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First published online August 3, 2006
Journal of Experimental Biology 209, 3234-3240 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02376
Hydrogen sulfide mediates hypoxia-induced relaxation of trout urinary bladder smooth muscle
1 South Bend Center for Medical Education, Indiana University School of
Medicine, University of Notre Dame, Notre Dame, IN 46556, USA
2 Department of Biological Sciences, University of Notre Dame, Notre Dame,
IN 46556, USA
* Author for correspondence (e-mail: kolson{at}nd.edu)
Accepted 8 June 2006
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Summary |
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-lyase. H2S produced a
dose-dependent relaxation in unstimulated and carbachol pre-contracted
bladders and inhibited spontaneous contractions. Bladders pre-contracted with
80 mmol l-1 KCl were less sensitive to H2S than bladders
contracted with either 80 mmol l-1
KC2H3O2 (KAc) or carbachol, suggesting that
some of the H2S effects are mediated through an ion channel.
However, H2S relaxation of bladders was not affected by the
potassium channel inhibitors, apamin, charybdotoxin, 4-aminopyridine, and
glybenclamide, or by chloride channel/exchange inhibitors
4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt,
tamoxifen and glybenclamide, or by the presence or absence of extracellular
HCO3-. Inhibitors of neuronal mechanisms, tetrodotoxin,
strychnine and N-vanillylnonanamide were likewise ineffective.
Hypoxia (aeration with N2) also relaxed bladders, was competitive
with H2S for relaxation, and it was equally sensitive to KCl, and
unaffected by neuronal blockade or the presence of extracellular
HCO3-. Inhibitors of H2S synthesis also
inhibited hypoxic relaxation. These experiments suggest that H2S is
a phylogenetically ancient gasotransmitter in non-mammalian non-vascular
smooth muscle and that it serves as an oxygen sensor/transducer, mediating the
effects of hypoxia.
Key words: H2S, hypoxia, smooth muscle, urinary bladder, trout
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Introduction |
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TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
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; Kimura,
2000; Kimura,
2002), vascular (Hosoki et al.,
1997; Zhao et al.,
2001; Zhao and Wang,
2002; Cheng et al.,
2004), gastrointestinal (Hosoki
et al., 1997; Teague et al.,
2002), genitourinary
(Patacchini et al., 2004;
Patacchini et al., 2005) and
reproductive (Hayden et al.,
1989; Sidhu et al.,
2001; Teague et al.,
2002) tracts, pulmonary system
(Shi et al., 2003;
Zhang et al., 2003;
Cheng et al., 2004), and heart
(Zhang et al., 2003;
Geng et al., 2004).
H2S relaxes most mammalian smooth muscles including systemic
vessels (Hosoki et al., 1997;
Zhao et al., 2001;
Zhao and Wang, 2002;
Cheng et al., 2004), intestine
(Hosoki et al., 1997;
Teague et al., 2002), uterus
(Sidhu et al., 2001) and vas
deferens (Teague et al.,
2002). Rat urinary bladder detrusor muscle is the only tissue
reported to date where H2S produces a contraction
(Patacchini et al., 2004;
Patacchini et al., 2005).
ATP-sensitive K+ channels (KATP) have been proposed to
mediate H2S-mediated relaxation of vascular smooth muscle
(Zhao et al., 2001;
Zhao and Wang, 2002), but they
do not appear to be involved in either gastrointestinal or reproductive smooth
muscle relaxation (Teague et al.,
2002). Contraction of the rat urinary bladder appears to be
indirect via stimulation of capsaicin-sensitive afferent neurons
(Patacchini et al., 2004;
Patacchini et al., 2005).
We have shown that H2S may relax or contract vascular smooth
muscle in non-mammalian vertebrates and many vessels relax at lower
H2S concentrations ([H2S]) and then contract at higher
[H2S] (Dombkowski et al.,
2004; Dombkowski et al.,
2005; Olson,
2005). We (Olson et al.,
2006) recently observed that H2S also constricts, or
has multi-phasic dilation/constriction effects on some mammalian vessels such
as bovine and rat pulmonary arteries. To our knowledge, there is no evidence
for a direct H2S-mediated contraction of non-vascular smooth
muscle, nor is there any information on the effects of H2S on
non-mammalian, non-vascular smooth muscle.
