Reaction of nitric oxide with superoxide inhibits basolateral
K+ channels in the rat
CCD
Ming
Lu and
Wen-Hui
Wang
Department of Pharmacology, New York Medical College, Valhalla, New
York 10595
 |
ABSTRACT |
We previously demonstrated that nitric oxide (NO) stimulates the
basolateral small-conductance K+
channel (SK) via a cGMP-dependent pathway [M. Lu and W. H. Wang. Am. J. Physiol. 270 (Cell Physiol. 39): C1336-C1342,
1996]. Because NO at high concentration has been shown to react
with superoxide (O
2) to form
peroxynitrite (OONO
)
[W. A. Pryor and G. L. Squadrito. Am. J. Physiol. 268 (Lung Cell. Mol.
Physiol. 12): L699-L722, 1995 and M. S. Wolin.
Microcirculation 3: 1-17,
1996], we extended our study to examine, using patch-clamp technique, the effect of high concentrations of NO on SK in cortical collecting duct (CCD) of rat kidney. Addition of NO donors
[100-200 µM
S-nitroso-N-acetyl-penicillamine
(SNAP) or sodium nitroprusside (SNP)] reduced channel activity,
defined as the product of channel number and open probability, to 15 and 25% of the control value, respectively. The inhibitory effect of
NO was completely abolished in the presence of 10 mM Tiron, an
intracellular scavenger of O
2. NO
donors, 10 µM SNAP or SNP, which stimulate channel activity under
control conditions, can also inhibit SK in the presence of an
O
2 donor, pyrogallol, or in the
presence of an inhibitor of superoxide dismutase, diethyldithiocarbamic acid. The inhibitory effect of NO is still observed in the presence of
exogenous cGMP, suggesting that the NO-induced inhibition is not the
result of decreased cGMP production. We conclude that the inhibitory
effect of NO on channel activity results from an interaction between NO
and O
2.
peroxynitrite; potassium transport; guanosine
3',5'-cyclic monophosphate; patch clamp; cortical
collecting duct
 |
INTRODUCTION |
THE CORTICAL COLLECTING duct (CCD) plays an important
role in K+ secretion and
hormone-regulated Na+ reabsorption
(27, 30). The basolateral K+
channels in the CCD participate in generating the cell membrane potential and are involved in K+
recycling across the basolateral membrane. Because
Na+ reabsorption and
K+ secretion are electrogenic in
the CCD, alteration in cell membrane potential is expected to have an
effect on Na+ and
K+ transport. Inhibition of
basolateral K+ conductance by
Ba2+ reduced
Na+ reabsorption in the CCD, an
effect presumably related to the Ba+-induced depolarization (28).
At least three types of K+
channels, small conductance (28 pS), intermediate conductance (85 pS),
and large conductance (145 pS), have been identified in the basolateral
membrane of the CCD (11, 33). However, a previous study showed that the
small-conductance K+ channel (SK)
is involved in determining the cell membrane potential (17).
The constitutive nitric oxide synthase (NOS) has been identified in the
kidney (32) and plays an important role in regulation of kidney
function (13). Reaction of nitric oxide (NO) in a variety of cells
includes stimulation of guanylate cyclase and interaction with
superoxide (O
2) (3, 13, 35). We
previously found that NO stimulates the basolateral SK in the rat CCD
(17) and is involved in protein kinase C-induced activation of the SK
(18). The effect of NO on the SK is mediated by a cGMP-dependent
pathway, since a cGMP analog mimics the effect of NO (17). In addition,
activation of a cGMP-dependent pathway has been shown to hyperpolarize
the cell membrane in the CCD (12). On the other hand, reaction of NO
with O
2 to form peroxynitrite
(OONO
) has been shown to
oxidize a variety of molecules such as thiols (24, 25, 29). Redox
mechanisms have been found to modulate several ion channels, including
L-type Ca2+ channel (6) and
Ca2+-dependent
K+ channel (4). In the present
study we examine the effect of NO and
O
2 on the SK in the basolateral
membrane of the CCD.
 |
METHODS |
Preparation of rat CCD.
