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Divisions of Pulmonary and Critical Care Medicine, Royal Victoria Hospital, and the Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada H2X 2P2
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The hemodynamic response to reductions in systemic oxygen availability serves to redistribute blood flow and maintain vital organ function. The efficacy of this response depends on the degree to which hypoxia alters the function of the vascular tissues themselves. In this study we have evaluated these effects in rats exposed to 10% oxygen for 0 (control), 12, and 48 h and for 48 h followed by 12 h of normoxic recovery. In aortic segments from each group, the cumulative concentration response relationships were constructed for phenylephrine and KCl. Maximum tension generated during activation by these agents was reduced after both 12 and 48 h of hypoxic exposure. After 48 h of hypoxia, the maximum tension during activation by phenylephrine was 0.46 ± 0.04 vs. 1.31 ± 0.09 g/mg dry wt for the control group (P < 0.05 for difference). The maximum tension during activation by KCl was similarly affected (0.32 ± 0.02 vs. 0.98 ± 0.06 g/mg dry wt, 48 h of hypoxia vs. control, respectively; P < 0.05 for difference). Exposure to hypoxia did not alter the EC50 for either agent. Twelve hours of normoxic recovery did not fully restore contractility after 48 h of hypoxia. In aortic rings from control rats, endothelial removal enhanced contraction, whereas, in rings from rats exposed to hypoxia, removal of the endothelium was associated with a decrease in maximum tension. Prolonged exposure to hypoxia results in impairment of systemic arterial smooth muscle contractility. This is partly compensated by the release of vasoconstricting substances from the endothelium.
vascular smooth muscle; phenylephrine; potassium chloride; oxygen delivery
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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HYPOXIA IS FREQUENTLY OBSERVED in patients with pulmonary disease and shock (15) and in normal subjects at high altitude. The vascular responses that are elicited under these conditions preserve vital organ function by redistributing blood flow (16) and by enhancing the capacity of these organs to extract oxygen (5). In view of the importance of these adaptations in ensuring survival, the systemic vasculature itself should properly be considered among those vital organs having functions that may be threatened if conditions of inadequate oxygen and substrate supply are prolonged.
Previous studies suggest that the mechanisms mediating the systemic vascular responses to hypoxia vary with time. Acute hypoxia (minutes) elicits changes in arterial tone (constriction or relaxation, depending on the vascular bed) that are immediately reversible on return to normoxia (20, 28). Chronic hypoxia (months), in contrast, results in impairment of systemic vasoreactivity that is not reversed by acute restoration of normoxia (7). With continued exposure of the systemic circulation to hypoxia, therefore, secondary attenuation of vascular reactivity becomes superimposed on the initial, reversible adjustments of arterial smooth muscle tone (7).
Many cardiopulmonary illnesses associated with hypoxia (e.g., pneumonia, exacerbations of chronic obstructive lung disease, congestive heart failure) evolve over an intermediate time frame (hours to days) and are not well represented by the experimental conditions of either acute or chronic studies. It is unknown, therefore, whether the changes demonstrated in chronically hypoxic animals develop quickly enough to be relevant to the clinical course of these disorders. If they do, progressive impairment of the capacity to actively regulate the systemic vasculature may play an important, and unrecognized, role in the pathophysiology of organ system dysfunction and hemodynamic instability in critically ill patients. Moreover, because no previous studies have evaluated the rate at which systemic vascular hyporeactivity resolves after restoration of normoxia, the potential for this abnormality to alter hemodynamic responses and complicate pharmacological management in the posthypoxic recovery period cannot be assessed.
To clarify these issues, we studied the effect of prolonged
(12-48 h) in vivo hypoxia on the in vitro reactivity of rat
aortic segments to 
-adrenoceptor stimulation and to depolarization
with KCl. In addition, the degree to which the effects of hypoxic
exposure on aortic contractility are reversed by 12 h of normoxic
recovery was determined. Finally, because hypoxia is also known to
elicit changes in endothelium-dependent pathways of vasoregulation (17, 25), a further goal was to evaluate the role of the endothelium in
modulating the effects of hypoxia on the contractile responses.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Exposure to hypoxia. Male Sprague-Dawley rats (200-250 g) were placed in a sealed Plexiglas chamber (12 × 7 × 5 in.). Flows of air and nitrogen into the chamber were controlled independently. Outflow was through an underwater seal. In animals exposed to hypoxia, the gas inflow consisted of air at a rate of 3 l/min and nitrogen at 3 l/min (inspired O2 concentration = 10%). 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 by using a temperature probe (model SST1, Physitemp Instruments, 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 from a cannula in the carotid artery, the arterial PO2 averaged 38 Torr (range 35-42 Torr) and the arterial PCO2 was 32 Torr (range 29-34 Torr).
