Department of Pediatrics, The Ohio State University and The Wexner Institute for Pediatric Research, Children's Hospital, Columbus, Ohio 43205
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ABSTRACT |
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Studies were conducted to determine if the response of in vitro mesenteric artery from 3- and 35-day-old swine to acute hypoxia was age dependent. Isometric tension developed by mesenteric artery rings was measured using a standard myograph apparatus. When the buffer aeration gas was changed from 95% O2-5% CO2 to 95% N2-5% CO2, phenylephrine-precontracted rings from both age groups consistently demonstrated a triphasic response, consisting of, in order, an initial, brief dilation, a sharp contraction, and a sustained loss of tone. The only portion of the triphasic response that was age dependent was the constrictor response, hypoxic vasoconstriction (HVC), which was significantly greater in rings from younger animals. HVC appeared to be mediated by a hypoxia-induced loss of constitutive nitric oxide production. Thus HVC was eliminated by endothelial removal, significantly attenuated by pretreatment with NG-monomethyl-L-arginine (L-NMMA), but not with NG-monomethyl-D-arginine, restored by coadministration of L-arginine, and accentuated by pretreatment with superoxide dismutase. Blockade of endothelin A receptors with BQ-610 or inhibition of cyclooxygenase or lipoxygenase activities with indomethacin or phenidone had no effect on HVC in either group. HVC appeared to be dependent on reduction in PO2, not on reduced ATP secondary to hypoxia, as it did not occur in rings administered 2,4-dinitrophenol, an agent that uncouples oxidative phosphorylation. The magnitude of HVC, which appears to be mediated by hypoxia-induced supression of NO production, is greater in mesenteric artery from 3-day-old swine than from 35-day-old swine.
swine; newborn intestine; intestinal circulation physiology
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INTRODUCTION |
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THE ROLE OF NITRIC OXIDE (NO) in establishing mesenteric artery tone is age dependent (13). Thus blockade of NO synthesis in vivo with arginine analogs increases mesenteric vascular resistance to a significantly greater degree in 3-day-old swine than in 35-day-old swine, whereas administration of the NO-dependent vasodilators ACh and substance P relax newborn mesenteric artery rings to a significantly greater extent than rings from older swine. This age-dependent dominance of NO within the newborn gut vasculature may represent an important part of the physiological transition from fetal to newborn life, because it contributes to the very low basal vascular resistance characteristic of newborn intestine (16, 17). This circumstance, in turn, assures a rate of gut blood flow and hence O2 delivery sufficient to satisfy the exceptionally increased O2 consumption by newborn intestine, which is generally twofold greater immediately after parturition than at 1 mo of postnatal age (16, 17).
The enhanced participation of NO in setting basal vascular resistance within newborn intestine might affect the response of this regional vasculature to local or systemic circulatory perturbations, especially if the response to those perturbations involves a change in the rate of NO production. Thus it might be predicted that circumstances that reduce NO production would cause a significantly greater vasoconstriction in newborn intestine, because of the relative importance of this dilator pathway at this postnatal age. Conversely, the response to situations that necessitate an increase in NO production might be blunted in newborn intestine, since the basal rate of NO production may exist, at rest, at a near-maximal level within the gut vasculature early after parturition.
One means to test this hypothesis is to determine the response of in vitro mesenteric artery rings to hypoxia, a perturbation that significantly affects endothelial cell NO production. Greenberg and Kishiyama (5) and Teng and Barer (29) reported sequential dilation-contraction-dilation within in vitro pulmonary artery rings after exposure to hypoxia. Based on the effects of pharmacological manipulation of the NO-cGMP axis, it was proposed (5, 29) that the initial dilation was consequent to hypoxia-induced stimulation of NO production, whereas the subsequent contraction reflected loss of NO synthesis as O2, a necessary cofactor in the synthetic reaction, became rate limiting (9). If a similar effect occurs within the mesenteric artery, then the magnitude of the initial hypoxia-induced dilation and subsequent contraction should be age dependent, i.e., lesser and greater, respectively, in younger animals.
