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Johannes-Müller-Institut für Physiologie, Medizinische Fakultät Charité, Humboldt-Universität Berlin, 10117 Berlin, Germany
WITH THE EVOLUTIONARY
TRANSITION of life from water to land, adaptation of the organism
to changing environmental conditions became critical for survival. One
of the most dramatic life-threatening situations is a reduction in
oxygen supply to the vital organs. Decreased tissue oxygenation may
arise on such different occasions as exposure to low ambient oxygen,
i.e., at high altitude, or during severe blood loss. Over the past two
years, more than two dozen studies have appeared in the American
Journal of Physiology (AJP)-Regulatory, Integrative and Comparative
Physiology dealing with adaptational responses to acute and
chronic hypoxemia. Articles include investigations on cardiovascular
regulation (10, 20, 30), respiratory control (19,
26, 27), secretory mechanisms (2, 15, 16), and
synaptic transmission (13).
Peripheral vasoconstriction and redistribution of the cardiac output
toward the myocardial and cerebral circulations are among the
potentially life-saving mechanisms that are activated during hypoxemia.
Recent findings indicate that developing organisms depend primarily on
adrenergic control of cardiovascular function with only minor
contribution from the parasympathetic nervous system (9).
With the use of the The complex role of the nitric oxide (NO) system in the response to
tissue hypoxygenation is highlighted in several recent contributions.
As outlined in a review article by Liang and Knox (21), NO
is considered as a double-edged sword. For example, the proximal tubule
in the kidney produces large quantities of NO in response to various
stimuli, including hypoxia. Because NO usually inhibits sodium and
fluid reabsorption by the proximal tubule, enhanced generation of NO
may lower tubular oxygen consumption and thereby protect the kidney
against hypoxic/ischemic injury. On the other hand, stimulation
of NO production during hypoxia, presumably depending on
macrophage-type inducible NO synthase, caused severe damage to proximal
tubular cells.
Participation of the NO system in the hypoxic and hypercarbic drive to
breathing was analyzed in the toad Bufo paracnemis (12). Chemoreception of CO2 and the breathing
response to hypoxia in the amphibian brain involve signaling through
the nucleus isthmi in the mesencephalon. Microinjection of the NO
synthase inhibitor NG-nitro-L-arginine methyl ester
(L-NAME) into the nucleus isthmi of B. paracnemis revealed that locally acting NO has an inhibitory effect on the tidal volume (VT) when the respiratory drive
is high such as under hypoxia or hypercarbia (12).
Improved tissue oxygenation can result from NO-mediated hypoxic
vasodilation. Recent findings indicate that the contribution of NO to
hypoxia-induced vasorelaxation varies considerably between vascular
beds in the developing organism. Thus inhibition of NO attenuated the
increase in coronary blood flow and increased gastrointestinal vascular resistance during hypoxia but had no effect on hypoxic vasodilation in
the brain (14). Interestingly, altered signaling of NO
appears to play a role also in the constriction of the ductus
arteriosus after birth. As the full-term ductus constricts, oxygen
concentration in its inner vessel wall falls to <0.2%. With the use
of isolated rings of fetal lamb ductus arteriosus, it was shown
recently that decreased responsiveness of the vascular wall to the
vasodilatory action of endogenous NO (and prostaglandins) prevents
ductus arteriosus reopening despite the severe local tissue hypoxia
(17). Furthermore, the strong inhibitory effects of NO and
prostaglandins, in addition to a weaker intrinsic vascular tone, appear
to be responsible for the smaller increment in tension of preterm
compared with near-term ductus arteriosus (18). As a
consequence, the immature ductus arteriosus will fail to remodel
completely after birth.