Preparation of aortic segments.
The thoracic aorta from each rat was removed immediately after
decapitation, cleaned of connective tissue, and cut into segments 4 mm
in length. In some preparations the endothelium was gently rubbed off
by using a wooden spatula. The segments were mounted on stainless steel
hooks in 15-ml jacketed organ baths containing modified Krebs solution
[containing (in mM) 143.0 Na+, 5.9 K+, 2.5 Ca2+, 1.2 Mg2+, 153.9 Cl
, 25.0 HCO3, 1.2 SO24, 1.2 HPO24, and 10.0 dextrose]. The
hooks were connected to Grass force-displacement transducers (model
FT03), and tension was gradually adjusted to 2 g over 1 h. The solution
in the bath was kept at 37°C and was bubbled with a 95%
O2-5%
CO2 gas mixture.
5 M) was assessed after
contraction with 105 M
phenylephrine. All endothelium-intact rings demonstrated relaxation of
phenylephrine-induced contraction on addition of ACh to the bath. In
rings in which the endothelium had been removed, absence of
vasorelaxation in response to ACh was taken as evidence that the
deendothelialization procedure had been successful (10). Phenylephrine
and ACh were then washed out by changing the solution in the organ
bath.
Effects of hypoxia and endothelial ablation on optimal baseline
tension.
The tension generated during agonist-induced contraction of vascular
rings is dependent, in part, on the baseline tension at which the
contractile response is studied. Effects of the experimental conditions
on the relationship between baseline tension and the maximal tension
that may be generated during activation by agonists could alter the
contractile responses of aortic segments. Experiments were, therefore,
carried out to determine whether changes in optimal baseline tension
are induced by hypoxia or endothelial ablation. Aortic rings from six
normoxic rats and six rats exposed to hypoxia for 48 h were
studied. In one-half of the rings from each rat the
endothelium was left intact, and in the other one-half the endothelium
was removed. Values obtained in endothelialized and deendothelialized
rings from each rat were averaged, and the averaged values were counted
as single observations. After evaluation of the response to ACh, and
after the final buffer change, baseline tension was allowed to
reequilibrate to 2 g. The baseline tension was then slowly adjusted to
0.5, 1, 2, 3, or 4 g. After the baseline tension had stabilized at its
new value, phenylephrine
(105 M) was added to the
organ bath, and the maximum steady-state tension generated during the
ensuing contraction was recorded. Phenylephrine was washed out by
changing the buffer in the organ bath, and the baseline tension was
permitted to return to its precontraction level. The baseline tension
was then readjusted, in random order, to another of the predetermined
values (0.5, 1, 2, 3, or 4 g), and the response to phenylephrine
(105 M) was reevaluated. On
completion of the study, the aortic segments were removed from the
hooks, dried overnight at 50°C, and weighed so that tension could
be expressed in grams per milligram dry weight.
Concentration-response curves. Aortic rings from four groups (n = 14 per group) of animals were studied. These included control animals, animals exposed to hypoxia for 12 h, animals exposed to hypoxia for 48 h, and animals exposed to hypoxia for 48 h followed by 12 h of normoxic recovery. In one-half of the aortic rings from the control group, from the group exposed to hypoxia for 12 h, and from the group exposed to hypoxia for 48 h, the endothelium was removed before the concentration-response protocol was carried out. Values obtained in endothelialized and deendothelialized rings from each rat were averaged, and the averaged values were counted as single observations. In seven animals from each group the response to phenylephrine was evaluated, and in the other seven the response to KCl was determined. The concentration-response curves, therefore, represent averaged data for rings obtained from each of seven animals.
