Children's Research Institute, Children's Hospital, and Division of Neonatology, Department of Pediatrics, Ohio State University, Columbus, Ohio 43205
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ABSTRACT |
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Previous attempts to determine
developmental changes in the vascular myogenic response have been
confounded by the presence of competing vasoactive stimuli or the use
of isolated vessels with markedly different baseline diameters. To
circumvent these issues, small mesenteric arteries (diameter ~150
µm) from 1- and 10-day-old piglets were studied in vitro under
no-flow conditions. In situ studies demonstrated that the intravascular
pressure and diameter of these vessels were similar in both age groups,
allowing an effective comparison of the myogenic response not obscured by differences in basal diameter. The pressure-diameter relationship was age specific. Thus, although small mesenteric arteries from both
age groups demonstrated myogenic constriction in response to stepwise
increases in pressure (0 to 100 mmHg, in 20-mmHg increments), the
intensity of contraction was significantly greater in vessels from
1-day-old piglets particularly within the pressure range normally
experienced by these vessels in situ. Attenuation or activation of PKC with calphostin C or indolactam, respectively, substantially altered the pressure-diameter relationship in 1-, but not
10-day-old arteries; thus calphostin C essentially eliminated the
contractile response to pressure elevation in younger subjects, whereas
indolactam significantly increased the intensity of the myogenic
response and shifted its activation point to a lower pressure range.
Immunoblots carried out on protein recovered from these arteries
revealed the presence of ,
,
,
, and
; notably, expression of the
- and
-isoforms substantially decreased between postnatal days 1 and 10.
newborn intestine; intestinal circulation
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INTRODUCTION |
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VASOCONSTRICTION IN
RESPONSE to an abrupt increase in transmural or intravascular
pressure defines the myogenic response. This response represents the
inherent property of vascular smooth muscle (VSM) to contract in
response to a stretch stimulus, i.e., a contraction that occurs in the
absence of extrinsic neural, metabolic, or hormonal influences
(5). The physiological relevance of the myogenic response
is substantial as it contributes to pressure-flow autoregulation
(17) and is a key participant in setting basal vascular
tone (9). The mechanistic basis of the myogenic response is calcium-dependent activation of the actin-myosin motor unit, as
evidenced by a brisk rise in VSM intra-cellular Ca2+
concentration ([Ca2+]i) in response
to the mechanostimulus of pressure and by subsequent phosphorylation of
myosin light chain kinase (3, 22, 34). However, other
factors also play a role in the initiation and maintenance of myogenic
vasoconstriction, reviewed most recently by Davis and Hill
(5); of these, that which has direct bearing on the
present work is PKC (6, 13, 15, 16, 19, 27). For example,
pressure stimulation applied to coronary arterioles caused a transient
increase in [Ca2+]i, but a sustained
translocation of PKC from cytosol-to-membrane in VSM, indicating
its activation (6). It was suggested that PKC
enhanced the Ca2+-sensitivity of VSM by phosphorylation and
thus disinhibition of the myosin binding proteins calponin and
caldesmon, facilitating maintenance of the pressure-induced arteriolar
contraction despite reduction of [Ca2+]i
(10, 24, 32).
The myogenic response is present within the postnatal intestinal circulation; however, it is not clear whether significant changes in the intensity of this response occur during early postnatal development. Studies carried out within in situ gut loops prepared in 1- to 35-day-old swine suggested that the magnitude of vasoconstriction in response to an acute elevation of mesenteric venous pressure, the perturbation used to elicit the myogenic response within the entire gut circulation, was greater in older subjects (2, 26). Interpretation of these data was confounded by the presence of myriad vasoactive stimuli present in the whole organ preparation. For example, the absence of vasoconstriction in response to venous pressure elevation in 1-day-old subjects was attributed to a vasodilatory metabolic feedback signal (derived from the parenchyma) overriding myogenic vasoconstriction (2). Studies (23, 29) carried out in small mesenteric arteries mounted in vitro suggested the opposite developmental pattern, i.e., that the magnitude of the myogenic response was greater in younger subjects. However, the baseline diameters of the vessels that comprised the two age groups were significantly different. This discrepancy could be important, because the intensity of pressure-induced myogenic vasoconstriction is proportional to the vessel diameter (4). Thus the difference in the magnitude of pressure-induced vasoconstriction could have reflected the different starting diameters, rather than a difference on the basis of developmental changes in the myogenic response.