The CCD was isolated from kidneys of pathogen-free Sprague-Dawley rats
(Taconic, Germantown, NY) and transferred onto a 5 × 5-mm cover
glass coated with Cell-Tak (Collaborative Research, Bedford, MA) to
immobilize the tubules. The cover glass was placed in a chamber (1,000 µl) mounted on an inverted microscope (Nikon), and the tubules were
superfused with HEPES-buffered NaCl solution. The method for exposing
the basolateral membrane was previously described (33). The temperature
of the chamber was maintained at 37 ± 1°C by circulating warm
water surrounding the chamber.
Patch-clamp technique.
Patch-clamp electrodes were pulled with a vertical pipette puller
(model 700C, David Kopf Instruments, Tujunga, CA) using glass
capillaries (Degan, Minneapolis, MN) and had resistances of 4-6
M
when filled with 140 mM KCl. An Axon 200A patch-clamp amplifier
was used to record channel activity. The output of the amplifier was
low-pass filtered at 1 kHz using an eight-pole Bessel filter (902LPF,
Frequency Devices, Haverhill, MA) and was digitized at a sampling rate
of 44 kHz using a modified Sony PCM-501ES pulse code modulator and
stored on videotape (Sony SL-2700). For analysis, the data stored on
the tape were replayed and collected by an IBM-compatible 486 computer
(Gateway 2000) at a rate of 5 kHz and analyzed using the pCLAMP
software system 6.02 (Axon Instruments, Burlingame, CA).
We used NPo as an
index of channel activity and made no efforts to examine whether the
alteration of channel activity was due to a change in channel number
(N) or in channel open probability (Po). The
NPo was
calculated from data samples of 1-min duration at the steady state.
However, if NPo
decreased to zero for 20-30 s, we changed the bath solution
immediately to increase the
Po and restore
channel activity. Accordingly, only 30-s data were collected for
calculation of
NPo. We used the
following equation to obtain
NPo
where
the maximum number of superpositions of current level seen in the patch
is taken as N, and
t is the fractional open time spent at
each of the observed current levels (1 to
n).
cGMP and protein concentration assay.
The CCDs (total length of 10 mm) were collected and incubated in a
Ringer solution (300 µl) in the presence of 1 mM IBMX at 37°C for
15 min. After addition of either 10 µM
S-nitroso-N-acetyl-penicillamine (SNAP) or vehicle solution (DMSO) to the tubule suspension for 2 min at
37°C, experiments were terminated by addition of 0.7 ml ice-cold
ethanol. The sample was frozen in liquid nitrogen and dried in a speed
vacuum concentrator. The residues were resuspended in 100 µl of
phosphate buffer and acetylated. cGMP content was measured with
specific ELISA (Cayman Chemical). The Pierce protein assay reagent was
used to measure protein concentration. This assay is based on the
competition between free cGMP and a cGMP tracer (cGMP linked to an
acetylcholinesterase molecule) for a limited number of cGMP-specific
rabbit antiserum binding sites.
Experimental solution.
The bath solution was composed of (in mM) 140 NaCl, 5 KCl, 1.8 CaCl2, 1.8 MgCl2, and 10 HEPES (pH 7.40). The
composition of the pipette solution was (in mM) 140 KCl, 1.8 MgCl2, and 10 HEPES (pH 7.4).
Sodium nitroprusside (SNP), pyrogallol,
4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron),
diethyldithiocarbamic acid, and 8-bromo-cGMP (8-BrcGMP) were purchased
from Sigma (St. Louis, MO). SNAP was obtained from Calbiochem (La
Jolla, CA) and was dissolved in pure ethanol. The final concentration
of ethanol in the bath was 0.1% and had no effect on channel activity.
The chemicals were added directly to the bath to reach the final
concentration. After addition of chemicals, experiments were carried
out in a standing bath. The response of the channel to a given agent is
the same in experiments performed either in running bath or in standing
bath.
Statistics.