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METHODS |
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Blood vessel removal. Animal care was provided in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals [DHHS Publication No. (NIH) 85-23, Revised 1985, Office of Science and Health Reports, Bethesda, MD 20892], and all experimental protocols were approved by the Institutional Animal Care and Use Committee of Children's Hospital. Studies were conducted using farm-bred swine, and the following two age groups were studied: 3-day-old (range 2-4 days) and 35-day-old (range 32-38 days) swine. All animals were obtained on the day before use and fasted for 12-18 h before surgery. Swine were anesthetized with tiletamine hydrochloride/zolazepam hydrochloride (6 mg/kg ip) and xylazine (4 mg/kg ip), catheterized via the carotid artery, exsanguinated, and finally killed by overdose of pentobarbital sodium (6 mg/kg iv). The entire mesenteric artery was removed en bloc, immediately placed in iced Krebs buffer, cleansed of adherent connective tissue, and cut into 3-mm rings. Care was taken to avoid stretching the vessel or touching the intimal surface. Rings used in these experiments were cut from the main mesenteric trunk between the colic and first jejunal branch. In some experiments, mechanical removal of the endothelium was deliberately achieved by passing a coarse silk thread through the vessel lumen three times.
Preparation of in vitro arterial rings. Rings were mounted between two stainless steel stirrups placed within water-jacketed 20-ml glass wells. One stirrup was fixed to the bottom of the well, and the second was tethered to a force transducer (model FT03, Grass Instruments, Quincy, MA) to facilitate continuous measurement of isometric tension on a multichannel recording device (model 7 polygraph, Grass Instruments). The well was filled with 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. The buffer was maintained at 38°C and, except during the induction of hypoxia, was continuously aerated with 95% O2-5% CO2.
The mesenteric artery rings were progressively stretched over 1-2 h to the optimal point on their length-tension curve, as determined by noting the maximal contractile response to Krebs buffer containing 80 mM KCl. Rings were then allowed to equilibrate for 1 h in fresh buffer at this tension. Endothelial integrity was determined in all rings by noting their response to 10Experimental protocols. A similar protocol was used for all experiments, as follows. After we determined optimal resting tension and endothelial integrity for each ring, the rings were allowed to equilibrate in Krebs buffer aerated with 95% O2-5% CO2 until resting tension was stable, defined as maintenance of tension within 2% of baseline. This initial stabilization generally required 20 min. When indicated by the experimental protocol, agonists and/or antagonists were added to the buffer wells at this time. Thereafter, the rings were precontracted to ~75% of their maximal tension with phenylephrine. Once new steady-state tensions were noted, hypoxia was induced by changing the aeration gas to 95% N2-5% CO2. Hypoxia was continued until ring tension reached its final steady-state value over a period of ~15 min.
Six variations of this protocol were carried out in mesenteric artery rings from 3- and 35-day-old swine. First, to determine if the endothelium participated in the response of mesenteric artery rings to acute hypoxia in vitro, a comparison was made between endothelium-intact (E+) and endothelium-denuded (EDrugs and reagents. ACh, phenylephrine, SOD, and phenidone were obtained from Sigma Chemical (St. Louis, MO), while L-NMMA, D-NMMA, and L-arginine were obtained from Calbiochem (La Jolla, CA). Stock solutions of these agents were prepared in distilled water at concentrations adequate to produce the final desired concentration when 0.1 ml stock was added to a 20-ml myograph well. BQ-610, obtained from Peptides International (Louisville, KY), was first dissolved in DMSO and then diluted in distilled water. Indomethacin (Sigma Chemical) was first dissolved in 100 mM sodium carbonate and then diluted in distilled water. DNP and dexamethasone (Sigma Chemical) were first dissolved in 95% ethanol and then diluted in distilled water. All drugs were prepared daily and kept on ice until use.
Statistical methods. Absolute changes in isometric ring tension were recorded in grams but were expressed as a percentage of baseline to facilitate comparison between age groups. This transformation proved necessary because the resting tension and magnitude of change were consistently greater in rings from 35-day-old swine, since their internal and external diameters were substantially greater (13). The means used to carry out data transformation are shown in Fig. 1. All observations were made in paired rings, and the mean response was used for analysis. In all instances, n refers to the number of individual animals in which observations were made. Statistical significance was determined by a three-way analysis of variance (ANOVA), which utilized age group, time after induction of hypoxia, and experimental condition as main effects. When the F statistic for ANOVA was significant (P < 0.05), post hoc Student's t-tests were carried out to determine the sites of significant difference within each data set.