The goal of these experiments was to reevaluate the developmental features of the myogenic response within the postnatal intestinal circulation by using an experimental format that circumvented the confounding variables present in earlier studies. To this end, the myogenic response was studied in vitro in small mesenteric arteries (diameter ~150 µm) harvested from 1- and 10-day-old swine. These age groups were chosen because the intravascular pressures and diameters of these arteries from these age groups are similar under in situ conditions. The putative role of PKC in generation and maintenance of myogenic vasoconstriction to increased transmural pressure was evaluated by activation of PKC with indolactam or attenuation of its function with calphostin C. As well, immunoblots were carried out to determine the presence of specific PKC isoforms in homogenates prepared from mesenteric arteries.
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METHODS |
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Animal Acquisition and Handling
Two age groups of postnatal swine were studied: 1 and 10 days old. Age ranges were not used in this study. Hence, subjects in the 1-day-old group were consistentlyIn Situ Studies of Small Mesenteric Arteries
These arteries are the distal-most portion of the mesenteric arterial arcade in swine and run, unbranched, from their origin in a dense arterial plexus to pierce the intestinal wall. A substantial pressure drop occurs across these vessels in situ, indicating their role as resistance vessels in the swine intestinal circulation. We have previously reported the in situ hemodynamic conditions for small mesenteric arteries in 2- to 6- and 32- to 40-day-old swine (29). It was necessary to duplicate these in situ studies for this project, however, because we did not have in situ data relevant to the 10-day-old age group. Intra-arterial pressures within these arteries were measured in anesthetized, ventilated, 1- and 10-day-old piglets. Saline-filled glass micropipettes, tip diameter 40 µm, were inserted into the vessels with the aid of a micromanipulator and dissecting microscope, and connected to a low-compliance pressure transducer. Separate arteries were impaled proximal to their origin at the arterial plexus, at midvessel, or at a distal site, just before their penetration of the intestinal wall (i.e., each artery was impaled at only 1 site). In all instances the micropipette was <40% of the luminal diameter of the artery. These measurements were carried out in five subjects in each age group; in all instances, these subjects were also used to harvest small mesenteric arteries for the immunoblot studies described below (harvested arteries were different from those used for the pressure measurements).In Vitro Studies of Small Mesenteric Arteries
Preparation. Arteries were removed from the mesentery of the distal jejunum and proximal ileum and mounted in the proper proximal-distal orientation between two glass micropipettes seated within a plastic chamber (Living Systems, Burlington, VT). The inflow pipette was fixed, whereas the outflow pipette was mounted on a micrometer to allow adjustment along the long axis of the vessel that was secured in place by 11-0 ophthalmic suture. Perfusion was achieved by using oxygenated Krebs buffer of the following composition (in mM): 118.1 NaCl, 4.8 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25.0 NaHCO3, 11.1 glucose, and 0.026 EDTA, pH 7.4 when gassed with 16% O2-5% CO2-balance N2 at 37°C. The perfusion circuit was designed as a "blind sac," i.e., the outflow circuit was closed to the artery once buffer had filled the arterial lumen. Pressure within the artery was regulated by a pressure transducer driven by a servo-controlled pump. This system allowed rapid and precise changes in pressure within the artery in the absence of intraluminal flow. This approach was chosen to study the myogenic response to changes in pressure inside the mesenteric artery in the absence of flow-induced mechanostimuli (29). The vessel chamber, and thus the exterior surface of the artery was continuously suffused with warmed, oxygenated Krebs buffer at a rate of 50 ml/min. The suffusate was continuously recirculated (total volume 200 ml). The vessel chamber was mounted on the stage of an inverted microscope set in line with a video camera. Vascular dimensions were measured with a precalibrated video dimension analyzer (V94; Living Systems) that displayed wall thickness and intraluminal diameter.