After evaluation of the response to ACh, and after the final buffer change, baseline tension was allowed to return to 2 g. Phenylephrine (108-104
M) or KCl (10-90 mM) was then administered in a cumulative
fashion. The responses to phenylephrine and KCl were evaluated in
separate rings. On completion of the concentration-response protocol,
the aortic segments were removed from the hooks, dried, and weighed as
described in Effects of hypoxia and endothelial
ablation on optimal baseline tension.
Data analysis. Concentration-response relationships were evaluated by comparing the tension achieved during maximum constriction and the EC50. EC50 values were derived from nonlinear least squares regression analysis. Between-group comparisons were performed by ANOVA. If the ANOVA revealed significant overall differences, variations among individual means were evaluated post hoc by using the Student-Newman-Keuls procedure. Results are expressed as means ± SE for aortic rings from n animals, with P < 0.05 representing significance.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Effect of hypoxia on optimal baseline tension. The tensions generated in response to phenylephrine by endothelialized and deendothelialized rings from control animals and from animals exposed to hypoxia for 48 h at each value of baseline tension are presented in Fig. 1. In all groups, maximum tension was generated when baseline tension was adjusted to 2 g.
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Effect of hypoxia on ACh-induced relaxation.
The tensions recorded during initial contraction by phenylephrine
(105 M) and after the
subsequent addition of ACh
(104 M) to the organ bath
for all groups of aortic rings are presented in Table
1. In rings from normoxic rats, ACh
elicited relaxation that reversed 69.2 ± 5% of the
phenylephrine-induced contraction. Comparable responses have been
observed in aortic rings from control rats in previous studies (6). ACh
reversed 50.7 ± 7% of the phenylephrine-induced
contraction in the group exposed to hypoxia for 12 h and 39.5 ± 5%
in the group exposed to hypoxia for 48 h
(P < 0.05 for differences between
control and hypoxic groups). Tension was unchanged by ACh in rings in
which the endothelium had been removed.
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Effect of hypoxia on aortic contractility. In Figs. 2 and 3, respectively, the concentration-response curves for phenylephrine and KCl in endothelialized and deendothelialized rings from control rats and from rats exposed to hypoxia for 12 and 48 h are illustrated. The mean values for EC50 and maximum tension during phenylephrine- and KCl-induced contraction for these groups and for endothelialized rings from rats permitted 12 h of normoxic recovery after 48 h of hypoxia are presented in Tables 2 and 3, respectively. In control rings, removal of the endothelium increased the maximum tension generated and decreased the EC50 for activation by phenylephrine and KCl. In contrast, removal of the endothelium decreased both the maximum tension and the EC50 in aortic rings from rats exposed to hypoxia for 12 or 48 h. Aortic rings from rats permitted 12 h of normoxia after a 48-h hypoxic exposure evidenced some recovery of contractility; however, maximum tensions remained significantly depressed compared with rings from control animals. Hypoxia did not alter the EC50 values for either phenylephrine or KCl.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The novel findings of this study are as follows:
1) exposure to hypoxia in vivo
results in rapid (within 12 h) attenuation of
1-agonist- and KCl-induced
aortic contraction; 2) the changes in aortic contractility induced by 48 h of hypoxia persist for a
significant period (at least 12 h) after restoration of normoxia; and
3) after hypoxic exposure the
maximum tension generated by aortic rings during phenylephrine- and
KCl-induced contraction is enhanced by endothelium-dependent factors,
whereas normally the endothelium exerts an inhibitory influence on
these responses.
Critique. In the present study, we have evaluated the effects of exposure to hypoxia in vivo on the in vitro reactivity of aortic segments. The study does not include experiments designed to dissociate the direct effects of hypoxia from those of changes in flow or neurohumoral mediators. Nonetheless, these factors comprise part of the response to systemic hypoxia, and the hypoxic exposures presented in this study simulate a clinically and physiologically relevant condition.
