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First published online August 22, 2008
Journal of Experimental Biology 211, 2727-2734 (2008)
Published by The Company of Biologists 2008
doi: 10.1242/jeb.010066
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Commentary |
Hydrogen sulfide and oxygen sensing: implications in cardiorespiratory control
Indiana University School of Medicine, South Bend Center, South Bend, Indiana 46617, USA
Author for correspondence (e-mail: olson.1{at}nd.edu)
Accepted 18 June 2008
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Summary |
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 TOP Summary IntroductionTypes of hypoxia and...Oxygen-sensing tissuesMechanism of oxygen sensingHydrogen sulfide as an...Conclusions and future...References |
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Key words: chemoreceptors, carotid body, neuroepithelial cells
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Introduction |
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TOPSummaryIntroductionTypes of hypoxia and...Oxygen-sensing tissuesMechanism of oxygen sensingHydrogen sulfide as an...Conclusions and future...References |
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Types of hypoxia and importance of oxygen sensing |
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TOPSummaryIntroductionTypes of hypoxia and...Oxygen-sensing tissuesMechanism of oxygen sensingHydrogen sulfide as an...Conclusions and future...References |
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).
Compared to air, aquatic hypoxia is especially problematic because water has a
lower capacity for O2 (1/30), diffusion through water is slower
(Krogh's diffusion coefficients 1/200 000) and O2 solubility
decreases by around 20% for every 10°C increase in temperature and another
20% in seawater compared to freshwater. In addition, the high viscosity of
water (60 times that of air) impedes breathing, and even mixing of
O2. Life on land has problems of its own. Terrestrial animals may
be exposed to hypoxia when they ascend to higher altitudes due to the fall in
barometric pressure (at 3000 m PO2 is 30% lower
than at sea level) or enter burrows where there may be little convective
delivery of fresh air (Ramirez et al.,
2007). Even the mammalian fetus experiences a form of external
hypoxia. Global internal hypoxia can originate from a decrease in the
ventilation/perfusion ratio in the respiratory organs resulting in a decrease
in O2 uptake, or it can be more localized following an increase in
the metabolism/perfusion ratio in systemic tissues. Low O2 content
in blood is called hypoxemia and if it produces tissue hypoxia this is
hypoxemic hypoxia. Ischemia (or ischemic hypoxia) refers to tissue hypoxia
resulting from insufficient blood flow.
In order to adequately and rapidly respond to potential shortfalls in
oxygen, animals have developed O2-sensing tissues capable of
detecting hypoxia in the environment, in blood, or within tissues. Notable
among these are chemoreceptors that initiate central cardio-respiratory
responses, chromaffin cells in the adrenal medulla or central veins that
provide a humoral source of catecholamines and blood vessels that exert local
control over tissue perfusion (Lahiri et
al., 2006; Milsom and
Burleson, 2007; Reid and
Perry, 2003; Weir et al.,
2005). While all cells are affected by hypoxia, these
`O2-sensing' cells appear exquisitely sensitive to subtle degrees
of hypoxia and thereby serve important homeostatic functions during the
initial (acute) hypoxic challenge. Long-term (chronic) effectors of hypoxic
responses that regulate genetic responses, such as the hypoxia inducible
factor (HIF) transcription factor family, sustain and augment the initial
responses but are not considered here.
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Oxygen-sensing tissues |
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) (for a
review, see Gilmour and Perry,
2007). In some fish (e.g. trout) these NECs are predominantly on
the first gill arch, the homolog of the mammalian carotid body; in others
(bowfin, catfish) they are more evenly distributed over the gills and even the
orobranchial cavity (Gilmour and Perry,
2007; Milsom and Burleson,
2007). These externally oriented receptors are absent in the
obligate air-breathing South American lungfish, Lepidosiren paradoxa,
and it has been suggested that this mode of O2 sensing was lost
early in vertebrate evolution (Sanchez et
al., 2001).
Cells similar to NECs are grouped in clusters called neuroepithelial bodies
(NEBs) that line the airways of mammalian lungs especially near bifurcations
(Peers and Kemp, 2001;
Kemp et al., 2002). NEBs are
most prominent in neonatal lungs and are believed to monitor airway
PO2 and help initiate breathing and thereafter
optimize ventilation/perfusion matching through central reflexes and by
paracrine stimulation of adjacent pulmonary vasculature
(Kemp et al., 2002). Although
they are more responsive to airway hypoxia than hypoxemia, their function as
general monitors of environmental PO2 in adult
animals is unclear.