Recently, we (Olson et al.,
2006) proposed that H2S serves as a vascular oxygen
sensor and that it plays an integral role in both hypoxic vasoconstriction of
pulmonary vessels and cyclostome aortas and it is also involved in hypoxic
dilation of mammalian systemic vessels. This model is based on continual
oxidative inactivation of constitutively generated H2S during
normoxia and the development of vasoactive levels of H2S when
available oxygen falls. It is not known if this model is only applicable to
vascular smooth muscle or if it is a feature of smooth muscle in general.
Spontaneous and agonist-induced contraction of rat urinary bladder, like
that of systemic vessels, decreases when exposed to hypoxia
(Leven et al., 1999;
Whitbeck et al., 1999;
Waring and Wendt, 2000), which
is opposite to the contractile effect of H2S, albeit indirect, in
this same tissue (Patacchini et al.,
2004; Patacchini et al.,
2005). To our knowledge, the effects of hypoxia on non-mammalian
non-vascular smooth muscle are not known.
The purpose of the experiments reported here were threefold: (1) to determine if H2S affects contractile properties of non-mammalian, non-vascular smooth muscle and examine the mechanism(s) involved, (2) to evaluate the effects of hypoxia on the same tissue, and (3) to determine if H2S mediates the hypoxic response. To this end we used urinary bladders from steelhead and rainbow trout and measured H2S production, H2S effects on spontaneous and agonist-induced contractions and possible mechanisms of action, effects of hypoxia on bladder contractions, and the effects of inhibiting H2S synthesis on the hypoxic responses.
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Materials and methods |
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Because the steelhead trout were no longer available after March, we used urinary bladders from rainbow trout (O. mykiss, Walbaum, kamloops strain, 0.3-0.8 kg) for several experiments. Rainbow trout of either sex were purchased from a local hatchery (Homestead Trout Farm, Harrietta, MI, USA), and maintained throughout the year in 2000 liter tanks containing circulating well-water at 12-15°C, aerated with filtered room air, with a 12 h:12 h light:dark cycle. The fish were fed a maintenance diet of commercial trout pellets (Purina, St Louis, MO, USA). The rainbow trout were stunned by a blow to the head and the bladders prepared for myography, as described above. Although the bladders from the rainbow trout were considerably smaller than those from the steelhead trout, their sensitivity to NaHS, Na2S, and N2 was identical to steelhead bladders, therefore, `trout' is used hereafter to refer to experiments on either strain. All procedures followed NIH guidelines and were approved by the local IACUC Committee.
Myography
Circular smooth muscle rings, approximately one-half centimeter long, and
immediately distal to the trigone were mounted on 280 µm-diameter stainless
steel wire hooks and suspended in 5 ml water-jacketed smooth muscle baths
filled with 14°C Hepes buffer and aerated with room air. The bottom hooks
were stationary; the upper ones were connected to Grass model FT03C
force-displacement transducers (Grass Instruments, West Warwick, RI, USA).
Tension was measured on a Grass Model 7E or 7F polygraph (Grass Instruments,
West Warwick, RI, USA). Polygraph sensitivity was set to detect changes as
small as 5 mg. Data was archived on a PC computer at 1 Hz using SoftWire
(Measurement Computing, Middleboro, MA, USA). The chart recorders and software
were calibrated prior to each experiment.
Baseline (resting) tension of approximately 200 mg was applied and continuously adjusted for at least 1 h prior to experimentation as the bladders exhibited substantial stress relaxation. The bladders were then contracted with 80 mmol l-1 KCl, washed twice, and resting tension re-established for a minimum for 30 min before further experimentation. A second KCl contraction was given in initial studies, but as this contraction was not different from the first it was omitted in later experiments.
H2S responses
The cumulative dose-response characteristics of NaHS, which forms HS- and
H2S in solution similar to that produced by gassing with
H2S gas (Zhao et al.,
2001), were examined in otherwise unstimulated bladders. Because
H2S inhibited spontaneous contractions and relaxed unstimulated
bladders, the cumulative dose-response characteristics of NaHS were also
examined in 10 µmol l-1 carbamylcholine chloride (carbachol,
CARB)-prestimulated bladders. In later experiments, Na2S, which
also forms HS- and H2S in solution, was used, because of its
availability with a reduced amount of elemental sulfur impurities
(Doeller et al., 2005). As the
effects of Na2S and NaHS were similar, H2S is used in
the context of either NaHS or Na2S unless otherwise specified.