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RESULTS |
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Reduction of buffer PO2 consistently caused a triphasic change in ring tension in both age groups (Fig. 1). Tension initially decreased slightly. This phase, hereafter termed hypoxic vasodilation-1 (HVD-1), began ~1 min after the aeration gas mixture was changed to 95% N2-5% CO2, a delay that corresponded to the time necessary for buffer PO2 to fall to <40 mmHg. The nadir of HVD-1 consistently occurred ~1 min after its initiation in both age groups, and the relative magnitude of HVD-1 was similar in both age groups (Fig. 2). Rings then demonstrated hypoxic vasoconstriction (HVC). The elapsed time between the nadir of HVD-1 and the peak of HVC was consistently ~2 min in both age groups. However, the relative magnitude of HVC was significantly greater in rings from younger swine (Fig. 2). Finally, all rings demonstrated a gradual dilation that continued until ring tension returned to prehypoxia baseline (~10 min). The relative magnitude of this second hypoxic vasodilation (HVD-2) was similar in both age groups (Fig. 2).
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HVD-1 was clearly endothelium dependent in both age groups, as
evidenced by its virtual elimination in
E rings (Fig. 2). The
addition of agents that affect NO, cyclooxygenase, or lipoxygenase
failed to exert a significant effect on this phase of the hypoxic
response; pretreatment of E+ rings
with L-NMMA or SOD (Figs.
3 and 4) and
indomethacin, dexamethasone, or phenidone (Table
1) did not significantly alter HVD-1 in
either age group. However, the means used to precontract
the study rings did modify HVD-1 in both age groups. When
precontraction of E+ rings to 75%
of maximal tension was achieved by depolarization with 40 mM KCl-Krebs
buffer, instead of phenylephrine, the magnitude of HVD-1 was reduced.
In rings from 3-day-old animals, HVD-1 after depolarization-precontraction was decreased from
16 ± 4%
(control) to
5 ± 6% (P < 0.05). In rings from 35-day-old swine, HVD-1 was reduced from
12 ± 3% (control) to
1 ± 2%
(P < 0.05).
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HVC was also clearly endothelium dependent in both age groups, being
virtually abolished in E
rings (Fig. 2). Basal ring tension and the magnitude of HVC were significantly altered by agents that affect NO production or half-life. The initial addition of L-NMMA
to the myograph well, applied under normoxic conditions, increased
vessel tone to a modest degree (+14 ± 2% and +9 ± 1%, in 3- and 35-day-old swine, respectively). To account for this contraction,
the subsequent addition of phenylephrine was adjusted in each ring so
that its final precontraction tension was 75% of the maximal tension
possible for that specific ring. This adjustment in dosing was made to
ensure that the subsequent response to hypoxia was not affected by a
variable degree of initial ring tension (5). Pretreatment with
L-NMMA
(10
4 M) significantly
reduced HVC in 3- and 35-day-old rings. In both groups, however, HVC
was restored by coadministration of
L-arginine (10
3 M; Figs. 3 and 4). In
contrast to L-NMMA,
D-NMMA
(10
4 M) had no effect on
HVC or on any other phase of the hypoxic response in either age group
(Table 1). Furthermore, D-NMMA
did not affect vessel tone under normoxic conditions. Pretreatment with
SOD (50 U/ml) increased the magnitude of HVC in rings from younger
swine (Fig. 3). Although a similar trend was noted in older swine, the
magnitude of the response was not statistically significant (Fig. 4).
Pretreatment of E+ rings with
BQ-610 (10
3 M),
indomethacin (10
5 M),
dexamethasone (10
5 M), and
phenidone (10
6 M) had no
effect on the magnitude of HVC in either age group (Table
1).