Experimental protocols.
In all instances the mounted artery was initially pressurized to 40 mmHg and allowed 30-45 min to reach a steady-state diameter. During this time, all functional arteries demonstrated a significant reduction in diameter (i.e., >20% reduction from the initial diameter when pressurized to 40 mmHg); arteries that did not demonstrate this
spontaneous constriction were discarded. A similar percentage of
arteries were discarded in both age groups. Pressure was then increased
to 45 mmHg, and the average midvessel pressure noted under in situ
conditions. The arteries either contracted or maintained their diameter
in response to this pressure challenge, indicating a myogenic response
to the increase in pressure. The suffusion buffer was switched to 40 mM
KCl-Krebs buffer, which elicited a brisk contraction in all arteries.
Substance P (108 M) was added to the suffusion buffer to
verify the presence of an intact endothelial layer, inasmuch as this
peptide activates the endothelial isoform of NOS in swine intestinal
endothelial cells (25). Vessels that did not contract
>50% to KCl or dilate >25% to substance P were discarded. A similar
percentage of arteries were discarded from both age groups. The buffers
were replaced with fresh Krebs and the pressure was left at 40 mmHg.
Thereafter, pressure was reduced to 0 mmHg and then increased to 100 mmHg in progressive increments of 20 mmHg (pressure ramp). Each
pressure was maintained until the vessel diameter attained a new
steady-state value. A second pressure ramp was then carried out after
the addition of either vehicle (dimethylsulfoxide), indolactam (0.1 µM), or calphostin C (1.0 µM) to the suffusion buffer, and again
after exchanging the suffusion buffer with a Ca2+-free
buffer containing 1 mM EGTA to determine the passive response of the
vessels to stepwise pressure increases. The doses of indolactam and
calphostin C were selected based on pilot studies in which the effects
of increasing drug concentrations on vessel diameter were noted at a
pressure of 50 mmHg.
Western Blotting
Terminal mesenteric arteries (TMAs) were removed from study subjects used for the in situ pressure experiments and were frozen by immersion into liquid N2. Frozen tissue was pulverized to a fine powder in a mortar filled with liquid N2 and then suspended in homogenization buffer of the following composition: 20 mM MOPS, 1% Triton, 4% SDS, 10% glycerol, 5.5 mM leupeptin, 5.5 mM pepstatin, 200 KIU aprotinin, 1 mM Na3VO4, 10 mM NaF, 100 µM ZnCl2, 20 mMData Analysis
Myogenic responsiveness of the vessels was determined by expressing vessel diameter in the presence of Ca2+ to the diameter under passive conditions (Ca2+ absent, EGTA added) at the same pressure. Comparisons of the pressure-diameter relationships were similar for the control portion of the studies for all four treatment groups within each age group. The control data for each age group were therefore pooled for the initial statistical comparison of control data between age groups (Fig. 1). This comparison was carried out by using a two-way ANOVA for repeated measures that utilized age group (1 and 10 day) and pressure (0-100 mmHg) as main effects. Comparison of treatment vs. control data was carried out by using the control data specific for that treatment group (i.e., not the pooled control data) (Figs. 4 and 5). These comparisons were carried out by using a three-way ANOVA for repeated measures that utilized age group, treatment (drug vs. control), and pressure as main effects. The F-statistic for both ANOVAs was significant (P < 0.01); thereafter, post hoc Tukey's B tests were carried out to determine the sites of significance, again accepting significance at the P < 0.01 level. Western blots for the PKC
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RESULTS |
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The intravascular pressures within small mesenteric arteries from 1- and 10-day-old subjects were similar under in situ conditions. In 1-day-old animals, pressures within the proximal, midpoint, and distal portions of the arteries were 50 ± 2, 43 ± 2, and 36 ± 2 mmHg. Pressures within similar portions in arteries from 10-day-old animals were 51 ± 3, 42 ± 3, and 36 ± 2, respectively. A substantial pressure drop from the proximal-to-distal portion of the artery was present under in situ conditions in both age groups (14 ± 2 mmHg in 1-day-old, 15 ± 2 mmHg in 10-day-old subjects), confirming that these vessels function as part of the resistance vasculature in postnatal swine intestine. The diameters of the small mesenteric arteries were similar in both age groups: 152 ± 13 microns in 1-day-old vs. 164 ± 14 µm in 10-day-old, respectively.