Potential mechanisms of H2S-induced relaxation were evaluated in carbachol prestimulated bladders. The rings were treated with the inhibitor, followed 15 min later by prestimulation with carbachol (10 µmol l-1), and at the plateau contraction they were exposed to 1 mmol l-1 H2S. Control rings were treated similarly omitting the inhibitor, and only one experiment was performed per ring. Potassium channels were inhibited with apamin (APA, 100 nmol l-1), a small conductance KCa channel (SKCa) inhibitor, charybdotoxin (CTX, 50 nmol l-1), a large conductance KCa channel (BKCa) inhibitor, 4-aminopyridine (4-AP, 100 µmol l-1), a voltage sensitive K+ channel inhibitor, and by using APA and CTX in combination. Chloride channel/exchangers were inhibited with glibenclamide (GLY, 10 µmol l-1), a cystic fibrosis transmembrane conductance regulator (CFTR) and KATP channel inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate (DIDS, 400 µmol l-1), an inhibitor of Cl-/HCO3- exchange, and tamoxifen (TAM, 100 µmol l-1), a volume-sensitive Cl- channel inhibitor. The effects of the primary afferent nerve irritant N-vanillylnonanamide (10 µmol l-1; a synthetic capsaicin with similar biological activity) were also examined.
In order to determine if the H2S relaxation was affected by the type of pre-contraction stimulus, the effects of 1 mmol l-1 H2S were also examined on bladders contracted with 80 mmol l-1 KCl or 80 mmol l-1 KC2H3O2 (KAc). The effects of strychnine (10 µmol l-1), a glycine/NMDA receptor antagonist, tetrodotoxin (TTX, 10 µmol l-1), a fast Na+ channel inhibitor, and a bicarbonate-based buffer (Cortland) on H2S-induced relaxation were also examined in the KCl and KAc prestimulated bladders.
H2S production
Pieces from ten different bladders were pooled for each experiment, blotted
dry, weighed, and homogenized on ice in 100 mmol l-1 potassium
phosphate buffer (pH 7.4). H2S production was measured as described
previously (Zhao et al.,
2003), with minor modifications. Briefly, the homogenates were
brought to a final volume of 1:10 tissue mass:nutrient buffer volume. Nutrient
phosphate buffer contained 10 mmol l-1 cysteine and 2 mmol
l-1 pyridoxal-5'-phosphate. In other experiments, the
nutrient buffer also contained the cystathionine -lyase (CSE)
inhibitor, D,L-propargylglycine (PPG; 20 mmol
l-1) or the cystathionine ß-synthase (CBS) inhibitor,
amino-oxyacetic acid (AOA; 1 mmol l-1). The final mixture was then
drawn into 10 ml polyethylene syringes, air bubbles were expelled, and the
syringes sealed with three-way stopcocks and gently rotated for 24 h at room
temperature. A glass bead in the syringe assisted mixing. At the end of the
incubation, 1 ml samples of the homogenate solution were placed in 1.5 ml
centrifuge tubes and immediately centrifuged. The supernatant was removed and
mixed 1:1 with an antioxidant buffer made according to the manufacturer's
specifications. This buffer converted all H2S and HS- to
S2-, which was then measured with a sulfide electrode (Lazar
Research Laboratories, Los Angeles, CA, USA) on a Fisher Accumet AR50 pH meter
(Fisher Scientific, Pittsburgh, PA, USA) following the manufacturer's
directions. Standards were prepared from Na2S, all measurements
were done in triplicate.
Hypoxic responses
The effects of hypoxia, produced by gassing with N2 rather than
air, were examined in otherwise un-stimulated and 10 µmol l-1
carbachol, 80 mmol l-1 KCl, or 80 mmol l-1 KAc
pre-contracted bladders. Similar to the mechanistic examination of
H2S, N2 was also tested on prestimulated bladders. The
effects of strychnine, tetrodotoxin and Cortland saline on the hypoxic
response were also examined in KCl and KAc pre-contracted bladders.
