(Stroke. 1997;28:837-843.)
© 1997 American Heart Association, Inc.
Articles |
Effects of a Novel Inhibitor of Guanylyl Cyclase on Dilator Responses of Mouse Cerebral Arterioles
From the Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City.
Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, E329-2 GH, University of Iowa College of Medicine, Iowa City, IA 52242.
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Abstract |
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Background and Purpose Nitric oxide–induced vasodilatation is mediated by both cGMP-dependent and -independent mechanisms. Previous studies that examined the role of soluble guanylyl cyclase in cerebral vessels have used methylene blue and LY-83583, compounds that generate superoxide anion and are not specific for inhibition of soluble guanylyl cyclase. We examined the effects of ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one), a novel and highly selective inhibitor of soluble guanylyl cyclase, on responses of cerebral arterioles.
Methods The effects of ODQ on responses of cerebral arterioles to acetylcholine, nitroprusside, 8-bromo-cGMP, and adenosine were examined in anesthetized mice by means of a cranial window. The effects of two concentrations of ODQ were examined in the absence and presence of superoxide dismutase. The effects of NG-nitro-L-arginine, an inhibitor of nitric oxide synthase, were also tested.
Results ODQ (3 and 10 µmol/L) produced concentration-dependent inhibition of dilatation of cerebral arterioles (control diameter=29±1 µm) (mean±SE) in response to acetylcholine and nitroprusside. For example, 10 µmol/L acetylcholine and 1 µmol/L nitroprusside dilated cerebral arterioles by 28±3% and 44±2% in the absence and 6±2% and 7±1%, respectively, in the presence of 10 µmol/L ODQ (P<.05 versus control). The inhibitory effects of ODQ were not altered by superoxide dismutase. Vasodilatation in response to 8-bromo-cGMP and adenosine was not inhibited by ODQ. NG-Nitro-L-arginine (100 µmol/L), an inhibitor of nitric oxide synthase, inhibited responses to acetylcholine by approximately 80% but tended to enhance responses to nitroprusside.
Conclusions Thus, nitric oxide–mediated dilatation of mouse cerebral arterioles is profoundly inhibited by ODQ, an inhibitor of activity of soluble guanylyl cyclase. Cerebral vasodilator responses to adenosine and 8-bromo-cGMP were preserved in the presence of ODQ, indicating that inhibition by ODQ was selective. In contrast to previously used inhibitors of soluble guanylyl cyclase (methylene blue and LY-83583), the effects of ODQ are not mediated by generation of superoxide anion.
Key Words: cerebral arteries • nitric oxide • mice • vasodilation
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Until recently, relaxation of vascular muscle in response to nitric oxide has generally been considered to be mediated exclusively by activation of soluble guanylyl cyclase and accumulation of intracellular cGMP.1 2 Recent findings, however, suggest that nitric oxide may also directly induce hyperpolarization and relaxation through activation of potassium channels on vascular muscle by a mechanism that does not involve soluble guanylyl cyclase or cGMP.3 4 Furthermore, it is now apparent that interactions between nitric oxide, cGMP, and potassium channels are complex because cGMP can activate potassium channels,5 and vasodilator responses to nitric oxide may involve potassium channel activation only under select conditions and in some vascular beds.6 7
Definitive study and elaboration of the mechanisms and functional importance of nitric oxide– and cGMP-mediated vascular relaxation require pharmacological inhibitors with selective actions. Methylene blue and LY-83583 are two commonly used inhibitors of soluble guanylyl cyclase, but interpretation of findings is difficult because both compounds have additional effects, including generation of superoxide anion8 9 10 11 and inhibition of nitric oxide synthase in endothelium.12 13
Recently, an oxadiazoloquinoxaline derivative, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), has been described as a novel selective inhibitor of soluble guanylyl cyclase in vitro.14 Studies in vitro have reported that ODQ inhibits soluble guanylyl cyclase in brain14 15 and a variety of tissue preparations.16 17 18 19 20 It has been reported that ODQ does not generate superoxide anions and does not inhibit nitric oxide synthase.14 The first goal of this study was to determine whether ODQ can selectively inhibit cerebral vasodilator responses in vivo to endogenous and exogenous nitric oxide. The second goal was to test whether the effects of ODQ in vivo are dependent on generation of superoxide anions. We anticipate using genetically altered mice in future studies of cerebral blood vessels. Thus, the present study was performed in mice to establish the in vivo cranial window model in our laboratory. Studies with ODQ should provide insight into mechanisms by which nitric oxide dilates cerebral arterioles, which may be useful in future studies of nitric oxide in mutant strains of mice.
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Materials and Methods |
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Experimental Animals
Procedures used in these experiments were approved by the University of Iowa Animal Care and Use Review Committee. Experiments were performed on 28 male ICR mice (weight, 25 to 38 g). Animals were anesthetized with pentobarbital sodium (90 mg/kg IP). Pentobarbital was supplemented regularly at approximately 10 to 20 mg·kg-1·h-1. The trachea was cannulated, and the animals were ventilated mechanically (120 to 170 breaths per minute) with air and supplemental oxygen. A femoral artery was cannulated for measurement of systemic pressure and to sample arterial blood. End-tidal CO2, which was continuously monitored throughout each experiment with the use of a microcapnometer (Colombus), was maintained between 2.5% and 3.5% (mean±SE, 2.99±0.08%) by adjusting the ventilation rate. At the end of each experiment, a sample of arterial blood was drawn into a capillary tube for measurement of blood gases, which were found to be as follows: PCO2, 35±1 mm Hg; PO2, 146±8 mm Hg; and pH, 7.40±0.01. Skeletal muscle paralysis was produced with gallamine triethiodide (15 to 30 mg·kg-1·h-1 IP). We evaluated depth of anesthesia by applying pressure to a paw or the tail and observing changes in heart rate or blood pressure. When such changes occurred, additional anesthetic was administered. Arterial pressure averaged 74±2 mm Hg and was similar among the different experimental treatment groups. Rectal temperature was continuously monitored and was kept at 37°C to 38°C with a heating pad.