Despite their similar in situ diameters and pressure characteristics, the behavior of these vessels when pressurized under in vitro conditions was age specific (Fig. 1). Arteries from 1-day-old subjects demonstrated a significant decrease in vessel diameter when pressure was increased above the average in situ pressure of 42 mmHg, whereas vessels from 10-day-old subjects did not. Arteries from the 10-day-old subjects maintained their diameter when pressure was increased to 60 and then to 80 mmHg, i.e., they did not behave in a passive manner; yet, their response was clearly not as abrupt as that noted in the 1-day-old arteries.
The effects of calphostin C (1 µM), a selective PKC antagonist, were
age specific. The contractile response to pressure was significantly
attenuated by calphostin C in arteries from 1-day-old animals (Fig.
2). Treatment with calphostin C caused
small mesenteric arteries from 1-day-old animals to dilate in response
to pressure increments in a manner nearly identical to that caused by
eliminating Ca2+ from the perfusion and suffusion buffers.
In contrast to the dramatic change noted in younger subjects, arteries
from 10-day-old subjects failed to demonstrate a significant change in
the pressure-diameter relationship after pretreatment with calphostin
C, but did demonstrate completely passive behavior in response to
incremental increases in intravascular pressure when Ca2+
was removed from the buffers (Fig. 3).
The effects of calphostin C were specific to its action on PKC; thus
application of calphostin C did not effect the contractile response to
membrane depolarization induced by increasing the KCl concentration
within the suffusate buffer.
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Response of small mesenteric arteries to activation of PKC by
indolactam was also age-specific. Indolactam (0.1 µM) significantly increased the contractile response to pressure at all pressures >0
mmHg in TMAs from 1-day-old subjects and also shifted the initiation of
the response to a lower pressure level (Fig.
4). In contrast, indolactam did not exert
a significant effect on the contractile response to pressure in
arteries from 10-day-old animals (Fig. 5). However, the addition of greater
concentrations of indolactam to the superfusate buffer in arteries from
10-day-old animals increased their contractile response to pressure.
Thus in the presence of 1.0 µM indolactam, pressurization of 10-day
arteries to 40 and 60 mmHg led to an increased contraction, such that
the ratio of active to passive diameter decreased to 0.43 ± 0.03 and 0.42 ± 0.05, respectively, a level similar to that observed
in 1-day-old arteries. Pretreatment of arteries with calphostin C significantly attenuated the effect of indolactam on the response of
1-day-old arteries to step increases in pressure.
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Immunoblots carried out on homogenates of small mesenteric arteries
revealed the presence of five PKC isoforms in both age groups: ,
,
,
and
. (Fig. 6). Of
these, a clear reduction in expression of the
and
isoforms was
noted between postnatal days 1 and 10, whereas no
change in the
-,
-, or
-isoform was noted (Fig.
7). Densitometry was carried out on the
blots for the PKC
and -
isoforms. The intensity of PKC
,
expressed as a function of
-actin, was 87 ± 5 and 37 ± 4% for mesenteric arteries from 1- and 10-day-old subjects,
respectively (P < 0.01 by unpaired t-test). The intensity of PKC
was 32 ± 3 and
17 ± 3% for mesenteric arteries from 1- and 10-day-old subjects,
respectively (P < 0.01 by unpaired t-test).
