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Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-5218
Submitted 23 December 2002 ; accepted in final form 10 March 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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-phenylnitrone and
4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt). The effects of HLL
administration on vascular smooth muscle (VSM) membrane potential were
assessed in superior mesenteric artery strips in the presence and absence of
zinc protoporphyrin IX or iberiotoxin. The vasodilatory responses to exogenous
CO were assessed in the presence and absence of ODQ or iberiotoxin. HLL
administration produced a dose-dependent vasodilatory response that was nearly
eliminated in the presence of iberiotoxin. Neither ODQ, spin traps, nor
ryanodine altered the vasodilatory response to HLL, although ODQ abolished the
vasodilatory response to S-nitroso-N-acetyl-penicillamine.
HLL administration produced a zinc protoporphyrin IX- and
iberiotoxin-sensitive VSM cell hyperpolarization. Iberiotoxin and ODQ
inhibited the vasodilatory response to exogenous CO. Thus the vasodilatory
response to endogenous CO involves cGMP-independent activation of VSM
large-conductance Ca2+-activated K+ channels
and does not likely involve the formation of Ca2+ sparks
emanating from ryanodine-sensitive stores.
carbon monoxide; Ca2+-activated K+ channels; mesenteric; isolated vessel; soluble guanylyl cyclase; hypoxia
Functional evidence for a role of endogenous CO in the regulation of vascular tone has come from whole animal (19, 29, 34) and isolated vessel preparations (3, 7, 9, 13, 14, 22, 46). For example, systemic administration of zinc protoporphyrin IX (ZnPPIX), an HO inhibitor, increases renal vascular resistance in chronically hypoxic rats (34). Furthermore, exogenous administration of CO or the HO substrate heme-L-lysinate (HLL) produced concentration-dependent increases in vessel diameter (13, 24, 30). In addition, our laboratory has previously shown that HO-derived CO may be important in both blunted agonist-induced vasoconstriction (3, 8, 9, 13, 34) as well as blunted myogenic reactivity (11) following chronic hypoxia. Taken together, these results suggest a potential role for endogenous CO in the regulation of vascular tone.
Although CO has been shown to produce vasodilation in a number of vascular beds, a variety of mechanisms have been proposed for its effects. CO has been postulated to produce vasodilation by both soluble guanylyl cyclase (sGC)-dependent (3–5, 14, 28, 36, 39, 41, 42, 46) and -independent (6, 40, 45–47) mechanisms. Indeed, CO-induced vasodilation has been shown to occur through a cGMP-dependent mechanism in the rabbit aorta (14) as well as the lung (31), aorta (3), and tail artery from rats (46). In contrast, CO has been suggested to elicit cGMP-independent vasodilation in the lamb ductus arteriosus (7) as well as the gracilis arterioles (22) and rat lung (6, 40).
Activation of vascular smooth muscle (VSM) large-conductance Ca2+-activated K+ (BK) channels has been shown to play a role in CO-induced vasodilation in the rat tail artery (49), porcine pial artery (24), and gracilis arterioles (50). In previous studies that investigated the vasodilatory response to CO, abluminal application of exogenous CO was used. Although these data provide support for a role of VSM BK channels in the vasodilatory response to CO, it is not known whether physiological levels of CO can activate BK channels. In addition, whether activation of VSM BK channels in response to endogenous CO occurs through a direct effect on the channel itself (45, 47) or through a cGMP-dependent mechanism is unclear.
It has been proposed that VSM cell BK channel opening is regulated by a localized release of Ca2+ from ryanodine-sensitive Ca2+ release channels (RYR) in the VSM sarcoplasmic reticulum. A single Ca2+ spark is capable of increasing local Ca2+ concentrations (10–100 µM) without causing global increases in Ca2+ (16, 33). Ca2+ sparks act on VSM cell BK channels to produce spontaneous transient outward currents. Increased outward K+ currents hyperpolarize the VSM cell membrane potential and thereby reduce the open probability of L-type Ca2+ channels. This reduction in cytosolic Ca2+ concentration results in relaxation of VSM. Vasodilation in response to many activators of the sGC-cGMP-dependent protein kinase (PKG) pathway involves activation of the VSM cell BK channel (37). Indeed, VSM relaxants that increase cGMP have been shown to activate BK channels through Ca2+ spark formation (17, 35).