Data are shown as means ± SE. Paired Student's
t-tests were used to determine the
significance of differences between the control and experimental
periods. Statistical significance was taken as
P < 0.05.
 |
RESULTS |
We confirmed the previous finding that addition of 10 µM SNAP
increased channel activity (17). The notion that the effect of 10 µM
SNAP is mediated by a cGMP-dependent pathway is further supported by
experiments in which 10 µM SNAP significantly increased cGMP
concentration from 44 to 92 fM/µg (Table
1). In addition to stimulation
of soluble guanylate cyclase (13), it has been suggested that
increasing NO production can enhance the formation of
OONO
by facilitating the
interaction between NO and O
2 (24,
35). OONO
has been shown to
modulate several types of ion channels (4-6). Therefore, we
extended our study to investigate the effects of a high concentration
of NO on the SK. Figure 1 is a
representative experiment recorded from a cell-attached patch showing
the effect of 100-200 µM SNAP on channel activity. It is
apparent that application of 100 µM SNAP reversibly inhibited the SK,
and channel activity in nine such experiments was reduced by 85 ± 10%. Because several NO donors have been shown to directly modify
channel activity (4, 5, 10), we examined the effect of 100 µM SNAP on
the SK in inside-out patches (Fig. 2). From
inspection of Fig. 2, it is clearly demonstrated that 100 µM SNAP has
no direct effect on the SK in inside-out patches within 100-120 s.
Because the activity of the SK in inside-out patches decreased
progressively, it is beyond the technical limitation to maintain
channel activity in a steady state for >5 min. Thus we are unable to
examine the effect of SNAP on channel activity in inside-out patches
for >2 min without channel rundown. However, it is believed that the direct effect of NO donors should occur within 1 min. Thus it is safe
to conclude that SNAP has no direct effect on the SK.

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Fig. 1.
A channel recording made in a cell-attached patch shows that addition
of 100 µM
S-nitroso-N-acetyl-penicillamine
(SNAP) inhibited channel activity. C, channel closed level. Holding
potential was 0 mV. Top: whole trace
of experiment. Bottom: 4 parts of
trace, numbered
1-4,
are extended to display details of channel activity.
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Fig. 2.
A channel recording made in an inside-out patch shows effect of 100 µM SNAP on channel activity. C, channel closed level. Cell membrane
potential was 30 mV. Trace at
bottom is continuation of trace at
top.
|
|
To exclude the possibility that the high concentrations of SNAP
decreased channel activity by a mechanism other than release of NO, we
examined the effect of another NO donor, SNP. Figure 3 shows that addition of 100-200 µM
SNP also blocked channel activity in cell-attached patches. The
inhibitory effect averaged 75 ± 10%
(n = 8) and was fully reversible. Thus
the results suggested a biphasic effect of NO on the SK: low
concentrations of NO stimulate the SK, whereas high concentrations of
NO inhibit the SK. This view has been further tested by examining the
dose-response curve of the SK to SNAP in the presence of 100 µM
nitro-L-arginine methyl ester
(L-NAME) to block the endogenous
NO production. Figure 4 summarizes the
results from such experiments. It is apparent that the stimulatory
effect of SNAP is predominant at concentrations below 20 µM, whereas
the inhibitory effect of SNAP can be observed at concentrations >40
µM.

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Fig. 3.
A channel recording made in a cell-attached patch shows that addition
of 100 µM sodium nitroprusside (SNP) inhibited channel activity.
Top: whole trace of experiment.
Bottom: 4 parts of trace, numbered
1-4,
are extended at fast time resolution. C, channel closed level. Holding
potential was 0 mV.
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Fig. 4.
A dose-response curve shows effect of SNAP. Endogenous nitric oxide
synthase activity was blocked by 100 µM nitro-L-arginine
methyl ester, and experiments were performed in cell-attached
patches.
|
|
Having established that a high concentration of NO inhibited the SK, we
explored the possible role of O
2 in
mediating this effect. Because Tiron has been used as an intracellular scavenger for O
2 (8), we examined the
effect of 100-200 µM SNP in the presence of Tiron. Figure
5 summarizes results from five such
experiments. It is apparent that application of 10 mM Tiron has no
significant effect on channel activity
(n = 8). However, the inhibitory
effects of 100-200 µM SNP were completely abolished in the
presence of Tiron. Furthermore, in the presence of Tiron, addition of
100-200 µM SNP significantly increased channel activity by 30 ± 7% (Fig. 5).

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Fig. 5.
