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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The effect of prior in vivo hypoxia on the in vitro responses to changes in transmural pressure,
-adrenoceptor activation, and depolarization with KCl were evaluated in first-order diaphragmatic arterioles. Rats (n = 14 per group) were exposed to normoxia (controls) or to hypoxia (inspired O2
concentration = 10%) for 12 or 48 h. The arteriolar pressure-diameter relationships were recorded
over a pressure range from 10 to 200 mm Hg. In separate groups of arterioles (n = 12 per group), the
diaphragmatic arteriolar responses to phenylephrine (10
8 to 105 M) or KCl (10 to 100 mM) were
determined after exposure to either room air or hypoxia for 48 h. In half of the arterioles studied, the
endothelium was removed. After 12 h of hypoxia, the pressure-diameter relationship was normal in
endothelialized arterioles but was shifted upward in de-endothelialized vessels (p < 0.05). After 48 h
of hypoxia, the constrictor response to increasing transmural pressure was severely suppressed in all
arterioles. The intraluminal diameters during activation with phenylephrine and KCl were larger in
arterioles from rats exposed to hypoxia (103 ± 8 and 81 ± 7 µm, respectively) than in control arterioles (41 ± 5 and 54 ± 6 µm, respectively; p < 0.05 for differences). During maximum phenylephrine-
and KCl-induced constriction in de-endothelialized arterioles, diameters averaged 125 ± 8 and 105 ± 8 µm, respectively, for arterioles from hypoxic rats and 32 ± 6 and 40 ± 5 µm, respectively, for arterioles from control vessels. Exposure to hypoxia results in impairment of diaphragmatic arteriolar smooth
muscle reactivity and reversal of the normal inhibitory influence of the endothelium on diaphragmatic arteriolar tone.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Hypoxia is frequently observed in patients with pulmonary disease, in patients with shock (1), and in normal subjects at high altitude. The maintenance of vital organ function in these conditions depends on adaptive responses from the systemic vasculature which redistribute blood flow and enhance the capacity for oxygen extraction (2, 3). These responses are particularly important in the diaphragm because oxygen and substrate supply to this muscle must be maintained in proportion to its metabolic requirements in order to sustain spontaneous ventilation (4, 5).
Both the intrinsic arteriolar responses to changes in transmural pressure and reactivity to adrenoceptor activation are
important in regulating diaphragm oxygen supply. Pressure-dependent responses permit the phrenic circulation to autoregulate its blood flow during fluctuations in systemic blood
pressure (6). Regional adjustment adrenergic tone is required
for optimization of intramuscular blood flow distribution in
order to maximize oxygen extraction (7, 8). These mechanisms are interdependent since the pressure sensitivity of arterioles is governed by the level of sympathetic tone (9) and
pressure-dependent responses contribute to the constriction
elicited by -adrenoceptor stimulation (10, 11). Any deleterious effect of hypoxia on pressure-dependent or adrenergic responses of diaphragmatic arterioles will, therefore, have a negative impact on the capacity to preserve diaphragm energy
status.
This study was undertaken to determine if systemic hypoxia induces alterations in diaphragmatic arteriolar smooth
muscle function which impair the contractile responses to increases in transmural pressure and -adrenoceptor activation.
Hypoxia is also known to elicit changes in endothelium-dependent pathways of vasoregulation (12, 13). A second goal, therefore, was to evaluate the role of the endothelium in modulating the effects of hypoxia arteriolar responses.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies performed on diaphragmatic arterioles from male Sprague-Dawley rats (150 to 200 g). The protocols were approved by the animal use committees of McGill University and the Royal Victoria Hospital.