To elucidate the mechanism of vasodilation in response to endogenously produced CO, we examined the vasodilatory response to HLL, which is the substrate for HO, in isolated, pressurized small mesenteric arteries from rats exposed to chronic hypoxia to elicit upregulation of vascular HO-1 expression (13, 24, 30). Indeed, data derived from administration of exogenous CO may not be representative of the effect of endogenously produced gas. We hypothesized that CO-induced vasodilation in the mesenteric circulation is mediated through a cGMP-dependent activation of the VSM BK channel and possibly involves Ca2+ sparks.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Isolated mesenteric resistance artery diameter measurements. Rats
were anesthetized with pentobarbital sodium (50 mg ip). A midsternal incision
was made to expose the heart, and 100 units of heparin were injected directly
into the left ventricle. The mesenteric arcade was excised through a midline
abdominal incision and placed in ice-cold physiological saline solution [PSS,
composed of (in mM) 129.8 NaCl, 5.4 KCl, 0.5 NaH2PO4,
0.83 MgSO4, 19 NaHCO3, 1.8 CaCl2, and 5.5
glucose] aerated with a 21% O2-6% CO2-73% N2
gas mixture. The arcade was secured in a Silastic-coated petri dish that
contained cold aerated PSS. After veins and adipose tissue were removed,
fourth-order arteries were transferred to a beaker of cold aerated PSS.
Arteries were then cannulated and pressurized to 60 Torr as described
previously (9,
11,
13). Measurements of internal
diameter (ID) were made using a high-resolution charge-coupled device video
camera (model XC-73, Sony) and a video-tracking device (Video Dimension
Analyzer V 94, Living Systems). Vessels were continuously superfused (5
ml/min) with aerated PSS warmed to 37°C and were allowed to equilibrate
for 60 min before any experimental manipulation. Viability of the vessel was
assessed by administering phenylephrine (PE, 10-4 M). To
reduce the possibility of interactions with nitric oxide, all experiments were
performed in the presence of 100 µM
N
-nitro-L-arginine (L-NNA).
Passive diameter was determined at the end of each experiment by superfusing
the vessel in Ca2+-free PSS [composed of (in mM) 129.8
NaCl, 5.4 KCl, 0.5 NaH2PO4, 0.83 MgSO4, 19
NaHCO3, 5.5 glucose, and 3 EGTA] for 30 min. Data were stored and
subsequently analyzed on a microcomputer using a commercial data-acquisition
system (CODAS, Dataq Instruments).
VSM cell membrane potential. With the use of glass intracellular microelectrodes filled with KCl (3 M) solution, VSM membrane potential was recorded from nonpressurized endothelium-intact superior mesenteric artery (SMA) strips. Our laboratory has previously shown that membrane potential responses in SMA strips are consistent with both vascular reactivity and membrane potential responses in fourth-order pressurized vessels (9, 11, 12). Rats were anesthetized with pentobarbital sodium (50 mg ip) and the SMA was isolated and excised. Artery strips were secured in an organ bath with the luminal surface exposed. Strips were superfused (1 ml/min) with PSS warmed to 37°C and aerated with a gas mixture of 21% O2-6% CO2-73% N2. Membrane potential recordings were performed using a Neuroprobe amplifier (model 1600, A-M Systems). Analog output from the amplifier was low pass filtered at 1 kHz and visualized using a Tektronix type RM502A oscilloscope and a Gould 3200 chart recorder. Data were stored and subsequently analyzed on a microcomputer using the CODAS commercial data-acquisition system. Criteria for acceptance of membrane potential recordings were 1) an abrupt change in potential in the negative direction as the microelectrode was advanced into a cell, 2) stable membrane potential for at least 2 min, and 3) an abrupt change in potential to 0 mV after the electrode was retracted from the cell.