Effects of Tiron (10 mM), SNAP (100-200 µM), SNP (100-200
µM), and Tiron (10 mM) + SNP (100-200 µM) on normalized
channel activity. * Significantly different from control group.
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These results strongly suggest that the inhibitory effect of NO is the
result of interaction between O
2 and
NO. Because the formation of
OONO
can be enhanced by
increasing either NO or O
2 concentration (35), we examined the effect of NO in the presence of an
O
2 donor, pyrogallol (19). Addition of
50-100 µM pyrogallol decreased channel activity by 45 ± 8%, and further application of 10 µM SNAP, which increased channel activity under control conditions, resulted in a complete inhibition of
channel activity (Fig. 6). The effect of
pyrogallol and 10 µM SNAP was partially reversible (Fig. 6). Further
support that OONO
mediates
the inhibitory effect of NO was obtained from experiments in which the
channel activity was inhibited by addition of 10 µM SNAP in the
presence of 1 mM diethyldithiocarbamic acid to block superoxide
dismutase. Figure 7 is a typical channel
recording made in a cell-attached patch showing that, after blockade of superoxide dismutase, addition of 10 µM SNAP reduced channel activity by 95 ± 10% (n = 6) and that the
effect was partially reversed by washout.

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Fig. 6.
A channel recording shows effects of pyrogallol (100 µM) and SNAP (10 µM) on channel activity in a cell-attached patch. Addition of
pyrogallol and SNAP blocks small-conductance
K+ channel (SK) completely. C,
channel closed level. Holding potential was 0 mV.
Top: time course of experiment.
Bottom: 4 parts of trace, numbered
1-4,
are extended to show channel activity at a fast time course.
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Fig. 7.
A channel recording shows effects of diethyldithiocarbamic acid (DDC)
and SNAP (10 µM) on channel activity in a cell-attached patch. Tubule
was incubated with 1 mM DDC-containing solution for 10 min. Addition of
10 µM SNAP in continuous presence of DDC blocks SK completely. C,
channel closed level. Holding potential was 0 mV.
Top: time course of experiment.
Bottom: 4 parts of trace, numbered
1-4,
are extended to show channel activity at a slow time course.
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Because the activity of SK is stimulated by a cGMP-dependent pathway,
we next examined whether the inhibitory effect of NO resulted from an
inhibition of guanylate cyclase and decreased cGMP production. Figure
8 is a channel recording made in a
cell-attached patch showing the effect of SNAP and pyrogallol in the
presence of a cGMP analog, which has been shown to stimulate the SK
(17). Addition of 10 µM SNAP and pyrogallol inhibited channel
activity. However, application of 100 µM 8-BrcGMP failed to restore
the channel activity, suggesting that the inhibitory effect of NO is
not the result of a decrease in cGMP production
(n = 6).

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Fig. 8.
A channel recording shows that addition of 100 µM 8-bromo-cGMP failed
to reverse inhibitory effects of pyrogallol (100 µM) and SNAP (10 µM) on channel activity in a cell-attached patch. C, channel closed
level. Holding potential was 0 mV.
Top: time course of experiment.
Bottom: 4 parts of trace, numbered
1-4,
are extended to show channel activity at a slow time course.
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|
 |
DISCUSSION |
At least three types of K+
channels, large-conductance channels (145 pS), intermediate-conductance
channels (85 pS), and SK (28 pS), have been identified in the
basolateral membrane of the CCD (11, 33). Several lines of evidence
indicate that the biophysical properties and regulation of the
basolateral SK are different from those in the apical membrane.
1) The basolateral SK is not
sensitive to ATP, whereas the apical SK is inhibited by ATP.
2) NO and cGMP have no effect on the
apical SK in either cell-attached or inside-out patches (unpublished
observations), whereas they activate the basolateral SK.
3) protein kinase A stimulates the
apical SK in both cell-attached and inside-out patches but has no
effect on basolateral SK in inside-out patches (unpublished
observations). 4) Previous studies
(33) showed that the SK in the basolateral membrane has two closed
states (0.5 and 10 ms) and two open states (3 and 35 ms). In contrast, the apical SK has only one open state (20 ms) and one closed state (1 ms). Figure 9 shows two
recordings of the basolateral SK and the apical SK, respectively. The
recordings were obtained from the same cell, in which the activity of
the apical K+ channels was first
recorded and then the lateral membrane was patched. Both patches have
the same channel number (confirmed by application of
Ba2+ after formation of an
inside-out patch). It is apparent that the channel kinetics of the two
K+ channels are different.