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DISCUSSION |
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The Myogenic Response Is Age Dependent in Small Mesenteric Arteries
The first novel observation made in these experiments is that the relationship between intravascular pressure and vessel diameter in small mesenteric arteries is age specific in 1- and 10-day-old piglets. Vessels from 1-day-old subjects demonstrated a significant reduction in diameter when pressure was increased above the average pressure normally experienced by these vessels in situ, i.e., they displayed a sharp myogenic response. In contrast, arteries from 10-day-old subjects failed to demonstrate a significant reduction in diameter in response to pressure elevation, but instead maintained diameter over the pressure range normally experienced by this vessel in situ. It is important to note that the lack of a reduction in diameter in small mesenteric arteries from 10-day-old animals does not imply absence of myogenic response to pressure elevation; indeed, comparison of Figs. 1 and 5 clearly demonstrates that these vessels demonstrated contraction in response to stepwise pressure elevation, inasmuch as the pressure-diameter curves generated under control vs. Ca2+-free conditions were quite different. Rather, it can be concluded that the intensity of the myogenic response is age dependent, being more substantial in younger subjects.The design of this study eliminated many of the confounding variables that plagued previous studies of the myogenic response to pressure elevation in postnatal intestine (2, 26). Observations were made in isolated arteries (i.e., vessels that were devoid of surrounding parenchyma) thus eliminating potential interference by the putative metabolic feedback signal. This signal, generated by parenchymal elements in response to their level of oxygen sufficiency, functions as a vasodilating stimulus designed to augment oxygen transport and thus ensure that the oxygen supply/demand ratio remains favorable (12). This vasodilation could clearly interfere with the observation of myogenic vasoconstriction. As well, the studies were conducted under "no-flow" conditions, i.e., flow within the artery lumen was absent, achieved by keeping the pressures at the inlet and outlet micropipettes precisely equal. This arrangement prevented the generation of flow-induced dilation, a process wherein the mechanostimulus of flow stimulates the endothelial isoform of NOS to augment nitric oxide production (28). We (23, 29) have previously demonstrated that flow-induced dilation is present in small mesenteric arteries from 1-day-old animals and that it dramatically attenuates the myogenic response to intravascular pressure elevation. Finally, the diameters of 1- and 10-day-old arteries are similar, both under in situ conditions and when set at a pressure of 0 mmHg in vitro. Davis (4) demonstrated that the intensity of the myogenic response is inversely proportional to the diameter of the vessel. Thus our prior observations regarding developmental differences in the myogenic response of these vessels from 1- and 40-day-old subjects could have reflected the significant difference in the basal diameters of these vessels at these postnatal ages (23, 29).
What might be the physiological relevance of postnatal transition in the intensity of the myogenic response? The fetal intestine is functionally dormant compared with the newborn intestine and has a high vascular resistance, most likely because its oxidative demands are significantly less (7). In this context, it might be anticipated that mechanisms would be in place designed to enhance vascular tone and thus enhance resistance within the fetal intestinal circulation, such as an intensified myogenic response. The requirement for an increased basal vascular resistance across the intestine changes dramatically at birth, however, as increased intestinal function demands an enhanced oxygen delivery. Hence, the need for an intensified myogenic response is eliminated after parturition. Although this notion is speculative in nature, it is logical to expect some type of transitional physiology within the intestinal circulation during the emergence from fetal life, as clearly occurs in the other dormant fetal organ, the lung (33).