Role of sGC in endogenous CO-mediated vasodilation. Mesenteric
arteries (n = 5/group) were excised from CH rats and were cannulated
and perfused as described above. Vessels were treated with the sGC inhibitor
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 50 µM)
or an equal volume of drug vehicle (DMSO) 30 min before experimental
manipulation. Because mesenteric arteries from CH rats have an impaired
myogenic response (11),
sequential doses of PE were administered until the vessel constricted by
30% of the baseline diameter. Once a stable level of constriction was
achieved, HLL (10-6 or 10-5 M) was
added to the reservoir. Indeed, others have shown that treatment of rat aortic
VSM cells with the HO substrate hemin resulted in a dose-dependent increase in
CO release (27). Moreover, we
have previously demonstrated that HLL administration results in a vasodilatory
response in mesenteric arteries that is mediated by a product of the HO
reaction (30). In a separate
set of experiments, the effectiveness of sGC inhibition was assessed by
examination of the vasodilatory response to the NO donor
S-nitroso-N-acetyl-penicillamine (SNAP,
10-8 to 10-6 M) in the presence of
ODQ or vehicle.
Role of sGC in exogenous CO-mediated vasodilation. Small
mesenteric arteries (n = 5/group) were excised from CH rats and were
isolated, cannulated, and superfused as described. Vessels were treated with
the sGC inhibitor ODQ (50 µM) or an equal volume of drug vehicle (DMSO) 30
min before experimental manipulation. Before each experiment, 10 ml of PSS
were vigorously bubbled with 100% CO or nitrogen gas for 10 min. Vessels were
preconstricted with PE to 30% of the baseline diameter. Once a stable
level of constriction was achieved, the vessel was superfused for 2 min
with a 20-fold dilution of the saturated CO solution in PSS (210 µl of
CO/100 ml of PSS) that contained the same concentration of PE used to
establish vascular tone. To control for pH differences between the standard
PSS and the CO solution, the response to a 20-fold-diluted
N2-equilibrated solution was assessed (n = 3).
Role of the VSM BK channel in endogenous CO-meditated
vasodilation. Mesenteric arteries were excised from CH rats and were
cannulated and perfused as described above. Vessels were pretreated with the
BK channel inhibitor iberiotoxin (n = 3, 10 nM) or an equal volume of
drug vehicle (n = 5) for 20 min before initiation of the experiment.
Sequential doses of PE were then administered until the vessel constricted by
30% of the baseline diameter. Once a stable level of constriction was
achieved, HLL (10-6 and 10-5 M)
was added to the reservoir.
Role of VSM cell BK channels in exogenous CO-meditated
vasodilation. Small mesenteric arteries were excised from CH rats and
were isolated, cannulated, and superfused as described above. Vessels were
treated with iberiotoxin (n = 5, 50 nM) or vehicle (n = 4)
for 15 min before experimental manipulation. The CO solution was prepared as
described. Vessels were preconstricted with PE to 30% of the baseline
diameter. Once a stable level of constriction was achieved, the vessel was
superfused for 2 min with a 20-fold dilution of the saturated CO solution
that contained the same concentration of PE used to establish vascular
tone.
Effect of endogenous CO on VSM cell membrane potential. SMA strips from CH and normoxic control rats (n = 5/group) were harvested as described. Before initiation of the experiment, SMA strips were superfused for 1 h with warmed (37°C) aerated PSS that contained L-NNA (100 µM) and either ZnPPIX (500 nM) or drug vehicle. At the end of the equilibration period, membrane potential recordings were made under baseline conditions. Under baseline conditions, once a membrane potential recording was held for 2 min, the perfusion reservoir was switched to one containing HLL (10-5 M). The recording was continued for an additional 2 min once the HLL solution contacted the tissue. If a recording was lost before the 2-min criteria was reached, a recording was made from another cell under HLL treatment. HLL-induced alterations in VSM membrane potential were also assessed in the presence and absence of the BK channel inhibitor iberiotoxin (50 nM).
Ca2+ sparks, BK channels, and endogenous CO-mediated vasodilation. Mesenteric arteries (n = 5/group) were excised from CH rats and were cannulated and perfused as described above. After the equilibration period, mesenteric arteries were preconstricted with the ryanodine-sensitive Ca2+ channel blocker ryanodine (1 µM). Control arteries were preconstricted with PE to achieve a similar degree of tone. Once a stable level of constriction was achieved, a single dose of HLL (10-5 M) was added to the reservoir. In a separate set of experiments, the effectiveness of ryanodine was assessed by examination of the vasodilatory response to the adenylate cyclase activator forskolin (50 nM), which has been shown to initiate Ca2+ sparks (35).