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Fig. 9.
Channel recordings show activity of basolateral SK
(A) and activity of apical SK
(B). Traces are continuous
recordings. Experiments were performed in a cell-attached patch.
Holding potential was 30 mV. C, channel closed level. Short
lines at left indicate each opening of
channel.
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|
Hirsch et al. (10-12) have found that the intermediate-conductance
K+ channel has a high open
probability and was abundant in their preparation. On the other hand,
we have observed that the SK is predominant and could be important for
determination of membrane potential. Although we do not know what
causes this discrepancy regarding the
K+ channel population, it is
possible that the difference may be the result of the animals' dietary
conditions. We used CCD from rats on a
high-K+ diet, whereas Hirsch et
al. (10-12) obtained tubules from rats on a
low-Na+ diet. Further experiments
are required to explore this possibility. Although we have found that
the SK is predominant under our experimental conditions, addition of
either L-NAME (15) or high
concentrations of SNAP (unpublished observations), both maneuvers that
inhibited the SK by 80%, did not proportionally decrease cell membrane
potential. It is possible that the contribution of the SK to the
overall cell membrane potential is limited and depends on the cell
membrane potential. We have observed that, if cell membrane potential
is higher than
70 mV, addition of either
L-NAME or 100 µM SNAP caused a
more than 10-mV depolarization (unpublished observations). On the other
hand, when cell membrane potential is below
50 mV, neither
L-NAME nor 100 µM SNAP has a
significant effect on cell membrane potential (unpublished
observations). This suggests that other basolateral ionic conductances
may be major factors under such circumstances. That the basolateral
membrane potential is controlled by several types of
K+ channels is important to
safeguard the cell function, since both K+ secretion and
Na+ reabsorption are electrogenic
processes and thus are affected by alteration of cell membrane
potential (23).
The main finding of this study is that increasing NO concentration or
raising O
2 concentration blocks the SK
in the CCD. Thus we have shown that NO has a biphasic effect on the SK:
low concentrations of NO stimulate the SK via a cGMP-dependent pathway,
and high concentrations of NO inhibit the SK via a cGMP-independent pathway. Hirsch et al. (10) have demonstrated that SNP directly stimulated the intermediate-conductance
K+ channel. However, we did not
observe the direct effect of SNAP/SNP on the SK in inside-out patches.
Therefore, it is possible that the effects of NO on the
intermediate-conductance K+
channel and on the SK are different. NO has been shown to elicit a
number of different responses in a variety of cells, including stimulation of guanylate cyclase and reaction with
O
2 (13, 35). Three lines of evidence
suggest that the inhibitory effect of high NO concentrations on the SK
results from an interaction between NO and
O
2. First, application of Tiron, which
scavenged O
2, abolished the inhibitory effect of NO. Second, addition of 10 µM SNAP, which has been shown to
stimulate the SK under control conditions, inhibits the channel activity in the presence of pyrogallol. Finally, inhibition of superoxide dismutase can also reverse the stimulatory effect of NO to
an inhibitory effect.
Three types of NOS have been found in the kidney (1, 20, 32). The
constitutive NOS has been shown to be expressed in the CCD (32). Our
unpublished observations have also confirmed that neuronal NOS is
expressed in the CCD. A large body of evidence indicates that NO plays
an important role in regulation of renal blood flow (2), renin
secretion (9), tubuloglomerular feedback (34), and tubular transport
(17, 31). In previous studies, we showed that NO activated the SK and
accordingly led to hyperpolarization of the cell membrane (15, 17). The
effect of NO is mediated by a cGMP-dependent process, since addition of
8-BrcGMP mimics the effect of NO. In the present investigation, we
observe that a high concentration of NO can also cause inhibition of
channel activity.
The present study shows that O
2
production is important for determining the effects of NO on
basolateral K+ channels.