The changes in responsiveness of aortic segments may or may not reflect abnormalities that affect the regulation of smaller vessels. Because perfusion of a specific vascular bed is determined by the tone of resistance arterioles, the effects of hypoxia on the regulation of blood flow distribution cannot be directly predicted from the present results. Further studies to determine whether or not our findings apply to vessels more directly involved in the regulation of systemic vascular resistance are, therefore, indicated. In vivo, endothelial release of vasoactive substances is normally regulated by shear stress at the endothelial-luminal interface. In the present experiments, the role of the endothelium in modulating the contractile responses is evaluated in vitro in the absence of this regulatory influence. The endothelial involvement in the effects of hypoxia on vascular reactivity, as determined in this study may, therefore, differ from that observed in vivo where the changes induced by hypoxia will interact with the effects of changes in blood flow.Attenuation of vasoreactivity. In the systemic circulation, depending on the vascular bed, acute hypoxia may elicit endothelium-dependent dilation (9, 19), endothelium-dependent constriction (24), and varying degrees of impairment of smooth muscle contractility (23). All of these acute effects are immediately reversed once the hypoxia is corrected.
Studies of the effects of chronic hypoxia on in vivo systemic vasoreactivity have yielded conflicting data. Aoki and Robinson (1) found augmented pressor responses to adrenoceptor agonists in the hindlimb of chronically hypoxic rats. In contrast, Jin et al. (14) have demonstrated impaired responses to vasopressin infusion in hypoxia-adapted rats. Others (11) have reported that changes in systemic vascular resistance during infusion of phenylephrine and angiotensin II were not different in chronically hypoxic guinea pigs and normoxic controls. Differences in species, method of anesthesia, and route of drug administration (intra-arterial vs. intravenous) may all affect the reflex systemic responses that interact with the direct vascular effects of these agonists and presumably account for this variation in results. Doyle and Walker (7) have reported that, in rats, 4 wk of exposure to hypobaric hypoxia results in attenuation of the pressor responses to infused phenylephrine and vasopressin. This decrease in vasoreactivity was not reversed by acute restoration of normoxia. The in vitro contractility of aortic segments from these rats was also depressed, indicating that hypoxia exerts a direct effect on arterial blood vessels (smooth muscle or endothelium) independent of changes in systemic reflex responses. Because the effects of acute hypoxia are promptly reversed on return to normoxia, whereas those of more prolonged hypoxia are not, these investigators suggested that the responses are mediated by different mechanisms. Despite the obvious relevance to numerous cardiopulmonary disorders, only one previous study has addressed the effects of hypoxic episodes of intermediate duration on systemic vascular responses (12). In that study, Heistad et al. (12) demonstrated impairment of reflex vasoconstriction to lower body negative pressure and a decrease in baseline forearm vascular resistance in human volunteers exposed to hypobaric hypoxia (inspired O2 concentration = 12.3%) for 36 h. These authors concluded that the decrease in forearm resistance was not attributable to hypoxia because it was not corrected by acute restoration of normoxia. In retrospect, it is likely that their observation reflects the induction of the same kind of systemic vascular dysfunction that has been reported more recently after chronic exposure to hypoxia in rats (7). This raises the possibility that depressed systemic vascular contractility may develop far more quickly than has previously been recognized and may contribute to altered vascular regulation in a much broader array of disease states than those represented by chronic hypoxic exposures. The present results extend those of previous studies because they demonstrate that agonist-induced contraction of aortic segments is impaired after only 12 h of in vivo hypoxia. Moreover, the impairment of contractility that is induced by exposure to hypoxia for 48 h persists for an extended period of time after return to normoxia. Consequently, impaired systemic vascular regulation and hemodynamic instability may be anticipated in patients who have suffered prolonged hypoxic episodes even when arterial oxygen tension has been successfully restored to normal. We have further demonstrated that the decrease in aortic contractility after exposure to hypoxia is due to altered vascular smooth muscle function and not to the release of endothelium-derived relaxing factors. Finally, because contraction during maximal depolarization with KCl is impaired, the effect cannot be entirely attributed to altered-adrenoceptor function or to
hyperpolarization of the smooth muscle cell membrane. The
lack of any effect of hypoxia on the sensitivity
(EC50) to phenylephrine or KCl
also argues against a major role for these mechanisms.
Role of the endothelium.
Normally, the endothelium exerts an inhibitory influence on aortic
contractility (13). Its removal shifts the phenylephrine concentration-response curve to the left (increased sensitivity) and
enhances the maximum tension generated (13). Our present results
indicate that, after exposure to hypoxia, the maximum tension generated
in response to both -adrenoceptor activation and KCl was greater in
aortic rings in which the endothelium was intact than in rings from
which the endothelium had been removed. The influence of the
endothelium on maximum constriction, therefore, was reversed by prior
hypoxic exposure.