Arteriole Isolation
The diaphragms were removed immediately after decapitation and placed in cold (0 to 4° C), oxygenated, bicarbonate-buffered, physiologic salt solution (PSS; in g/L: NaCl, 8.29; KCl, 0.35; MgSO4, 0.42; EDTA, 0.15; CaCl2, 0.41; KH2PO4, 0.16; glucose, 0.90 [pH 7.4] ). The muscle was pinned to the bottom of the silicone-lined base of a dissecting dish. A first-order arteriole was identified as the first major arteriole penetrating the muscle (14, 15). A segment 1 mm in length was cleared from the adhering tissue and transferred to a plexiglas vessel chamber (Living Systems, Burlington, VT) containing PSS. The proximal end of the arteriole was mounted to the inflow cannula and secured with 12-0 suture. The perfusion pressure was then increased to 20 mm Hg with a pressure-servo micropump system (Living Systems) taking its inflow from a reservoir of PSS buffered to pH 7.4. After the arteriole was cleared of clotted blood, its distal end was mounted to the outflow cannula. The arteriole was set to its in situ length using an eyepiece micrometer. The outflow cannula was closed, and the transmural pressure (i.e., intraluminal pressure relative to atmospheric pressure) was slowly increased to 70 mm Hg. The pressure-servo system was then placed in manual mode, where a stable pressure value indicated that there was no leak in the system. Vessels in which a leak was detected were discarded.
The apparatus was transferred to an inverted microscope (Nikon
TMS-F, 20× objective). Measurements of internal diameter were made using a high-resolution CCD video camera (Hitachi KPC503) and a video tracking device (Video Image Analyzer V94; Living Systems) calibrated using a stage micrometer. The vessel was continuously superfused with PSS flowing through the chamber at a rate of
6 ml/min. The chamber was warmed to 37° C using a heat exchanger
in line with the superfusion pump over 60 min and maintained at this
temperature throughout the experimental protocol. During this stabilization period, the superfusion solution and the vessel chamber were
bubbled with 21% O2, 5% CO2, balance N2 gas mixture. A plexiglas
cover excluded ambient air from the chamber. Chamber temperature
and pH were monitored continuously using a probe (Oakton Series
35616; Oakton, Singapore), and samples of the superfusing buffer
were periodically drawn from the chamber for gas analysis. Under
these conditions, the vessels gradually developed spontaneous tone
independent of vasoconstrictor agents, resulting in a reduction in diameter compared with the beginning of the equilibration period (Table 1). A greater than 20% further reduction in intraluminal diameter in response to 80 mM KCl was used as a second indicator of vessel viability (16). Endothelium-dependent and -independent dilation were
evaluated in all vessels by determining the ability of acetylcholine (Ach; 104 M) and sodium nitroprusside (SNP; 104 M), respectively,
to inhibit intrinsic tone. In all vessels used in this study, Ach inhibited
spontaneous tone (Table 1) and exposure to SNP resulted in dilation
to a diameter similar to that recorded under passive conditions at the
end of the experiments.
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Endothelial Removal
In all arterioles, the responses to Ach and SNP were evaluated following the initial equilibration period. In vessels in which the endothelium was to be removed, the intraluminal pressure was reduced to 20 mm Hg, the stopcock on the outflow cannula was opened, and the arterioles were perfused with 2 ml of air. The arterioles were then perfused with PSS for 10 to 15 min at 20 mm Hg to flush the separated endothelial layer from the vessel lumen and out of the cannula system. The outflow cannula was closed, the intraluminal pressure was restored to 70 mm Hg, and the dilatory responses to Ach and SNP were once again determined. In previous histologic studies (16), elimination of vasodilation in response to Ach with an intact vasodilatory response to SNP has been shown to be associated with ablation of the endothelial cell layer and, in the current study, was taken as evidence of successful endothelial removal.