HVD-2 was the only phase of the hypoxic response not altered by
mechanical removal of the endothelium (Fig. 2). Similarly, HVD-2 was
not affected by L-NMMA, SOD,
BQ-610, indomethacin, dexamethasone, or phenidone (Figs. 3 and 4; Table
1). Administration of DNP (103
M) to E+ rings
aerated with 95% O2-5%
CO2 caused relaxation of rings
from both age groups that was temporally and quantitatively similar to
the HVD-2 noted during hypoxic challenge (Fig.
5). Thus DNP caused a progressive reduction
in ring tension beginning ~4 min after its administration, a time of
onset that corresponded to the beginning of HVD-2 in
E+ rings exposed to
PO2
reduction. HVD-1 and HVC were not noted after DNP administration.
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DISCUSSION |
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Two novel observations were made in these experiments. First, the responses of in vitro postnatal mesenteric artery rings to hypoxia, i.e., sequential dilation-contraction-dilation, were qualitatively and quantitatively similar to that noted in the pulmonary artery by Greenberg and Kishiyama (5) and Teng and Barer (29). Second, the magnitude of one phase of this response, HVC, was significantly greater in mesenteric artery rings from 3-day-old swine than from 35-day-old swine. This latter observation was consistent with our working hypothesis, which predicted that hypoxia-induced attenuation of NO synthesis would exert a greater contractile effect in mesenteric artery from younger swine. We have previously demonstrated that the relative participation of NO in setting basal vascular tone is age dependent in postnatal swine mesenteric artery, i.e., that the role of the NO-cGMP axis is greater in younger swine (13).
The present observations strongly support the conclusion that HVC was
mediated by hypoxia-induced reduction of NO synthesis, a conclusion
also reached by Greenberg and Kishiyama (5). HVC was eliminated by
mechanical removal of the endothelium, the presumed site of
constitutive NO production within blood vessels (3, 5, 25). Second, HVC
was significantly attenuated by prior administration of
L-NMMA, but not
D-NMMA, an arginine analog that competes with L-arginine for the
catalytic site on NO synthase (NOS) and thus decreases NO production in
a stereo-specific fashion. Furthermore, the
L-NMMA effect was blunted by
coadministration of L-arginine
(4). The magnitude of HVC was accentuated by administration of SOD, an
agent that enhances NO half-life by interfering with
-mediated conversion of NO to
peroxynitrite (19, 28). In contrast to these effects, administration of
agents that do not exert a direct effect on NO synthesis or half-life
had no effect on HVC. Administration of BQ-610, a highly selective
antagonist of the ETA receptor,
had no effect on the magnitude of HVC. This observation effectively
eliminates a role for endothelin-1 in mediating HVC. This observation
was expected, however, because regulation of endothelin production
appears to be mediated at the level of gene transcription, a process
that requires hours (8, 30, 31). The HVC noted in these studies occurred minutes, not hours, after the induction of hypoxia. Blockade of cyclooxygenase, phospholipase
A2, and lipoxygenase had no effect on the magnitude of HVC, suggesting that eicosanoids do not mediate this response in postnatal mesenteric artery.
What is the basis for the hypoxia-induced attenuation of NO production? Hypoxia most likely compromised endothelial NOS (ecNOS) activity by limiting the substrates required by this enzyme. The conversion of L-arginine to L-citrulline by ecNOS requires molecular O2 and NADPH as obligatory cosubstrates. Indeed, the O2 atom within the NO released during this reaction is derived from the molecular O2 cosubstrate (9, 10, 24). One might question whether reduction of buffer PO2 to <40 mmHg was actually sufficient to reduce the availability of molecular O2. However, this work was carried out in a hemoglobin-free solution, so that the actual molar concentration of O2 during hypoxia was certainly very low. The paramount role of hypoxia in causing HVC was supported by the DNP data. DNP, an agent that uncouples oxidative phosphorylation, leading to rapid exhaustion of ATP (3), did not cause HVC, as DNP has no effect on buffer PO2.