-agonist-induced contraction is mimicked by treatment with
L-arginine analogs
[inhibitors of nitric oxide synthase (NOS)] (6, 13, 22)
and, consequently, has been attributed to elimination of endothelial
nitric oxide (NO) release. The effect of hypoxia on the expression of
the endothelial cell isoform of NOS (ecNOS) has been evaluated in
cultured endothelial cells. The results of these studies,
however, conflict. In endothelial cells from human umbilical vein,
hypoxic incubation inhibits ecNOS expression (18), whereas it is
associated with an increase in both ecNOS protein and mRNA (2) in
endothelial cells obtained from bovine aorta. The effect of hypoxia on
ecNOS expression in the systemic circulation in vivo is unknown. An
increase in endothelial NOS activity in the present study is unlikely
because the effect of endothelial removal on the contractile response
to agonists would then be opposite to that observed and relaxation to
ACh would be enhanced, not diminished. Suppression of NO release by
prior hypoxic exposure is also insufficient to account for our
findings, however, because removal of the endothelium would then have
no effect on contractile responses and this too is at variance with the
results obtained. Other mechanisms, specifically enhancement of
endothelium-derived constricting factor release, must, therefore, be
involved.
Exposure to normobaric hypoxia has previously been shown to increase
levels of the endogenous vasoconstrictor endothelin in plasma and aorta
of Sprague-Dawley rats (8). The source of endothelin release, however,
was found to be the pulmonary, rather than the systemic, circulation
(8). The reduction in maximum tension that accompanies endothelial
removal after exposure to hypoxia in the present study, therefore,
cannot readily be attributed to elimination of the source of
endothelin. Also against this hypothesis is the fact that endothelin is
known to elicit prolonged vasoconstriction once bound to its smooth
muscle receptor (30). Therefore, even if the aortic endothelium were
the source of endothelin release during hypoxia, its removal should not
immediately reverse vasoconstriction initiated by this
mechanism.
An endothelial contribution to contraction elicited by exogenous
endothelin has recently been identified in normotensive and spontaneously hypertensive rats (4, 27). Evidence that this is due to stimulation by endothelin of the release of thromboxane A2 (26) and its precursor
prostaglandin H2 (3) has been
presented. Accordingly, an increase in circulating endothelin during
hypoxia could account for the findings of our present study, if its
synergistic effect on vasoreactivity to phenylephrine (21) were
mediated through the endothelial release of these short-acting
secondary mediators. In light of our present results, therefore,
further studies to test these hypotheses are indicated.
Reflex sympathetic augmentation of systemic vascular tone is essential
to maintaining arterial blood pressure and vital organ perfusion during
hemorrhage and other hypotensive stresses. Adrenergically mediated
adjustment of systemic arteriolar tone is also important in the
microvascular adaptations that augment oxygen extraction during
reductions in oxygen delivery (5, 29). Our present results indicate
that systemic vascular smooth muscle contraction in response to
1-adrenoceptor stimulation is
impaired during and after hypoxic episodes. If a similar alteration in
smooth muscle function occurs at the level of resistance arterioles, this mechanism could contribute to the pathophysiology of organ dysfunction and hypotension. Because the abnormality develops over
hours rather than weeks or months, it is relevant not only in patients
with chronic hypoxia but also in patients with cardiorespiratory illnesses who have been hypoxic for a relatively short period of time.
Hemodynamic instability in such patients is commonly attributed to
infection or to right or left ventricular dysfunction. The present
findings highlight an additional mechanism, primary impairment of
arterial smooth muscle contractility, that may contribute to altered
hemodynamic responses and complicate pharmacological management in this
setting.
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ACKNOWLEDGEMENTS |
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This study was supported by a grant from the Medical Research Council of Canada. M. Ward is a scholar of the Medical Research Council of Canada.
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FOOTNOTES |
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Address for reprint requests: M. E. Ward, Meakins-Christie Laboratories, 3626 Saint Urbain St., Montreal, Quebec, Canada H2X 2P2 (E-mail: mward{at}meakins.lan.mcgill.ca).