PKC Plays a Role in the Myogenic Response in Small Mesenteric Arteries from 1-Day-Old Subjects
The second novel observation made in these experiments was the age-specific participation of PKC in modulating the intensity of the myogenic response. Attenuation of PKC activity with the selective antagonist calphostin C (20) virtually eliminated the myogenic response in small mesenteric arteries from 1-day-old subjects, whereas stimulation of PKC activity with indolactam (14) significantly increased the degree of contraction in response to stepwise increases in intravascular pressure. In contrast to these effects, these agents failed to have a significant impact on the pressure-diameter relationship in small mesenteric arteries from 10-day-old subjects. A possible explanation for this age-specific response was found in the immunoblots; thus expression of theThe initial reports of the involvement of PKC in modulating the
myogenic response were on the basis of the effects of relatively nonspecific PKC antagonists (H7, staurosporine) on hemodynamic regulation within the microvasculature (15, 21). These
observations followed studies that demonstrated significant changes in
the myogenic response by -agonists, such as norepinephrine, inasmuch as it was established that
1 receptor binding enhanced the
production of diacylglycerol, one of several agents necessary to
activate the classic isoforms of PKC
, -
, and -
(8). Later work by Osol et al. (27) and
Karibe et al. (19) confirmed a role for PKC in the
myogenic response by using a more specific PKC antagonist, calphostin C
(20). These observations were pivotal in establishing a
key role for PKC in modulating the myogenic response because H7 and
staurosporine function by binding to the catalytic domain of PKC, a
domain shared by many kinases. Thus earlier observations could have
reflected attenuation of myosin light chain kinase function, rather
than just PKC (15, 21, 30). In contrast, calphostin C
functions by binding to the regulatory domain of PKC, an area not
shared by other kinases, making the agent highly specific for PKC
function (20). Subsequent work has suggested that the
effect of PKC on vascular tone is independent of changes in VSM
[Ca2+]i (10, 32). Instead, PKC
appears to function by phosphorylation of myosin binding proteins, such
as caldesmon and calponin; this action attenuates the inhibitory effect
of these proteins on the actin-myosin motor unit and thus increases the
Ca2+ sensitivity of the contractile apparatus, i.e.,
enhancing the degree of contraction achieved at a given VSM
[Ca2+]i (10, 24, 32).
The fact that expression of the - and
-isoforms of PKC decrease
between postnatal days 1 and 10 is certainly not
sufficient to conclude that these isoforms were responsible for the
changes in the pressure-diameter relationships noted in small
mesenteric arteries from 1-day-old animals after calphostin C or
indolactam. Indeed, although these agents are specific for PKC, they
are not selective in their function vis-à-vis a specific isoform
(14, 20). However, it is important to note that published
reports have linked these isoforms with vascular regulation,
particularly in modification of VSM contraction in response to a
pressure or stretch stimulus (1, 6, 13, 16). Thus Horowitz
et al. (16) applied the PKC
and -
isoforms to
saponin-permeablized VSM and noted the induction of contraction by the
isoform only, a contraction that was ablated by the PKC
pseudosubtrate inhibitor peptide PKC19-31. Later work from
the same laboratory demonstrated translocation of the
-isoform of
PKC in ferret coronary arterioles in response to a pressure stimulus
(6). In this context, translocation of PKC
occurs as
part of its activation, so that demonstration of PKC
translocation
implies activation of the enzyme in response to the stretch stimulus
provided by pressure increase.
In summary, three novel observations were made in these experiments.
The pressure-diameter relationships of small mesenteric arteries from
1- and 10-day-old piglets are different when studied in vitro, under
no-flow conditions; thus the magnitude of the myogenic contraction to
stepwise pressure elevation is present in both age groups, but is more
substantial in the 1-day-old group. Blockade or activation of PKC with
calphostin C or indolactam, respectively, significantly changes the
pressure-diameter relationship of small mesenteric arteries from 1-, but not 10-day-old subjects in a manner suggesting that PKC modulates
the myogenic response in younger subjects. Finally, protein expression
of the PKC and -
isoforms substantially decreases between
postnatal days 1 and 10. We conclude that the
intensity of the myogenic response in small mesenteric arteries from
postnatal intestine is developmentally regulated and speculate that
developmental expression of PKC, particularly PKC
and PKC
, may
participate in this phenomenon.
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ACKNOWLEDGEMENTS |
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We thank Chuck Miller and David Dunaway for outstanding technical support in these studies and Karen Watkins for secretarial support.
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FOOTNOTES |
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This study was supported by National Institute of Child Health and Human Development Grant HD-25256 (to P. T. Nowicki) and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-58580 (to K. M. Reber).
Address for reprint requests and other correspondence: P. T. Nowicki, Children's Hospital, 700 Children's Drive, Columbus, OH 43205 (nowickip{at}pediatrics.ohio-state.edu).
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. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00259.2002
Received 2 July 2002; accepted in final form 19 November 2002.
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