Alternative mechanisms of HO-mediated vasodilation. Mesenteric
arteries were excised from CH (n = 3) and normoxic control
(n = 3) rats and were cannulated and perfused as described above.
Sequential doses of PE were administered until the vessel constricted by
30% of the baseline diameter. Once a stable level of constriction was
achieved, biliverdin (10-7 to 10-5
M) or iron (10-5 M, n = 2) was added to the
reservoir. Additional experiments were performed to examine the mechanism of
biliverdin-induced vasodilation. Mesenteric arteries were excised from CH rats
and were cannulated and perfused as described above. Vessels were pretreated
with either iberiotoxin (10 nM, n = 2) or vehicle (n = 5)
for 20 min. Sequential doses of PE were administered until the vessel
constricted by 30% of the baseline diameter. Once a stable level of
constriction was achieved, biliverdin (10-6 and
10-5 M) was added to the reservoir. In a separate set of
experiments, the effects of scavenging free radicals on HLL-induced
(10-6 and 10-5 M) vasodilation
were assessed in mesenteric arteries pretreated with either
N-tert-butyl--phenylnitrone (PBN, 1 mM) or
4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt (tiron, 10 mM).
Calculations and statistics. For all experiments, changes in vessel ID were expressed as a percent reversal of active tone (myogenic plus agonist induced). To meet the assumption of a normal distribution necessary for parametric statistics, percent changes in ID underwent arcsine transformation before analysis. Data were analyzed using a three-way repeated-measures ANOVA, two-way repeated-measures ANOVA, two-way ANOVA, or unpaired Student's t-test as appropriate. Where significant main effects occurred, individual groups were compared using the Student-Newman-Keuls post hoc test. A probability of P ≤ 0.05 was accepted as statistically significant for all comparisons.
Drugs and solutions. HLL was made as described previously (13). ZnPPIX (Porphyrin Products) was prepared as described previously (34). ZnPPIX stock solution was aliquoted and stored at -80°C for a maximum of 1 wk. PE, iberiotoxin, and ryanodine were dissolved in deionized H2O, aliquoted, and stored at -80°C until use. Biliverdin was dissolved in 0.1 N NaOH and stored at -80°C until use. PBN and ODQ were dissolved in DMSO and stored at -80°C until use. SNAP was dissolved in ethanol on the day of the experiment and stored on ice until use. Tiron and L-NNA were dissolved in PSS on the day of the experiment. All drugs were obtained from Sigma-Aldrich (St. Louis, MO) unless otherwise noted.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Role of sGC in exogenous CO-mediated vasodilation. Changes in ID in response to exogenous CO in the presence and absence of the sGC inhibitor ODQ are presented Fig. 3. Exogenous CO elicited vasodilation in small mesenteric arteries from CH rats that was inhibited by ODQ. Superfusion with an N2-equilibrated solution produced a modest transient vasoconstriction (data not shown).
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Role of VSM BK channels in endogenous CO-meditated vasodilation. Figure 4 depicts the effects of inhibition of BK channels on the vasodilatory response to endogenous CO. Administration of the substrate for HO produced a dose-dependent increase in ID in pressurized small mesenteric arteries pretreated with normal PSS. Iberiotoxin produced a slight vasoconstriction (data not shown). BK channel inhibition nearly eliminated the vasodilatory response to HLL.
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Role of VSM cell BK channels in exogenous CO-meditated vasodilation. Changes in ID in response to exogenous CO in the presence and absence of the BK channel inhibitor iberitoxin are presented Fig. 5. Exogenous CO elicited vasodilation in small mesenteric arteries from CH rats that was attenuated by iberiotoxin.
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Effect of endogenous CO on VSM cell membrane potential. The effect of endogenous CO on VSM cell membrane potential in SMA strips from both control and CH rats are presented in Fig. 6. As previously reported, chronic hypoxia was associated with hyperpolarization of VSM cell resting membrane potential relative to normoxic control animals (9). Administration of HLL produced further hyperpolarization of VSM cell membrane potential in arteries from CH animals. However, HLL had no effect on membrane potential in arteries from control rats. In addition, both the hypoxia and HLL-induced hyperpolarization were eliminated in vessels pretreated with ZnPPIX. Inhibition of HO had no effect on membrane potential in arteries from normoxic animals.