Received 26 March 1997; accepted in final form 19 March 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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  T. V. Serebrovskaya, E. B. Manukhina, M. L. Smith, H. F. Downey, and R. T. Mallet Intermittent Hypoxia: Cause of or Therapy for Systemic Hypertension? Experimental Biology and Medicine, June 1, 2008; 233(6): 627 - 650. [Abstract] [Full Text] [PDF]
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 J. B. Ray, S. Arab, Y. Deng, P. Liu, L. Penn, D. W. Courtman, and M. E. Ward Oxygen regulation of arterial smooth muscle cell proliferation and survival Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H839 - H852. [Abstract] [Full Text] [PDF]
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J. Z. He, A. Quan, Y. Xu, H. Teoh, G. Wang, J. E. Fish, B. M. Steer, S. Itohara, P. A. Marsden, S. T. Davidge, et al. Induction of matrix metalloproteinase-2 enhances systemic arterial contraction after hypoxia Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H684 - H693. [Abstract] [Full Text] [PDF]
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V. Govindaraju, H. Teoh, Q. Hamid, P. Cernacek, and M. E. Ward Interaction between endothelial heme oxygenase-2 and endothelin-1 in altered aortic reactivity after hypoxia in rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H962 - H970. [Abstract] [Full Text] [PDF]
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 L. P. Thompson, K. Aguan, and H. Zhou Chronic Hypoxia Inhibits Contraction of Fetal Arteries by Increased Endothelium-Derived Nitric Oxide and Prostaglandin Synthesis Reproductive Sciences, December 1, 2004; 11(8): 511 - 520. [Abstract] [PDF]
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S. Earley, A. Pastuszyn, and B. R. Walker Cytochrome P-450 epoxygenase products contribute to attenuated vasoconstriction after chronic hypoxia Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H127 - H136. [Abstract] [Full Text] [PDF]
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S. Earley and B. R. Walker Increased nitric oxide production following chronic hypoxia contributes to attenuated systemic vasoconstriction Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1655 - H1661. [Abstract] [Full Text] [PDF]
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H. Teoh, M. Zacour, A. D. Wener, L. Gunaratnam, and M. E. Ward Increased myofibrillar protein phosphatase-1 activity impairs rat aortic smooth muscle activation after hypoxia Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1182 - H1189. [Abstract] [Full Text] [PDF]
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S. Earley and B. R. Walker Endothelium-dependent blunting of myogenic responsiveness after chronic hypoxia Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2202 - H2209. [Abstract] [Full Text] [PDF]
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A. Lindqvist, K. Dreja, K. Sward, and P. Hellstrand Effects of oxygen tension on energetics of cultured vascular smooth muscle Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H110 - H117. [Abstract] [Full Text] [PDF]
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 S. Earley, J. S. Naik, and B. R. Walker 48-h Hypoxic exposure results in endothelium-dependent systemic vascular smooth muscle cell hyperpolarization Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R79 - R85. [Abstract] [Full Text] [PDF]
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 M. E. Zacour, H. Teoh, A. J. Halayko, and M. E. Ward Mechanisms of aortic smooth muscle hyporeactivity after prolonged hypoxia in rats J Appl Physiol, June 1, 2002; 92(6): 2625 - 2632. [Abstract] [Full Text] [PDF]
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R. J. Gonzales and B. R. Walker Role of CO in attenuated vasoconstrictor reactivity of mesenteric resistance arteries after chronic hypoxia Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H30 - H37. [Abstract] [Full Text] [PDF]
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N. L. Jernigan, T. L. O'Donaughy, and B. R. Walker Correlation of HO-1 expression with onset and reversal of hypoxia-induced vasoconstrictor hyporeactivity Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H298 - H307. [Abstract] [Full Text] [PDF]
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T. L. O'Donaughy and B. R. Walker Renal vasodilatory influence of endogenous carbon monoxide in chronically hypoxic rats Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2908 - H2915. [Abstract] [Full Text] [PDF]
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 M. Toporsian, K. Govindaraju, M. Nagi, D. Eidelman, G. Thibault, and M. E. Ward Downregulation of Endothelial Nitric Oxide Synthase in Rat Aorta After Prolonged Hypoxia In Vivo Circ. Res., March 31, 2000; 86(6): 671 - 675. [Abstract] [Full Text] [PDF]
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Tension)
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