 In the
present
study, application of L-NAME did not appreciably change oxygen
consumption (Fig 5) during natural resting conditions when
sodium was
present. This result indicated that the sodium secretion/absorption
system was intact. Oxygen consumption was maintained by a doubling of
the AV oxygen difference (Fig 4) to compensate for the 50%
reduction in blood flow. Subsequent removal of sodium in the presence
of L-NAME reduced oxygen usage to less than half of that at rest when
L-NAME was present (Fig 5), providing additional evidence that
sodium absorption was intact in the presence of L-NAME. However,
because of the low blood flow during L-NAME plus mannitol exposure (Fig
1), part of the decrease in metabolism during these
conditions may have been due to flow limitations on oxygen
delivery.
If flow-dependent release of nitric oxide occurs normally as part
of the overall process to support sodium secretion and reabsorption,
then blockade of nitric oxide formation should have dramatically
decreased intestinal blood flow, which it did, as shown in Fig
1.
Furthermore, suppression of sodium absorption with mannitol increased
distribution arteriole resistance 2.5 times more than terminal
vascular resistance (Fig 3). Likewise, suppression of nitric
oxide
release by L-NAME also increased distribution arteriolar resistance
2.5 times more than terminal vascular resistance (Fig 3).
Therefore,
suppression of sodium secretion/reabsorption and interference with
nitric oxide release have parallel effects on intestinal regional
vascular resistances. In addition, shear rate in the large arterioles
was 77.0±3.4% of control during mannitol suffusion and 70.7±6.0%
of
control during suffusion with L-NAME, and the vessels constricted by
9 and 14%, respectively, further demonstrating the comparable
effects of sodium replacement and suppression of nitric oxide on
microvascular parameters.
An alternative way to evaluate these data is to consider flow
velocities during mannitol as the basal state. Absorption of sodium,
the natural state, is associated with an 30% to 35% increase in
flow velocity above the basal state. We propose that this increase in
flow velocity stimulates the release of nitric oxide. Kuo and
colleagues23 30 have shown that isolated coronary
arterioles, comparable in diameter to the 1A observed in the
present study, demonstrate flow-mediated dilatory responses
that are endothelial cell dependent and can be
suppressed by an arginine analogue. Furthermore, Smiesko et
al31 have shown that the small mesenteric arteries
immediately preceding the intestinal microvasculature demonstrate
flow-mediated vasodilation. Therefore, we believe that it is
reasonable to conclude that flow-mediated dilation occurs at rest
in the small arteries and larger arterioles of the small intestine.
There are very likely mechanisms other than flow-mediated release
of nitric oxide that influence intestinal vascular resistance when the
metabolic rate is reduced, as during the suppression of the
sodium secretion/absorption cycle. Known major regulatory systems that
cause intestinal vasodilation include substance P,32
vasoactive intestinal polypeptide,32 and
prostaglandins.33 However, blockade of their
actions32 33 decreases blood flow by only a small
amount
compared with the effects of replacing sodium with mannitol or nitric
oxide blockade in the present study. We also considered the
possibility of a myogenic response in the larger vessels. However,
during mannitol exposure, pressure in 2A decreased (see
"Results"), and presumably, pressure decreased in the immediate
upstream arterioles, the 1A. The decrease in pressure during mannitol
suffusion would be a stimulus for myogenic vasodilation, when in fact
vasoconstriction occurred (Figs 2 and 3).
Therefore, it would appear
that nitric oxide flow-mediated dilation of resistance arteries and
larger arterioles is a dominant vasodilatory mechanism in the small
intestine during the resting natural state. In addition, the mechanisms
that initially adjust vascular resistance in the terminal vasculature
in response to natural sodium absorption very likely have a component
related to nitric oxide release. We propose this because L-NAME
application was associated with 40% increase in resistance in the
terminal microvasculature (Fig 3), which primarily consists of
the
submucosal glandular and mucosa villus vasculatures. However, we do not
know to what extent nitric oxide released into blood passing through
upstream vessels might reach and dilate the terminal arterioles in
addition to local release of nitric oxide in the mucosa and deep
submucosa. The local release of nitric oxide may be related to the
hyperosmotic villus environment caused by sodium absorption.
Steenbergen and Bohlen13 have shown that about half of the
dilation of intestinal arterioles in response sodium hyperosmolarity is
mediated by nitric oxide. In effect, the generation of a hypertonic
villus interstitium by active sodium absorption is a major contributor
to both intestinal oxygen consumption and blood flow regulation through
both hypertonic and flow-mediated nitric oxide release in the small
intestine.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-20605. The authors wish to thank Mary Ann Neil for excellent technical assistance.
Received August 4, 1995; accepted October 12, 1995.
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