The mechanistic basis for the initial, brief dilation noted in response to hypoxia, HVD-1, is not clear from the data collected in this study. The sole conclusion that can be reached regarding HVD-1 is that it is endothelium dependent, since it was virtually eliminated by mechanical removal of the endothelium. It has been suggested that HVD is mediated by enhanced production of NO by the vascular endothelium. Chief among the proponents of NO-based HVD are Pohl (22, 23) and Pittman (21), who have suggested that the endothelium serves as an O2 sensor, i.e., that changes in blood PO2 are determined by the endothelium and that this signal activates NOS. The presence of a heme cofactor bound to endothelial cell NOS enhances the plausibility of this contention, because it provides a specific site where PO2 might change the tertiary structure of the enzyme and hence alter its functional capabilities (10). In this context, Greenberg and Kishiyama (5) concluded that HVD-1 noted in rat pulmonary artery was mediated by a hypoxia-induced increase in NO production, as evidenced by the effect of agents that alter NO synthesis on this response. A partial role for NO in mediating HVD-1 in the present study cannot be ruled out. Thus HVD-1 observed after L-NMMA was numerically, but not significantly, less than that noted under control conditions. Strong evidence has been presented in other studies (1, 2, 11, 14, 18, 20, 22) implicating endothelial production of prostacyclin as the basis for in situ or in vitro HVD. In contrast to these findings, we noted no change in HVD-1 in rings pretreated with indomethacin at a dose previously established to create satisfactory blockade of cyclooxygenase activity. Finally, it is possible that HVD-1 is mediated, at least in part, by an endothelium-derived hyperpolarizing factor. Indirect support for this contention can be derived from the KCl-precontraction data. Thus precontracting the rings by depolarization with KCl attenuated the magnitude of HVD-1 in both age groups. Prior depolarization would prevent the subsequent relaxant effect of a hyperpolarizing factor.
Several conclusions can be drawn regarding the mechanistic basis for the final dilation, or HVD-2. HVD-2 is clearly endothelium independent and does not appear to involve the NO-cGMP axis since it was unaffected by mechanical removal of the endothelium or administration of L-NMMA or SOD. These observations are consistent with those made by Greenberg and Kishiyama (5), Messina et al. (11), and Muramatsu et al. (12). A role for vasodilatory eicosanoids in HVD-2 was eliminated by incubation with the appropriate agents. The time course of the DNP data (i.e., HVD-2 commencing when HVC was occurring in control rings) suggests that HVD-2 was not consequent to a decrease in O2 levels but rather was due to a reduction in intracellular ATP concentration, ultimately leading to an inability of the vascular smooth muscle to contract, a process that requires energy (26).
Control of intestinal hemodynamics is determined by a dynamic balance among a variety of vasoactive effector systems, including those whose origin is extrinsic to the gut (e.g., sympathetic innervation) and those whose origin is intrinsic to the gut parenchyma and its attendant vasculature (e.g., metabolic regulation, autacoids such as NO). The perturbation of acute hypoxemia most certainly engages most if not all of these mechanisms. In newborn swine, the net response to acute arterial hypoxemia is profound vasoconstriction to an extent significantly greater than that noted in older swine. In part, this response is mediated by increased adrenergic tone generated in response to arterial hypoxemia, as evidenced by the ameliorating effect of surgical or pharmacological gut denervation on HVC (17). We interpret the present data to indicate that part of the intense HVC noted within newborn gut in situ is also mediated by a loss of constitutive NO production by the gut vascular endothelium. Basal or constitutive production of NO plays a more substantial role in setting resting vascular tone in newborn than in older intestine (13). Factors that damage the endothelium or otherwise interfere with NO production, such as acute hypoxia, would thus eliminate the strong dilatory influence of NO and contribute to vasoconstriction and ischemia (15). We speculate that this circumstance may explain the increased propensity of newborn intestine to ischemia and ischemic tissue damage (6, 7).
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ACKNOWLEDGEMENTS |
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We thank Dr. Philip Nowicki for review of the manuscript, David Dunaway for technical support, and Cecelia Battin and MeraDee Longnecker for secretarial assistance.
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FOOTNOTES |
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Address for reprint requests: C. A. Nankervis, Children's Hospital, 700 Children's Dr., Columbus, OH 43205.
Received 17 March 1997; accepted in final form 5 January 1998.
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