Relationship between H2S and hypoxia
Two experiments were employed to examine the relationship between
H2S and hypoxic relaxation. The first experiments were designed to
determine if the relaxation produced by H2S and hypoxia was
additive or competitive. Bladders were pre-contracted with carbachol, KCl or
KAc and then exposed to either 1 mmol l-1 H2S or
hypoxia. When tension stabilized, the other stimulus (hypoxia or
H2S, respectively) was applied. In the second experiments, the
effects of inhibiting H2S synthesis on hypoxic relaxation of
un-stimulated and carbachol, KCl, or KAc pre-contracted bladders was examined.
The CSE and CBS inhibitors (PPG, 10 mmol l-1, and AOA, 1 mmol
l-1, respectively) were added at least 15 min prior to hypoxia.
Data analysis
Dose-response curves were fit for each vessel using Table Curve®
(Jandel Corp., Chicago, IL, USA). Student's t-tests were used for
comparisons between groups with SigmaStat® (Jandel Corp.). Results are
provided as mean ± s.e.m. Significance was assumed at
P
0.05.
Chemicals
Unless otherwise stated all chemicals were purchased from Sigma-Aldrich Co.
(St Louis, MO, USA). Na2S and NaHS were purchased from Fisher
Scientific (Pittsburgh, PA, USA). Concentrations for the Hepes-buffered trout
saline (pH 7.8) were as follows (in mmol l-1): 145 NaCl, 3 KCl,
0.57 MgSO4, 2 CaCl2, 5 glucose, 3 Hepes acid, and 7
Hepes Na+ salt. Concentrations of the Cortland-buffered trout
saline (pH 7.8) were as follows (in mmol l-1): 124 NaCl, 3 KCl, 1.1
MgSO4, 2 CaCl2, 5.55 glucose, 12 NaHCO3, 0.09
NaH2PO4, and 1.8 Na2HPO4. Hepes
and Cortland buffers were used within 72 h of preparation. NaHS and
Na2S stock solutions for electrode calibration and bath application
were used within 8 h of preparation.
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0.05) the force developed
(Fig. 4). The ability of
H2S to relax carbachol-contracted bladders was unaffected by GLY,
TAM or DIDS (Fig. 4).
Incubation with N-vanillylnonanamide (10 µmol l-1;
N=4) did not affect either the magnitude of a carbachol contraction
or the ability of H2S to relax the carbachol contraction (data not
shown). Strychnine (10 µmol l-1; N=4), tetrodotoxin
(TTX, 10 µmol l-1; N=4) or substituting Cortland buffer
for Hepes buffer (N=4) did not affect either KCl or KAc contractions
or the ability of H2S to relax them (not shown).
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Effects of hypoxia
Hypoxia (N2) reduced baseline tone and inhibited spontaneous
contractions in otherwise un-stimulated bladders and in 10 µmol
l-1 carbachol-contracted bladders
(Fig. 1C,D). As shown in
Fig. 2, hypoxia was
significantly less efficacious in relaxing KCl-contracted bladders
(49.0±1.6% relaxation) than it was in bladders contracted with
carbachol (89.8±2.5% relaxation). Hypoxic relaxation of KAc-contracted
bladders (65.6±9.7%) was not significantly different from hypoxic
relaxation of either carbachol- or KCl-contracted bladders
(Fig. 2; all N=8).
Strychnine (10 µmol l-1; N=4), tetrodotoxin (TTX, 10
µmol l-1; N=4) or substituting Cortland buffer for
Hepes buffer (N=4) did not affect the ability of N2 to
relax contractions produced by either 80 mmol l-1 KCl or 80 mmol
l-1 KAc (not shown; all N=4).
H2S production
Homogenates of trout urinary bladders produced H2S enzymatically
(Fig. 5). The cystathionine
-lyase inhibitor, D,L-propargylglycine (20 mmol
l-1), reduced H2S synthesis by over 80% and the
cystathionine ß-synthase inhibitor, amino-oxyacetic acid (1 mmol
l-1), reduced H2S synthesis by over 95%
(Fig. 5).
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Relationship between H2S and hypoxia
Hypoxia applied after H2S did not produce any additional
relaxation in bladders pre-contracted with carbachol, KCl or KAc
(Fig. 2). When H2S
was added after hypoxia in pre-contracted bladders it was similarly
ineffective (Fig. 2).