Exposure to Hypoxia
Rats were placed in a plexiglas chamber (12 × 7 × 5 inches). Flow of air and nitrogen into the chamber were controlled independently. Outflow was through an underwater seal. For animals exposed to hypoxia, the gas inflow consisted of air at a rate of 3 L/min and nitrogen at 3 L/min (FIO2 = 0.1). Control animals were exposed to air only. Gas samples were drawn periodically from the chamber for analysis (Model 995; AVL Instruments, Graz, Austria) to ensure that the appropriate ambient PO2 was maintained. A total flow rate of 6 L/min prevented CO2 accumulation. All rats were provided with rat chow and water ad libitum. Temperature within the chamber was monitored using a temperature probe (SST1; Physitemp Instruments Inc., Clifton, NJ) and remained the same as the surrounding room temperature throughout the exposure period. In preliminary experiments (n = 4), in which blood was sampled through a cannula in the carotid artery, exposure to hypoxia according to the above procedure resulted in arterial PO2 values of 35 to 39 mm Hg with arterial PCO2 values of 32 to 35 mm Hg.
Experimental Protocols
Protocol 1: pressure-diameter relationship. The relationships between intraluminal pressure and internal diameter were constructed for arterioles from control rats and rats exposed to hypoxia for 12 or 48 h. Fourteen arterioles (one arteriole per animal) from each group of rats were studied. In seven of these, studies were performed with the endothelium intact. In the remaining seven arterioles, the endothelium was removed before carrying out the pressure-diameter protocol. After the initial equilibration period, arteriolar diameter was measured at an intraluminal pressure of 70 mm Hg and, from that point, pressure was stepped downward or upward by 10 mm Hg over a range of 10 to 200 mm Hg. After each step change in pressure, arteriolar diameters reached steady state after approximately 1 min and recordings of internal diameter were taken after 5 min. Because vessels pressurized above 140 mm Hg generally failed to regain normal tone at lower pressures, recordings at pressures higher than this were performed last.
On completion of the protocol, pressure-diameter data were collected for the vessels in the passive state over a pressure range from 10 to 200 mm Hg. The passive state was achieved by bathing the arterioles in calcium-free PSS containing EGTA (4 mM) and adenosine
(104 M).
Protocol 2: responses to phenylephrine and KCl. In order to determine if smooth muscle contraction elicited by receptor activation and
by membrane depolarization are also impaired after exposure to hypoxia, concentration-response relationships were constructed for phenylephrine (107 to 103 M) and KCl (10 to 100 mM), respectively. Four
groups of arterioles (n = 12 per group) were studied. These groups
represent arterioles from control (normoxic) rats and rats that had
been exposed to hypoxia for 48 h in which the response to either phenylephrine or KCl was determined. Phenylephrine and KCl responses
were assessed in separate groups of arterioles. In six arterioles in each
group, studies were performed with the endothelium intact. In the remaining six arterioles, the endothelium was removed. Phenylephrine
and KCl (in PSS) were added to the bath using a syringe pump (Harvard) connected to the superfusion line. The concentrations of these agents in the syringe and the flow rate of this pump relative to that of
the superfusion buffer were adjusted to achieve the desired concentrations in the superfusion solution. The responses were evaluated at
an intraluminal pressure of 70 mm Hg. This level was chosen because
in vivo recordings have documented comparable pressures in arterioles of this size in intact rat skeletal muscle (17). The response to KCl
was tested in the presence of propranolol (106 M) and phentolamine
(105 M). These antagonists were added in order to block endogenous norepinephrine possibly released by depolarization of nerves. At the
end of the concentration-response protocol, the passive diameter at
an intraluminal pressure of 70 mm Hg was recorded for each arteriole
as described above.