Monitors of blood hypoxemia
Tissues: gill, carotid, chromaffin/adrenal
Monitors of blood O2 status such as vascularly oriented NECs in
fish gills and carotid bodies in tetrapods provide general information on
O2 delivery to systemic tissues and, not unexpectedly, are
predominantly associated with the arterial circulation. In addition,
O2-sensitive chromaffin cells are variously found in heart and
vasculature of the more ancient vertebrates and condensed in the adrenal
medulla of mammals. Their location suggests that they provide information on
the balance between O2 delivery and tissue utilization.
Gill NECs
Vascularly oriented NECs are found on all gill arches and in some fish are
especially prevalent surrounding the efferent branchial artery, the main
vessel draining oxygenated blood from the gill
(Milsom and Burleson, 2007).
Here, they are ideally situated to monitor blood oxygenation and, unlike
mammals, they may better distinguish blood O2 content than blood
PO2. Like other gill NECs and cells of the NEB
they secrete serotonin in response to hypoxemia.
Carotid bodies
The carotid bodies of mammals are small organelles located at the
bifurcation of the internal and external carotid arteries. They are supplied
by the carotid artery and have the highest blood flow and O2
consumption per tissue weight of any organ. As such, they are reporters of
blood PO2 rather than O2 content.
Carotid bodies are ideally positioned to monitor O2 delivery to the
brain and are the main, if not only, sensor of acute and chronic arterial
hypoxemia in the adult (Milsom and
Burleson, 2007). Type I glomus cells are the primary chemosensory
cell. Although chemoreceptor sensitivity varies from species to species, there
is also considerable difference depending on the site of measurement;
chemoreceptor discharge is half-maximal when arterial
PO2 is around 55 mmHg which is equivalent to 18
mmHg in the vicinity of the type I cells
(Kumar, 2007). Intracellular
PO2 is probably considerably lower.
Acetylcholine and ATP are the primary secretory products, although the carotid
body has been reported to have as many neurotransmitters as the brain
(Prabhakar, 2006). Arterial
hypoxia initiates an increase in ventilation and peripheral vasoconstriction,
whereas if breathing is not possible, a fall in
PO2 produces a reflex bradycardia and
peripheral vasoconstriction (Marshall,
1994).
Chromaffin cells
Chromaffin cells are associated with systemic veins in ancient fishes and
the posterior cardinal veins of teleosts. Catecholamines are secreted in
response to hypoxemia and stimulate cardiorespiratory responses as well as
increase O2 transport by red blood cells
(Perry and Thomas, 1991), but
this may not reflect direct O2 sensing by chromaffin cells
(Perry et al., 2000).
Conversely, hypoxemia stimulates mammalian chromaffin cells in the adrenal
medulla to release catecholamines into the bloodstream where they have general
cardiorespiratory effects (Nurse et al.,
2006).
Monitors of regional/local hypoxia
It is well known that in mammals hypoxia contracts pulmonary and relaxes
systemic vessels. Although these responses may be modulated by a variety of
factors such as paracrine signals from the endothelium or surrounding tissue,
the basic responses are intrinsic to the vascular smooth muscle cells (VSMCs)
(Madden et al., 1992). Hypoxic
pulmonary vasoconstriction (HPV) decreases perfusion of poorly ventilated
regions of the lung and thus decreases the potential for partial unsaturation
of pulmonary venous (systemic arterial) blood. Hypoxic vasodilation increases
tissue perfusion thereby increasing O2 delivery. Perfused gills and
lungs of non-mammalian vertebrates also exhibit hypoxic vasoconstriction, but
surprisingly, hypoxia also constricts many systemic conductance (large)
vessels in a range of vertebrates from hagfish and lamprey to birds (see
Russell et al., 2007). The
physiological significance of this is unclear and the effects of hypoxia on
resistance-size (0.01–0.2 mm diameter) vessels in many of these animals
remains to be determined.
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Mechanism of oxygen sensing |
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;
López-López and
Pérez-García, 2007), adrenal chromaffin cells
(Nurse et al., 2006),
pulmonary artery (Weir and Archer,
1995; Murry et al., 2006) and even fish gill neuroepithelial cells
(Jonz et al., 2004;
Burleson et al., 2006).