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-lyase inhibitor,
D,L-propargylglycine, caused a slight increase in
baseline tone and an increase in the frequency of spontaneous contractions but
did not prevent the N2-induced relaxation or inhibition of
spontaneous contractions in un-stimulated bladders
(Fig. 1C); this was consistent
in bladders from four fish. The cystathionine ß-synthase inhibitor,
amino-oxyacetic acid (1 mmol l-1) did not appear to have any effect
on resting tone, spontaneous contractions, or N2-induced relaxation
(N=4; not shown). Hypoxic relaxation of carbachol-pre-contracted
bladders was partially inhibited by amino-oxyacetic acid, and a mixture of
D,L-propargylglycine and amino-oxyacetic acid inhibited
hypoxic relaxation of both KCl- and KAc-contracted bladders
(Fig. 6; N=8 for
controls, N=4 for each treatment). |
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). Our experiments also show that both the response of trout
bladder to H2S and the potential mechanism of H2S action
is unlike that observed in the rat. Whereas some of the differences between
trout and rats may be due to the different derivation of the tissue, fish
bladders are mesodermal and noncloacal in origin whereas tetrapod bladders are
derivatives of the cloaca (Kardong,
2005), our results, nevertheless, suggest that H2S is
an endogenous signaling molecule in non-mammalian non-vascular smooth
muscle.
Mechanism of H2S actionH2
S-induced relaxation of mammalian vascular smooth muscle appears to be
partially mediated by the activation of ATP-sensitive potassium
(KATP) channels (Zhao et al.,
2001; Zhao and Wang,
2002). However, these channels do not seem to contribute to
H2S relaxation of mammalian non-vascular smooth muscle
(Teague et al., 2002), nor do
they appear to mediate responses in the trout urinary bladder because the
sulfonylurea KATP channel inhibitor, glibenclamide, which partially
inhibits H2S relaxation of rat aortas
(Zhao et al., 2001;
Zhao and Wang, 2002) is
ineffective in trout bladders (Fig.
4). In fact our findings failed to support the involvement of any
type of potassium channel because none of a variety of classical potassium
channel inhibitors affected the H2S response (Figs
3,
4), nor did elevation of
extracellular [K+] to 80 mmol l-1 with potassium acetate
(KAc). The latter would be expected to substantially reduce transmembrane
K+ gradients and obviate K+ channels.
The reduced H2S efficacy in bladders contracted with KCl,
compared to carbachol and KAc, suggests that the 80 mmol l-1
Cl- may interfere with H2S. It is possible that
HS-, which at physiological pH accounts for approximately 80% of
the total H2S + HS-
(Dombkowski et al., 2004)
interferes with a Cl- channel or transporter and that this
interference is diminished when transmembrane Cl- gradients are
changed. However, we could not find any evidence for a
Cl--dependent mechanism using a variety of inhibitors of
Cl- exchangers and channels
(Fig. 4). Glibenclamide, which
in addition to inhibiting KATP channels inhibits the cAMP-activated
cystic fibrosis transmembrane conductance regulator (CFTR) Cl-
channel at micromolar concentrations (Sheppard et al., 1992) was ineffective.
A Cl-/HCO3- exchange is also doubtful as the
Cl-/HCO3- exchange inhibitor, DIDS, was
ineffective (Fig. 4) and
H2S relaxation was unaffected by the absence (Hepes buffer) or
presence (Cortland buffer) of extracellular HCO3-.
Although it is possible that 400 µmol l-1 DIDS does not block
Cl-/HCO3- exchange in trout bladder, or the
nominal absence of extracellular HCO3- does not limit
the cell's ability to utilize a Cl-/HCO3-
exchange, this seems unlikely. This question is further compounded by the lack
of specificity of inhibitors of Cl--dependent mechanisms (Jentsch
et al., 2001). Clearly, additional studies with other inhibitors of
Cl--dependent mechanisms and variations in extracellular
[Cl-] are warranted.
Patacchini et al. (Patacchini et al.,
2004; Patacchini et al.,
2005) reported that rat urinary bladders are indirectly contracted
through H2S stimulation of capsaicin-sensitive nerves. We do not
know whether or not the trout bladder has capsaicin-sensitive nerves. However,
our results show that trout bladders are relaxed by H2S and this is
not affected by blocking intrinsic neurons with tetrodotoxin, glycine/NMDA
receptors with strychnine, or the presence of the capsaicin synthetic,
N-vanillylnonanamide. Thus both the response and the mechanism of
H2S action in trout urinary bladder are independent of intrinsic
nerves, and are therefore unlike those observed in the mammalian urinary
bladder.