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Figure 7 illustrates the effect of iberiotoxin on HLL-induced alterations in VSM cell membrane potential in SMA strips from CH rats. Administration of HLL caused hyperpolarization of the VSM cell membrane potential. Inhibition of BK channels with iberiotoxin prevented the HLL-mediated hyperpolarization. As previously shown (10), BK channel inhibition also reversed the chronic hypoxia-induced hyperpolarization of VSM cell resting membrane potential.
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Ca2+ sparks and endogenous CO-mediated activation of VSM BK channels. The effect of inhibition of ryanodine-sensitive Ca2+-release channels on the vasodilatory response to endogenous CO are illustrated in Fig. 8. Administration of ryanodine to pressurized isolated small mesenteric arteries caused a reduction in ID of 53.4 ± 7.5%. Application of HLL (10-5 M) caused a reversal of ryanodine-induced tone to a similar degree as in control arteries where tone was achieved using PE. In contrast, ryanodine attenuated the vasodilatory response to forskolin (Fig. 9).
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Alternative mechanism of HO-mediated vasodilation. Changes in ID in response to biliverdin administration are shown in Fig. 10. Biliverdin elicited a dose-dependent vasodilatory response in small mesenteric arteries from CH rats. Moreover, biliverdin produced a similar degree of vasodilation in mesenteric arteries from normoxic control rats. The effects of BK channel inhibition on biliverdin-induced vasodilation are presented in Fig. 11. Inhibition of BK channels produced an augmentation of the vasodilatory response to biliverdin. Administration of iron to PE-preconstricted mesenteric arteries had no effect on ID (data not shown). Changes in ID in response to HLL in the presence and absence of free radical spin traps are depicted in Fig. 12. HLL produced a dose-dependent vasodilatory response in PE-preconstricted mesenteric arteries that was not altered by free radical scavagers.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Although the mechanism of CO-induced vasodilation has been previously
examined, most investigators have employed application of exogenous CO. On the
basis of the results of these studies, it is well accepted that CO-mediated
vasodilation is cGMP dependent. However, this study demonstrates that the
vasodilatory response to native CO is cGMP dependent, whereas the vasodilatory
response to the stimulated production of endogenous CO is independent of sGC
activation. Hence, activation of sGC may require high cytosolic concentrations
of CO. Indeed, CO has been shown to be a poor activator of sGC in that it only
increases cGMP content 2.5–4-fold
(2,
21), whereas nitric oxide
increases sGC activity by 200-fold
(21). We postulate that the
vasodilatory response to exogenous CO is dependent on sGC activation, whereas
the response to HLL involves localized production of CO in proximity to its
site of action. It may be that application of exogenous CO results in a global
increase in CO of sufficient concentration within the cytosol to activate sGC.
Alternatively, endogenous CO [which we have previously shown is produced
within the endothelium (30)]
in the mesenteric circulation may only result in a local increase in CO
concentration in close proximity to the underlying VSM BK channels. Taken
together, the results of this study demonstrate the importance of studying
endogenously produced CO to elucidate the role that CO plays in the regulation
of vascular tone.
Our laboratory (as well as others) has shown that HLL-mediated vasodilation is mediated by a product of the HO reaction (13, 30). It is well established that catabolism of free heme by HO results in the production of equimolar quantities of CO, free iron, and biliverdin. Previous work from our laboratory has provided evidence that the vasoactive product of the HO reaction is CO. Indeed, neither free iron nor biliverdin reduced the active tension developed in PE-preconstricted aortic rings, whereas exogenous CO produced a dose-dependent reduction in tension (3). To further exclude other possible mediators of the vasodilatory response to HLL in resistance arteries, we investigated the vasoactive properties of both iron chloride and biliverdin in PE-preconstricted mesenteric arteries. Administration of iron had no effect on vessel diameter. Surprisingly, the application of biliverdin produced a dose-dependent vasodilatory response similarly in arteries from normoxic control and CH rats. However, unlike the response to HLL, inhibition of BK channels augmented biliverdin-induced vasodilation. Thus it is unlikely that the vasodilation observed in response to biliverdin is mediated through the same pathway as that of HLL. Furthermore, we have previously shown that HLL only elicits vasodilation in arteries from CH animals (13). In contrast, biliverdin administration produced vasodilation in arteries from both control and CH animals, which again suggests that the vasodilatory response to HLL occurs through a pathway different from that of biliverdin. To further test whether the vasodilatory response to HLL is mediated by the production of a product other than CO (i.e., the antioxidant biliverdin), experiments were performed in which the vasodilatory response to HLL was examined in mesenteric arteries pretreated with two free radial spin traps, PBN or tiron. Indeed, neither PBN nor tiron altered the vasodilatory response to HLL. The observation that biliverdin administration produced a similar degree of vasodilation in arteries from both control and CH animals as well as the inability of free radical scavengers to alter the vasodilatory response to HLL suggests that HO-mediated vasodilation may not involve the antioxidant properties of biliverdin. Therefore, it appears unlikely that another factor other than CO is responsible for HLL-induced vasodilation. Taken together, these results suggest that the administration of HLL augments the production of CO by the enzyme HO.