Conversely, hypoxic vasodilation (relaxation) has been proposed to result from
the metabolism-sensitive potassium channels (KATP channels) that
open during hypoxia (Weir and Archer,
1995), or a loss of O2-sensitive kV1.5 and
kV2.1 channels (Thorne et al.,
2002) that hyperpolarize the cell and decrease calcium
influx).
Beyond potassium channels
It has become evident, however, that while O2-sensitive
K+ channels may contribute to, or modulate the hypoxic response,
other factors `upstream' from these or other K+ channels most
likely couple hypoxia to K+ channel inactivation
(Peers and Kemp, 2001;
Peers and Kemp, 2004).
Although there are exceptions (see below).
In carotid body type I cells hypoxia has been reported to activate NADPH
oxidase and increase reactive oxygen species (ROS), activate AMP-activated
protein kinase, inhibit mitochondrial metabolism, or stimulate hemeoxygenase-2
(HO-2) production of carbon monoxide, and any of these could serve as the
O2-sensing mechanism (Peers and
Kemp, 2001; Dinger et al.,
2007; Gonzalez et al.,
2007; Lahiri et al.,
2006; Prabhakar,
2006; Riesco-Fagundo et al.,
2001; Kemp, 2005;
Wyatt and Evans, 2007;
Wyatt et al., 2007). In airway
NEB, hypoxia has been proposed to inactivate NADPH oxidase thereby decreasing
ROS (Kemp et al., 2002;
Nurse et al., 2006), and in
adrenal chromaffin cells a mitochondrial mechanism decreases ROS
(Nurse et al., 2006).
Pulmonary arteries have perhaps the greatest cadre of potential
O2-sensing mechanisms including redox sensors
(Archer and Michelakis, 2002),
either an increase or decrease in ROS
(Ward et al., 2006), NADPH and
NADPH oxidase (Jones et al.,
2000; Wolin et al.,
2005), cyclic ADP ribose
(Evans and Dipp, 2002) and Rho
kinase (Fagan et al., 2004).
Other upstream activators of hypoxic vasodilation, which may or may not be
associated with a decrease in intracellular calcium
(Thorne et al., 2004), include
intracellular acidosis (Nagesetty and
Paul, 1994), redox control of cytosolic NADPH
(Wolin et al., 2005), direct
modulation of internal Ca2+ stores and Rho kinase
(Thorne et al., 2004).
Can anyone be right?
The variety of potential O2-sensing systems suggests that either
this process evolved numerous times and now constitutes a highly redundant
system, or that perhaps many of these mechanisms may be either modulators of,
or even peripheral to, an even more fundamental process. Not surprisingly,
many of these proposed O2-sensing mechanisms have their detractors
and in many instances there are as many arguments against a particular sensing
mechanism as there are arguments for it. This has fostered reviews such as
`Detecting acute changes in oxygen: will the real sensor please stand up?'
(Kemp, 2006), `Hypoxic
pulmonary vasoconstriction: mechanisms and controversies'
Aaronson et al., 2006),
`Hypoxic pulmonary vasoconstriction is/is not mediated by increased production
of reactive oxygen species' (Ward et al.,
2006), `Oxidant and redox signaling in vascular oxygen-sensing
mechanisms: basic concepts, current controversies, and potential importance of
cytosolic NADPH' (Wolin et al.,
2005), `The mechanisms of hypoxic pulmonary vasoconstriction:
potassium channels, redox oxygen sensors, and controversies'
(Archer and Michelakis, 2002),
`Hypoxia, anoxia, and O2 sensing: the search continues'
(Schumacker, 2002),
`Mechanisms of hypoxic pulmonary vasoconstriction: can anyone be right?
(Ward and Aaronson, 1999). Are
there multiple and redundant O2 sensors, or does the lack of
unequivocal support for a unifying mechanism suggest that it remains to be
identified?
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Hydrogen sulfide as an oxygen sensor |
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TOPSummaryIntroductionTypes of hypoxia and...Oxygen-sensing tissuesMechanism of oxygen sensingHydrogen sulfide as an...Conclusions and future...References |
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) state, regarding airway (neuroepithelial) and carotid
chemoreceptors, that `...putative O2 sensors would be drawn from a
pool of proteins that naturally underwent oxido-reductive transitions.'
However, it is not exactly clear to me why the O2 sensor must be a
macromolecule. In fact we have recently proposed a novel O2-sensing
mechanism that is based on the metabolism of a very simple (but noticeable)
gas, hydrogen sulfide (H2S). This mechanism has both experimental
and anecdotal support, as described in the following paragraphs.