Data Analysis
In constructing the pressure-diameter relationships, diameters were normalized as a percentage of the passive diameter at an intraluminal pressure of 70 mm Hg since this is the pressure recorded in skeletal muscle arterioles of this size in vivo (17). In arterioles from normoxic animals, diameter did not change significantly over the pressure range from 40 to 140 mm Hg. The slopes of the pressure-diameter relationships over this range of intraluminal pressures were, therefore, calculated in order to illustrate differences in the responses to increasing transmural pressure among groups. Concentration-response relationships were evaluated by comparing the minimum diameters achieved during maximum constriction and the concentration of agonist that produces 50% of the maximal response (EC50). EC50 were derived from nonlinear least-squares regression analysis. Between-groups comparisons were performed by analysis of variance (ANOVA) corrected for repeated measures when appropriate. If the ANOVA revealed significant overall differences, variations among individual means were evaluated post hoc using the Student-Neuman-Keuls procedure. Results are expressed as the means ± SE for n number of vessels (one per animal), with p < 0.05 representing significance.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The internal diameters recorded at 70 mm Hg intraluminal pressure following the development of tone at the end of the equilibration period, during exposure to Ach, and during exposure to SNP for vessels used in protocols 1 and 2 are presented in Table 1. Diameters during exposure to SNP did not differ from those recorded under passive conditions and did not vary among groups. Spontaneous tone developed during the equilibration period in all vessels, as reflected by smaller diameters at the end of this period compared with those recorded under passive conditions (Table 1). The degree of spontaneous tone at the end of the equilibration period was less, and the diameter greater, in arterioles from rats exposed to hypoxia for 48 h compared with those from control rats and from rats exposed to hypoxia for 12 h (Table 1).
Protocol 1: Pressure-diameter Relationship
In Figure 1, the active and passive pressure-diameter relationships are plotted for vessels from control (normoxic) rats with and without endothelium. Smooth muscle activation was elicited, as reflected by a significant difference between the active
and passive diameters, at pressures as low as 20 mm Hg. Between pressures of 40 and 140 mm Hg, no significant change in
diameter occurred in either group and the slopes of the relationships over this pressure range did not differ (
0.038 ± 0.022 and 0.034 ± 0.018 for endothelialized and de-endothelialized arterioles, respectively). The active pressure-diameter
relationship is shifted downward in the de-endothelialized vessels in comparison to those in which the endothelium was left
intact (p < 0.05, ANOVA), indicating a tonic negative influence of the endothelium on arteriolar tone. The passive pressure-diameter relationship does not differ between vessels in
which the endothelium was intact and those in which the endothelium was removed.
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The effect of exposure to hypoxia for 12 h on the diaphragmatic arteriolar response to increasing transmural pressure is illustrated in Figure 2. The pressure-diameter relationship for endothelialized arterioles from animals exposed to hypoxia for 12 h does not differ from that for arterioles from normoxic animals (slope = 0.044 ± 0.029; p > 0.05 for difference from zero). Removal of the endothelium in this group of animals did not significantly alter the pressure-diameter relationship (slope = 0.029 ± 0.01; p > 0.05) for differences from zero and from endothelialized arterioles). In de-endothelialized arterioles from this group, the pressure-diameter relationship is shifted upward (p < 0.05, ANOVA) compared with that for de-endothelialized arterioles from control animals.
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The effect of exposure to hypoxia for 48 h on the arteriolar pressure-diameter relationship is illustrated in Figure 3. After 48 h of hypoxia, the response to increased transmural pressure is severely suppressed in both endothelialized and de-endothelialized vessels. The slope of the relationship over the pressure range from 40 to 140 mm Hg is 0.107 ± 0.01 (p < 0.05 for differences from zero and from control). In this group, the pressure-diameter relationship for arterioles in which the endothelium was removed did not differ from that for arterioles in which the endothelium was left intact. The slope of the relationship for the de-endothelialized arterioles is 0.117 ± 0.009 (p > 0.05 for difference from endothelialized arterioles; p < 0.05 for difference from control).
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Protocol 2
In Figure 4, the phenylephrine concentration-response relationship for endothelialized and de-endothelialized arterioles from control rats and rats exposed to hypoxia for 48 h is illustrated. The diameters during maximum constriction and the EC50 values for each of these groups are presented in Table 2. Exposure to hypoxia was associated with a marked impairment of maximum constriction. The EC50 was the same in arterioles from both control and hypoxia-exposed animals. Removal of the endothelium resulted in lower EC50 values in arterioles from both groups. In control vessels, maximum constriction was enhanced by removing the endothelium. In arterioles from animals exposed to hypoxia, endothelial removal reduced the maximum response to phenylephrine.