The present study provides evidence that HO-mediated vasodilation involves activation of VSM cell BK channels, in that both HLL-induced vasodilation and the vasodilatory response to exogenous CO were inhibited in vessels pretreated with iberiotoxin. Consistent with the present study, exogenous CO-mediated vasodilation has also been shown to be inhibited by iberiotoxin (24, 46) and to enhance whole cell K+ currents in rat tail artery VSM cells (45). For example, Leffler et al. (24) demonstrated that the vasodilatory response to exogenous CO administered to porcine pial arterioles in situ was abolished by either tetraethylammonium or iberiotoxin. The present study also demonstrates that HLL hyperpolarizes VSM cell membrane potential to a point nearing the K+ equilibrium potential, which was reversed by either iberiotoxin or ZnPPIX. This is consistent with a study by Wang et al. (45) in which application of exogenous CO hyperpolarized cultured VSM cells from -62 ± 2.5 to -84 ± 3.3 mV.
Results from the present study suggest that the vasodilatory response to
endogenous CO does not involve Ca2+ sparks. Although
administration of ryanodine resulted in an increase in vascular tone in our
preparation, the vasodilatory response to HLL was unaltered. In contrast,
ryanodine attenuated the vasodilatory response to forskolin (50 nM). Recently,
a role for Ca2+ sparks in CO-meditated dilation was
demonstrated in cerebral artery VSM cells, and HLL administration produced a
slight increase in Ca2+-spark frequency as well as a
profound enhancement of coupling between Ca2+ sparks and
VSM BK channels (15).
Inconsistencies between these results and those of the present study may be
explained by differences between species or vascular beds. Alternatively,
although the dose of ryanodine used in the present study produced a similar
degree of tone as that produced with PE, because Ca2+
sparks were not measured, it is possible that RYR channels were not completely
blocked. Indeed, Jaggar et al.
(15) observed that the
coupling of Ca2+ sparks to spontaneous transient outward
currents increased from 60 to 100% in response to HLL. Thus vasodilation
may occur if only a few functional RYR channels remain. Therefore, the lack of
an effect of ryanodine in the present study on endogenous CO-induced
vasodilation may be explained by incomplete inhibition of RYR channels.
CO has been shown increase BK channel activity independent of
Ca2+ sparks or another second messenger (e.g., cGMP).
Exogenous CO increased the open probability of rat tail artery VSM cell BK
channels in inside-out and outside-out membrane patches
(45). Furthermore, exogenous
CO augmented BK channel currents by a direct effect on the BK channel
-subunit expressed in COS-1 cells
(45,
48). The 
-subunit of the
BK channel has been reported to confer on the channel its
Ca2+-sensitive properties
(1). Exogenous CO has been
shown to increase the Ca2+ sensitivity of BK channels in
inside-out patches from rat tail artery VSM cells
(45). Taken together, the VSM
cell BK channel can be activated by both endogenous and exogenous CO
independent of second-messenger activation.
In summary, the current study provides evidence that endogenous CO results in cGMP-independent activation of VSM cell BK channels, hyperpolarization of the VSM cell membrane potential, and subsequent vasodilation. Additional studies are required to better elucidate the mechanism by which endogenous physiological concentrations of CO activate VSM cell BK channels.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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P < 0.05, significantly different than
10-8 M; *P < 0.05, significantly
different from vehicle.