Hydrogen sulfide as a biological stimulant
There is a rapidly accumulating body of evidence linking H2S
with nitric oxide (NO) and carbon monoxide (CO) as the third `gasotransmitter'
(Wang, 2002). Reports of the
physiopharmacological effects of H2S suggest an almost ubiquitous
presence in tissues. H2S has been implicated in neurological,
cardiovascular, gastrointestinal, genitourinary and endocrine systems where it
may have modulatory and/or cytoprotective effects
(Qu et al., 2007;
Li and Moore, 2008;
Leffler et al., 2006;
Li and Moore, 2008;
owicka and Be
towski,
2007; Szabó,
2007). H2S has also been proposed to be both pro- and
anti-inflammatory (Li et al.,
2006; Wallace,
2007) and it has even been reported to induce suspended animation
in mice (Blackstone et al.,
2005). In the cardiovascular system, H2S has long been
known to dilate systemic vessels (Hosoki
et al., 1997). H2S is synthesized in many, if not all,
tissues by two cytosolic pyridoxyl 5'phosphate-dependent enzymes,
cystathionine β-synthase (CBS) and cystathionine 
-lyase (CSE).
CBS is thought to be the primary source for H2S production in the
brain, and CSE in the vasculature
(Szabó, 2007;
Li and Moore, 2008).
Evidence supporting hydrogen sulfide mediation of vascular hypoxic responses
During the course of independent studies on the phylogeny of vascular
responses to hypoxia (Smith et al.,
2001; Olson et al.,
2001; Russell et al.,
2001; Russell et al.,
2007) and H2S
(Dombkowski et al., 2004;
Dombkowski et al., 2005;
Olson, 2005), it became
evident that these two stimuli evoked the same response in isolated blood
vessels, irrespective of whether the response was a contraction, relaxation or
was multi-phasic (Fig. 1). This
prompted further investigation into whether this was coincidental or if the
two stimuli were somehow related. We
(Olson et al., 2006)
subsequently showed that, (1) H2S was enzymatically generated by
many blood vessels, (2) inhibition of H2S production inhibited
vascular responses to hypoxia (Fig.
2), (3) addition of cysteine, the metabolic precursor for
H2S, greatly augmented the hypoxic response, (4) hypoxia and
H2S appeared to compete for a common downstream activation process,
and (5) hypoxia and H2S produce the same degree of cellular
depolarization in vascular smooth muscle. We also found evidence for
H2S mediation of hypoxic relaxation of the trout urinary bladder
(Dombkowski et al., 2006),
suggesting that this mechanism may be intrinsic to smooth muscle in
general.
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). In this model (Fig.
3) H2S is constitutively synthesized in the cell
cytoplasm and oxidized in the mitochondria. The actual concentration of
biologically active H2S is determined by the simple balance between
H2S production and the amount of O2 available for
H2S oxidation, i.e. tissue PO2. In
addition CBS and CSE also appear to be sensitive to
PO2 or intracellular redox state
(Maclean and Kraus, 2004;
Stipanuk, 2004;
Banerjee and Zou, 2005) and may
either directly contribute to intracellular [H2S] or may provide a
long-term mechanism to bias the rate of constitutive H2S
production. We recently found evidence coupling H2S production and
metabolism to O2. As shown in
Fig. 4A,B, H2S
production by minced trout heart (at PO2
0)
is increased by cysteine (Cys) and transiently inhibited by injection of
micromolar amounts of O2. Because this only occurs at very low
PO2, it suggests that under normal
circumstances intracellular H2S is very low. Conversely, there is a
net H2S consumption by purified trout mitochondria that is
increased in the presence of O2 and decreased when the mitochondria
are gassed with nitrogen (N2) or heat denatured
(Fig. 4C,D). Hildebrandt and
Grieshaber (Hildebrandt and Grieshaber,
2008) have recently summarized the pathways involved in
mitochondrial H2S oxidation.
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Most of our attention to date has focused on H2S metabolism as
the mediator of hypoxic vasoconstriction. However, in many vessels, i.e. trout
efferent branchial arteries (Dombkowski et
al., 2004) toad and duck pulmonary arteries
(Dombkowski et al., 2005) and
bovine pulonary arteries (Fig.