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In Figure 5, the KCl concentration-response relationships for endothelialized and de-endothelialized arterioles from control rats and rats exposed to hypoxia for 48 h are illustrated. The diameters during maximum constriction and the EC50 values for each of these groups are presented in Table 2. Exposure to hypoxia impaired maximum constriction to KCl. Note that prior hypoxic exposure was more detrimental to the response to phenylephrine than it was to KCl-induced constriction. The EC50 for KCl was the same in both groups and was not significantly altered by removal of the endothelium. In control vessels, maximum constriction was enhanced by removing the endothelium. In arterioles from animals exposed to hypoxia, endothelial removal further impaired the maximum response.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The main findings of this study are that prolonged exposure to
hypoxia results in: (1) impaired contraction of diaphragmatic arteriolar smooth muscle in response to increases in transmural pressure, -adrenoreceptor stimulation, and depolarization
with KCl; (2) elimination of the normal tonic endothelium-
dependent inhibition of arteriolar tone during increases in transmural pressure; and (3) endothelium-dependent enhancement
of maximum arteriolar constriction during activation by phenylephrine and KCl.
We have evaluated the effects of exposure to hypoxia in vivo on in vitro diaphragmatic arteriolar contractility. The study does not include experiments designed to dissociate the direct effects of hypoxia from those of increased blood flow or to neurohumoral mediators released as part of the systemic response. Nonetheless, hypoxia, as presented in this study, simulates a clinically and physiologically relevant condition. It should also be noted that we have evaluated the role of the endothelium in modulating the diaphragmatic arteriolar response to changes in transmural pressure and to agonists under zero-flow conditions. The endothelial involvement in the regulation of arteriolar diameter may, therefore, differ from that observed in vivo, where the changes induced by hypoxia will interact with the effects of flow.
Most previous studies of the cardiovascular effects of hypoxia have involved either acute (minutes) or chronic (weeks to months) exposures. In arterioles from rat skeletal muscle, acute exposure to hypoxia in vitro inhibits tone through endothelium-dependent mechanisms (18, 19). During acute hypoxia in vivo, both constriction and dilation of skeletal muscle arterioles have been observed (20). The response of the diaphragmatic microcirculation to hypoxia has been evaluated only by in vivo microscopy (2). In that study, acute reductions in diaphragmatic oxygenation were found to elicit both arteriolar dilation and constriction (2). In all of these previous studies, the changes in arteriolar diameter were fully reversed upon restoration of normoxia.
Studies of the effects of chronic hypoxia (weeks to months) on in vivo systemic vasoreactivity have yielded conflicting data. Augmented (21), impaired (22), and unchanged (23) systemic pressor responses to agonists have been reported. Differences in species, method of anesthesia, and route of drug administration (intravenous versus intra-arterial) are likely to account for this variability. Recently, Doyle and Walker (24) have reported that, in rats exposed to hypobaric hypoxia for 4 wk, pressor responses to infused phenylephrine and vasopressin are inhibited. This effect was not reversed on return to normoxia. The in vitro contractility of aortic segments from these rats was also depressed, indicating that chronic hypoxia produced a change in the vessel wall (smooth muscle or endothelium) independent of systemic reflexes.
Despite the obvious relevance to may congenital and acquired cardiopulmonary disorders, the effects of prolonged systemic hypoxia on arteriolar reactivity have not previously been evaluated in any vascular bed. The current results, therefore, extend the findings of prior studies because they demonstrate that arteriolar contractility is impaired. Furthermore, this change occurs much more quickly than has previously been recognized (i.e., within 12 h). Because the abnormality develops within hours, rather than weeks or months, it is relevant to cardiorespiratory illnesses (e.g., pneumonia, congestive heart failure, and exacerbations of chronic obstruction lung disease) whose natural histories may encompass a time frame not well represented by chronic studies.