In an effort to maintain adequate tissue oxygenation, the vasculature
frequently responds to hypoxia with a decrease in local resistance. In
contrast, hypoxic vasoconstriction is a characteristic of mammalian
pulmonary vascular smooth muscle. Recent findings indicate that the
capacity of vascular segments to constrict under hypoxia is a
phylogenetically old mechanism. By comparing the effect of low oxygen
on the tension of isolated vessel rings from the dorsal aorta of
different primitive vertebrates, it was shown that the antecedent of
hypoxic pulmonary vasoconstriction might be operating in cyclostomes
(25). Notably, removal of the endothelium was without
effect, suggesting that hypoxic vasoconstriction is an intrinsic
feature of the vascular smooth muscle cells (25). In a
related study, hypoxic vasoconstriction of dorsal aortas from sea
lamprey was found to correlate with an increase in cytosolic Ca2+ due to release from intracellular stores, while
Na+/Ca2+ exchange is used during hypoxic
vasoconstriction in hagfish (28). Major novel insights
into the ionic mechanisms of hypoxic vasoconstriction came from studies
on frog skin, an important vertebrate respiratory organ. Cutaneous
vasoconstriction in Xenopus laevis in response to hypoxia
was enhanced with the L-type Ca2+-channel opener Bay K 8664 and could be mimicked with the K+-channel antagonist
4-aminopyridine (23). The effect of 4-aminopyridine was
blocked by the L-type Ca2+-channel antagonist nifedipine,
which also inhibited hypoxic vasoconstriction (23). These
results indicate that, similar to hypoxia-induced increase in pulmonary
vascular resistance, hypoxic vasoconstriction in amphibian tissues may
involve a reduction in membrane K+ conductance with
subsequent depolarization of vascular smooth muscle cells and influx of
Ca2+ through L-type Ca2+ channels.
The concept that exposure to hypoxia elicits a drop in body temperature
is not new, but considerable advances have been made over the past few
years in elucidating the underlying mechanisms. In particular, it was
shown by intracerebroventricular microinjection of the adenosine
receptor antagonist aminophylline that adenosine is a central mediator
of hypoxia-induced hypothermia (6). Notably, prolonged
exposure of rats to an inspiratory oxygen concentration of 10%
completely disrupted the circadian rhythms of both the body temperature
and the level of activity (3, 4). This discovery has major
implications with regard to endocrine and metabolic regulation as it
raises the interesting possibility that the circadian clock is directly
sensitive to changes in the local oxygen tension.
As reviewed in an article by Bissonnette (5), the typical
respiratory response to acute hypoxia in the fetus and newborn consists
in an initial increase in ventilation, which is followed by a decline
below baseline levels, particularly in preterm neonates. Recent
progress in this area indicates that, in addition to temporal changes
in platelet-derived growth factor- This article would be incomplete without referring to the beneficial
effect that hypoxia can have under certain conditions. Studies with
mammals and birds demonstrated that exposure to brief periods of oxygen
deprivation protects the myocardium against ischemia-reperfusion injury. Several studies have recently
appeared in AJP-Regulatory, Integrative and Comparative
Physiology indicating that hypoxic/ischemic
preconditioning also exists in other vertebrates, including fish
(11, 22) and amphibians (8). Thus
preconditioning appears to represent a fundamental mechanism of
cardioprotection that developed early in the evolution of vertebrates.
It seems that enhanced expression of heat shock proteins
(8) and increased antioxidant enzyme capacity
(22) during brief episodes of tissue hypoxia play a
central role in this process.
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REFERENCES
-adrenergic antagonist phentolamine, it was
shown that 1-adrenergic receptors in embryonic chicken play a major role in the adaptational response of the vasculature to
hypoxia by maintaining basal vascular tone and by mediating the
redistribution of the cardiac output away from the peripheral circulations (24). Differences between the fetal and adult
organism in the distribution of blood flow during chronic hypoxic
stress are reflected by the differential adaptation of adrenergic
nerves to long-term hypoxic exposure. Thus stimulation-evoked
norepinephrine release from cerebral and facial sheep arteries was
higher during development compared with adult arteries
(7). On the other hand, the capacity to release
norepinephrine declined in fetal middle cerebral arteries after chronic
hypoxia but was maintained in adult blood vessels (7).
expression in the brain stem
(1), GABA in the nucleus tractus solitarii has a pivotal
role in hypoxic ventilatory depression (29). Thus an in
vivo microdialysis technique was used to demonstrate increased extracellular GABA concentrations in the nucleus tractus solitarii of
conscious rats during hypoxia-induced respiratory decline. This GABA
increase was dependent on normal innervation of the carotid bodies. In
the same study, local injection of GABA antagonists into the nucleus
tractus solitarii significantly attenuated ventilatory depression
during hypoxia (29).
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Scholz, Johannes-Müller-Institut für Physiologie, Medizinische Fakultät Charité, Humboldt-Universität Berlin, Tucholskystrasse 2, 10117 Berlin, Germany (E-mail: holger.scholz{at}charite.de).
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/ajpregu.00136.2002
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