1D), it appears that H2S produces both vasoconstriction
and vasodilation and that these occur at different H2S
concentrations. This implies that H2S has multiple effects on the
mechanical properties of vascular smooth muscle, a rare but not unheard of
attribute. This too may have physiological significance. For example, it is
predicted that low concentrations of H2S, which would be expected
in normoxia, may in fact aid in pulmonary vasodilation; this would then
convert to pulmonary vasoconstriction when O2 levels fall and
[H2S] increases.
Arguments that H2S-mediated contraction of vascular smooth is
only an indirect response have been presented by Koenitzer et al.
(Koenitzer et al., 2007). They
observed that a H2S-mediated dilation of rat aortas became more
sensitive to H2S at low PO2, whereas
a H2S-mediated contraction was only observed at high
[H2S] with concomitantly high PO2.
They proposed that the H2S-mediated contraction was due to an
oxidation product of H2S rather than a direct vasoconstrictory
action of H2S itself, implying that H2S is only a
vasodilator. However, rat aortas also dilate to hypoxia and may not be a good
model with which to examine H2S vasoconstriction. We
(Olson et al., 2008a) repeated
these studies in both hagfish and lamprey dorsal aortas, where hypoxia and
H2S only produce vasoconstriction and found that these vessels also
became more sensitive to H2S at low
PO2. Thus it is evident that the H2S
contraction is not the result of an oxidation product. This also provides
further support for our hypothesis of H2S in O2 sensing,
i.e. the vessels become more sensitive to exogenous H2S at low
PO2 because of the additive affect of
endogenous H2S production.
Hydrogen sulfide in chemoreception
If H2S metabolism is involved in O2 sensing in
vascular smooth muscle, we wondered if this could be a general
O2-sensing mechanism in other oxygen-sensitive tissues as well. To
examine this, we turned to the external chemoreceptors on the first gill arch
of trout. We (Olson et al.,
2008b) found that injection of H2S into the buccal
cavity mimicked the classical hypoxic induced bradycardia
(Fig. 5) and this response was
inhibited when the first, but not second, gill arches, were removed. In
addition, both hypoxia and H2S depolarized isolated zebrafish
neuroepithelial cells. This suggests that H2S metabolism may be an
O2-sensing mechanism in a variety of O2-sensitive
tissues. Interestingly, we also found in unanesthetized trout that whereas
hypoxia increased plasma sulfide when measured with a sulfide electrode, it
did not affect plasma H2S measured with a polarographic
H2S sensor. This suggests that some sulfide moiety is carried in
the plasma, but it is not H2S. This is considered further under
Curbing the exuberance (below).
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). Second, there is evidence to support intracellular
compartmentalization of H2S production and oxidation. Searcy
(Searcy, 2003) proposed that
mitochondria originated from sulfide (H2S) oxidizing thermophilic
bacteria and the nucleocytoplasm from sulfide-reducing Archaea. Thus the
mechanism for constitutive production of H2S and its
O2-dependent inactivation by mitochondria is a common feature of
all eukaryotic cells. Third, systemic arterioles consume O2 at a
rate of up to 500 times that of resting skeletal muscle
(Shibata et al., 2005). This
is far greater than that required to maintain wall tension and the reason for
this high level of O2 consumption is not readily apparent. Could it
be due to the continual need for H2S oxidation in these cells?
Curbing the exuberance
Like its predecessor nitric oxide (NO), H2S has garnered
considerable interest as a biologically important regulatory molecule in a
seemingly endless number and variety of physiological processes and for its
potential therapeutic value (Szabó,
2007). Before we get swept away in all the excitement we need to
examine several aspects of H2S signaling that are a bit
troublesome.
The first concerns reported levels of H2S in plasma. In the
approximately 25 studies conducted since 2000 all but one have reported plasma
or blood H2S in micromolar concentrations (typically 30–60
µmol l–1 but as high as 300 µmol l–1)
and all but one have used acidic or alkaline modification of the sample prior
to measurements [summarized in Whitfield
(Whitfield et al., 2008) and
detailed in the supplementary material]. These concentrations are typically
used in physiological studies, however, they are tens to hundreds of times
greater than that which inhibits purified cytochrome c oxidase (1
µmol l–1). Furthermore, at these concentrations, the smell
of H2S should be readily apparent in both plasma and exhaled
breath, which, fortunately, is not the case
(Whitfield et al., 2008).