The current results demonstrate that the decrease in arteriolar responsiveness following exposure to hypoxia is due to impaired smooth muscle contractility and not to the release of endothelium-derived relaxing factors. The effect cannot be attributed to altered adrenoceptor function or to hyperpolarization of the smooth muscle cell membrane since contraction during maximal depolarization with KCl is impaired. The maximum constriction that could be elicited by KCl, however, was less affected by hypoxia than that during activation by phenylephrine (Table 2). Agonist-receptor interactions activate intracellular calcium release and second messenger pathways which enhance myofilament calcium sensitivity to a greater extent than does depolarization (25, 26). The finding that phenylephrine-mediated contraction is preferentially impaired, therefore, suggests that part of the abnormality is at these sites in the activation cascade.
In arterioles from control rats, removal of the endothelium produced a downward shift of the pressure-diameter relationship and enhanced the maximum constriction that could be elicited by phenylephrine and KCl. Normally, therefore, the endothelium exerts a tonic negative influence on intrinsic arteriolar tone and inhibits agonist-induced responses. In arterioles from rats exposed to hypoxia, we found that removal of the endothelium did not alter the pressure-diameter relationship. Moreover, in arterioles from hypoxic rats, the maximum responses to phenylephrine and KCl were greater if the endothelium was left intact than if it had been removed. Systemic hypoxia, therefore, induces a change in endothelial function. This involves the loss of its tonic inhibitory influence on pressure-induced tone and the activation of mechanisms that enhance agonist-induced contraction.
In cultured endothelial cells, prolonged hypoxia has been shown to reduce basal release of the vasodilators prostacyclin and nitric oxide (12, 13). A reduction in the synthesis of these mediators could account for the decreased basal inhibition of arteriolar tone during increases in transmural pressure that we have observed. Recently, these substances have been found to suppress the release of endothelium-derived vasoconstrictors (27). A decrease in their synthesis, therefore, may also release an inhibitory influence on pathways capable of enhancing the response to exogenous vasoconstrictors. Acute hypoxia has been reported to evoke endothelial release of both endothelin (28) and thromboxane A2 (29) in some vascular preparations. Endothelin exerts a prolonged effect once bound to its smooth muscle receptor (30). If augmentation of agonist-induced constriction following hypoxic exposure in the current study is mediated by endothelin alone, therefore, one would not expect it to be immediately reversed by endothelial removal. It is likely that a short-acting mediator such as thromboxane A2 or its precursor, prostaglandin H2 (31), is also involved. Further studies are indicated to test these hypotheses.
Exposure to hypoxia elicits vasodilation in the phrenic circulation which redistributes blood flow toward the diaphragm at the expense of nonvital tissues (32). Acutely, this appears to be attributable to the increase in diaphragm contractile activity which hypoxia elicits since it does not occur in paralyzed, mechanically ventilated animals (33). The current results suggest that with persistence of the hypoxic state, a second mechanism, suppression of phrenic arteriolar smooth muscle contractility, may contribute to this preferential perfusion. Notwithstanding this potential benefit, the impairment of smooth muscle contraction is not entirely adaptive. The capacity to autoregulate diaphragm blood flow (6) and to maximize oxygen extraction during reductions in systemic oxygen availability (34, 35) will suffer if active regulation of intramuscular arteriolar tone is impaired. In addition, increases in arterial and venous pressure will have a greater impact on transcapillary fluid flux in the absence of countervailing myogenic vasoconstriction in upstream resistance arterioles (36, 37). The effect of these abnormalities on diaphragm function is unknown; however, edema formation and inability to respond to superimposed hypotension or subsequent hypoxic episodes are the expected pathophysiologic sequelae.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. M. E. Ward, Royal Victoria Hospital, L3.04, 687 Ave. des Pins Ouest, Montreal, PQ, H3A 1A1 Canada.
(Received in original form February 26, 1997 and in revised form May 8, 1997).
Funded by grants from the Medical Research Council of Canada, the Canadian Heart and Stroke Foundation, and the Association Pulmonaire du Quebec.Dr. Ward is a scholar of the Medical Research Council of Canada.
Acknowledgments: The writers thank S. Nuara for his technical assistance.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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