O
2 is produced by mitochondria and several oxidases such as NAD(P)H oxidases (35). Under normal conditions, the O
2 is degraded by
superoxide dismutase. However, when NO concentration increases, NO
competes with superoxide dismutase and enhances the formation of
OONO
(35). Alternatively,
when O
2 levels increase under
conditions such as ischemia, an excessive amount of
O
2 can also react with NO.
OONO
is a highly active
oxidant that can react with a variety of molecules (3, 24). Although
OONO
has been attributed to
NO-induced cell injury (14), it could also have a potentially important
role in signal transduction mechanisms (29, 35). For instance, several
types of ion channels have been shown to contain thiol groups in their
structures, and thiol oxidation has been suggested to be an important
mechanism through which
OONO
can directly affect
channel activity (4-6).
Although our data support the notion that the inhibitory effect of high
concentrations of NO is the result of an interaction between NO and
O
2, the mechanism by which the NO-O
2 product inhibits the SK is not
completely understood. It is unlikely that the inhibition is the result
of a decrease in cGMP production, since addition of cGMP analogs failed
to reverse the inhibitory effect of NO. The second possibility is that
OONO
may inhibit the SK by
thiol nitrosylation or by oxidation of the SK or its
associated proteins. Thiol nitrosylation has been shown to play an
important role in the regulation of the
Ca2+-dependent
K+ channel in smooth muscle cells
(4), L-type Ca2+ channels of
myocytes (6), and the "minK" channel expressed in
Xenopus oocytes (5). Further
experiments will be needed to determine whether thiol nitrosylation or
oxidation is the mechanism by which high concentrations of NO
inhibit the SK.
The experimental results indicate that NO has a dual effect on the
activity of the SK: NO increases cGMP production and accordingly activates the SK, and NO reacts with
O
2 to form OONO
, which blocks the SK.
Interestingly, intracellular Ca2+
has also been shown to have a dual effect on the basolateral K+ channels. We recently
demonstrated that raising intracellular Ca2+ from 10 to 100 nM activates
the SK (16). On the other hand, Hirsch et al. (10) reported that a high
concentration of Ca2+ (>100 nM)
inhibits the intermediate-conductance
K+ channel. It is possible that
the dual effect of NO might be related to
Ca2+. Further experiments are
required to explore this hypothesis.
The dual regulatory mechanisms may have important physiological and
pathophysiological relevance. Increasing
Na+ influx across the luminal
membrane stimulates the
Na+-K+-ATPase
(7). To maintain the activity of the
Na+-K+-ATPase,
the basolateral K+ conductance
must increase to cope with the turnover rate of
Na+-K+-ATPase.
Because an increase in Na+ influx
diminishes the driving force of the
Ca2+/Na+
exchanger, intracellular Ca2+
concentration increases. As the activity of neuronal NOS is stimulated by elevation in intracellular Ca2+
(21, 22), NO formation is enhanced and accordingly activates the
basolateral K+ channels. However,
if the increase in intracellular
Ca2+ is continued and sustained,
as during ischemia, the concentration of NO could increase
further so that NO reacts with O
2 to
form OONO
(36). As
OONO
reduces channel
activity via oxidation of the basolateral
K+ channels or their closely
related proteins, it prevents an excessive K+ leakage. In proximal tubules it
was demonstrated that cell damage evidenced by DNA breakdown and
lactate dehydrogenase leakage during ischemia is closely
related to the K+ leakage (26),
since inhibition of the basolateral
K+ channel partially reversed the
ischemia-induced cell damage.
We conclude that NO can have dual effects on the basolateral
K+ channel. The stimulatory effect
of NO is mediated by a cGMP-dependent mechanism, whereas the inhibitory
effect of NO is mediated by interaction between NO and
O
2.
 |
ACKNOWLEDGEMENTS |
We thank Drs. M. S. Wolin, T. M. Burke-Wolin, R. W. Berliner, and
G. Giebisch for helpful comments.
 |
FOOTNOTES |
This work was supported by National Institutes of Health Grants
DK-47402 and HL-34300.
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. §1734 solely to indicate this fact.
Address for reprint requests: W.-H. Wang, Dept. of Pharmacology, New
York Medical College, Valhalla, NY 10595.
Received 27 February 1998; accepted in final form 20 April 1998.
 |
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