These 25 studies have also largely ignored reports going back as far as the
1920s (c.f. Haggard, 1921)
that showed very little, or no, H2S in blood and that demonstrated
a large capacity for blood to absorb exogenously administered H2S
[summarized by Whitfield (Whitfield et
al., 2008)]. We (Whitfield et
al., 2008) used a newly developed polarographic sensor to measure
H2S gas in plasma or whole blood at sub-micromolar concentrations,
and without any chemical modification, and failed to find measurable amounts
of H2S in blood or plasma from lamprey, trout, mouse, rat, pig or
cow, or in an unanesthetized trout fitted with an extracorporeal loop.
Furthermore, exogenously administered H2S rapidly disappeared from
whole blood in vitro (Fig.
5A,B) and from blood of the unanesthetized trout
(Fig. 5C). We also found that
the antioxidant buffer commonly employed with S2–-selective
electrodes generated H2S from bovine serum albumin, presumably from
hydroxyl replacement of cysteine sulfur. Our studies with the polarographic
H2S sensor raise the question of the physiological relevance of
studies that employ what appears to be pharmacological concentrations of
H2S. What is too high, and what is physiological in the region of
the intracellular effectors? Although it is clear that H2S does not
circulate at 30 µmol l–1, it remains to be determined how
fast exogenous H2S moves across the cell membrane and how it is
distributed within the cell. Does it equilibrate, or does metabolism maintain
a lower intracellular concentration, and is H2S partitioned within
the cell? Are seemingly excessive exogenous H2S concentrations
pharmacological or are they necessary to produce a physiological increase in
intracellular H2S? Toxicological studies lend some credence to the
latter. Purified cytochrome c oxidase is inhibited by nanomolar
H2S concentrations whereas mitochondria and whole animals are
poisoned at micromolar concentrations and sulfide oxidizing bacteria survive
1–2 mmol l–1 H2S (Bagarino, 1992). (In our
experience some vessels even tolerate >10 mmol l–1
H2S.) Because there does not appear to be any species-specific
differences in cytochrome c oxidase (Bagarino, 1992), it seems likely
that differential rates of H2S metabolism could account for the
wide range in H2S sensitivity, and perhaps, the threshold
concentration necessary for physiological responses. Clearly, one of the next
breakthrough in H2S physiology will be measurement of
H2S concentration at the sub-cellular level. Our studies showing
rapid removal of exogenous sulfide from the blood, in vivo and in
vitro (Whitfield et al.,
2008) also raises the question of how numerous studies could show
that a variety of experimental manipulations have had lasting effects on
plasma [H2S].
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). Thus
ascribing definitive physiological effects to inhibition of H2S
production is somewhat tenuous. The third aspect is that H2S is a good reductant and can potentially react with other signaling molecules (i.e. NO) potentially removing them or modifying their biological attributes. Thus it is not always evident if the effect of H2S is direct or indirect, although this may not be critical.
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Conclusions and future directions |
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TOPSummaryIntroductionTypes of hypoxia and...Oxygen-sensing tissuesMechanism of oxygen sensingHydrogen sulfide as an...Conclusions and future...References |
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), H2S in solution exists as both H2S
gas and HS–. As an anion, HS– is very
similar in size to Cl– and could potentially become involved
in Cl–-mediated processes. (4) Does H2S
participate in O2 sensing in other oxygen-sensitive tissues, i.e.
is there a universal O2 sensor, or did O2-sensing
mechanisms evolve independently with different tissues? Can H2S
exemplify Occam's razor? |
Acknowledgments |
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References |
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TOPSummaryIntroductionTypes of hypoxia and...Oxygen-sensing tissuesMechanism of oxygen sensingHydrogen sulfide as an...Conclusions and future...References |
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-lyase (CSE). (B)
Hypoxic relaxation of a norepinephrine-contracted (NE; 10–6
mol l–1) rat thoracic aorta (TA) is significantly
(*) inhibited by the CSE inhibitor propargyl glycine (P). (C)
Hypoxic contractions of bovine pulmonary arteries (PA) are not affected by
propargyl glycine (P) but are increasingly inhibited by the CBS inhibitor
aminooxy acetate (A), hydroxylamine (H), or a combination of all three
inhibitors (HPA). Means ± s.e.m.; responses are normalized to an
initial KCl (80 mmol l–1) or NE contraction. (Adapted from
Olson et al., 2006
Significantly different from
pre-H2S; *significantly different from intact trout
after H2S injection. The bradycardia at 5 and 10 mmol
l–1 is significantly (*) attenuated in trout with
the first pair of gills removed relative to the two other groups. Adapted from
Olson (Olson et al., 2008b