H2S synthesis in mammalian vascular smooth muscle has been
attributed to the pyridoxal-5'-dependent enzyme, cystathionine
-lyase, whereas cystathionine ß-synthase does not appear to be
present (Zhao et al., 2001).
Both enzymes are involved in H2S synthesis in non-vascular tissue
(Zhao et al., 2003). Our
studies also suggest that both enzymes contribute to H2S synthesis
in the trout urinary bladder (Fig.
5). The increase in baseline tension and frequency of spontaneous
contractions following inhibition of cystathionine -lyase with
D,L-propargylglycine
(Fig. 1C) also suggest that
H2S is continuously synthesized by the bladder and has tonic
inhibitory activity.
H2S as an oxygen sensor
We (Olson et al., 2006)
recently proposed that H2S is an oxygen sensor in vascular smooth
muscle. This hypothesis is based on our observations that, (1) H2S
and hypoxia produce the same mechanical response in vessels from at least one
species in every vertebrate class, even though the response varies from a
contraction, to relaxation, to a multi-phasic one; (2) the effects of
H2S and hypoxia are competitive - in the presence of one, the
response to the other is greatly reduced or abolished; (3) blood vessels
enzymatically generate H2S and inhibitors of H2S
synthesis inhibit hypoxic responses, whereas the H2S precursor
cysteine augments it. The present study suggests that H2S is also
involved in oxygen sensing/signal transduction in the trout urinary
bladder.
In essentially all of the present experiments the effects of hypoxia are similar, if not identical, to those produced by H2S. Hypoxia relaxes otherwise un-stimulated and pre-contracted bladders (Fig. 1), it becomes less efficacious in KCl-pre-contracted bladders (Fig. 2) and it is unaffected by inhibition of neuronal mechanisms with strychnine, tetrodotoxin or N-vanillylnonanamide. In pre-contracted bladders, the presence of either H2S or hypoxia prevents relaxation by the other. This does not appear to be due to a mechanical inability of the bladders to relax beyond a certain point because, with the exception of a H2S relaxation of a carbachol contraction, neither H2S nor hypoxia produced 100% relaxation when applied initially (Fig. 2). Furthermore, hypoxic relaxation is reduced by inhibitors of bladder H2S synthesis (Fig. 6).
Inhibitors of cystathionine ß-synthase (amino-oxyacetic acid) and
cystathionione -lyase (D,L-propargylglycine)
appeared more efficacious in inhibiting H2S synthesis
(Fig. 5) than they were in
inhibiting hypoxic relaxation (Fig.
6). This may be due to inhibitor accessibility to the enzyme;
H2S production was measured in homogenized tissues whereas the
hypoxia effects were examined in intact bladder rings. Other studies have also
suggested that amino-oxyacetic acid is not readily taken up by smooth muscle
cells (Zhao et al., 2003). It
is also possible that there are other pathways for H2S synthesis
(Julian et al., 2002;
Maclean and Kraus, 2004;
Stipanuk, 2004) or that
H2S effects are compartmentalized within the cell
(Dombkowski et al., 2005).
Phylogeny of H2S and hypoxic responses
The similarity of H2S and hypoxic responses in vertebrate
vascular smooth muscle (Olson et al.,
2006) may be a property of non-vascular smooth muscle as well.
This suggests that H2S signaling in smooth muscle is a
phylogenetically ancient mechanism. Clearly, additional tissues need to be
examined. The primordial role of H2S in smooth muscle, or as a
signal molecule in general is unknown, but certainly it could be coupled to
O2 availability. The effect of hypoxia (and H2S) in
blood vessels is often commensurate with function: systemic vessels dilate to
increase blood flow and match perfusion to metabolism, and respiratory vessels
constrict to couple ventilation to perfusion. H2S seems ideally
positioned to mediate these hypoxic responses as the constitutive vascular
synthesis of H2S would be offset by H2S oxidation during
normoxia, but progressively unabated as oxygen levels fall. The benefit of
hypoxic relaxation of non-vascular smooth muscle is less obvious. Perhaps it
is a mechanism to reduce oxygen demand in less critical tissues.
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Acknowledgments |
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). Bladders relaxed with either
H2S or N2 did not respond to the other (N2 or
H2S, respectively), irrespective of the pre-contractile agonist
(*). There was no difference in the relaxation produced by
Na2S and NaHS.