Mice were placed in a head holder, and after the overlying skin was removed, dental acrylic was applied around the perimeter of the exposed skull to make a well to contain artificial CSF over the cranial window. Stainless steel ports for inward and outward flow of CSF were glued in place onto the acrylic well. A cranial window was made over the left parietal cortex, and a segment of a pial arteriole was exposed by removing the overlying portion of dura mater with the tip of a 30-gauge hypodermic needle. The cranial window was suffused at 5 mL/min with artificial CSF (temperature, 37°C to 38°C; ionic composition [mmol/L], NaCl 132, KCl 2.95, CaCl2 1.71, MgCl2 0.65, NaHCO3 24.6, D-glucose, 3.69) that was bubbled continuously with 95% N2/5% CO2 to produce the following levels in the cranial window: PCO2, 39±1 mm Hg; PO2, 71±2 mm Hg; and pH, 7.39±0.01. Diameter of the exposed pial arteriole was recorded with a microscope equipped with a television camera coupled to a video monitor. Images were recorded on videotape, and vessel diameters were measured with an image analyzer. All drugs were applied topically over the cerebral vessels. Application of vehicle did not affect vessel diameter.
Experimental Protocols
Five groups of animals were studied. In all groups, diameter of
one arteriole per animal was measured under control conditions and
during topical application of drugs.
In group 1 (time controls; n=4), changes in arteriolar diameter were measured in response to acetylcholine (1 and 10 µmol/L), sodium nitroprusside (0.1 and 1 µmol/L), and adenosine (0.1 and 1 mmol/L). The concentrations of each vasodilator were applied in a cumulative manner, and the order of application of drugs was varied between experiments. At least 15 minutes was allowed for vessel diameter to recover to control levels between application of vasodilators. When all three vasodilators had been applied, a 30-minute recovery period was allowed. The sequence of application of acetylcholine, sodium nitroprusside, and adenosine to the cranial window was alternated. This group of animals acted as a time control to establish whether responses to acetylcholine, sodium nitroprusside, and adenosine were reproducible.
In group 2 (L-NNA; n=8), changes in arteriolar diameter were measured in response to acetylcholine (1 and 10 µmol/L) and sodium nitroprusside (0.1 and 1 µmol/L). When both vasodilators had been applied, a 30-minute recovery period was allowed, and application of acetylcholine and sodium nitroprusside to the cranial window was repeated in the presence of L-NNA (100 µmol/L). The cranial window was treated with L-NNA for 20 minutes before and during application of vasodilators. The purpose of these experiments was to determine whether L-NNA, which inhibits synthesis of endothelium-derived relaxing factor/nitric oxide by nitric oxide synthase, selectively inhibits vasodilator responses of mouse pial arterioles to acetylcholine.
In group 3 (ODQ 3 µmol/L; n=6), changes in arteriolar diameter were measured in response to acetylcholine (1 and 10 µmol/L), sodium nitroprusside (0.1 and 1 µmol/L), and adenosine (0.1 and 1 mmol/L). When all three vasodilators had been applied, a 30-minute recovery period was allowed, and application of acetylcholine, sodium nitroprusside, and adenosine to the cranial window was repeated in the presence of ODQ (3 µmol/L). The cranial window was treated with ODQ for 20 minutes before and during application of vasodilators. The purpose of these experiments was to determine whether ODQ, which inhibits activation of soluble guanylyl cyclase in vitro, selectively inhibits vasodilator responses of mouse pial arterioles to acetylcholine and nitroprusside in vivo.
In group 4 (ODQ 10 µmol/L; n=6), changes in arteriolar diameter were measured in response to acetylcholine (1 and 10 µmol/L), sodium nitroprusside (0.1 and 1 µmol/L), and 8-bromo-cGMP (200 and 600 µmol/L). When all three vasodilators had been applied, a 30-minute recovery period was allowed, and application of acetylcholine, sodium nitroprusside, and 8-bromo-cGMP to the cranial window was repeated in the presence of ODQ (10 µmol/L). The cranial window was treated with ODQ for 20 minutes before and during application of vasodilators. There were two goals in performing these experiments. First, we determined whether a concentration of ODQ higher than 3 µmol/L might produce a more effective inhibition of responses to acetylcholine and sodium nitroprusside. Second, we tested whether ODQ, which inhibits production of cGMP in vascular muscle, affects vasodilator responses of cerebral arterioles to 8-bromo-cGMP, a stable analogue of cGMP.
In group 5 (ODQ plus SOD; n=4), changes in arteriolar diameter were measured in response to sodium nitroprusside (0.1 and 1 µmol/L) and adenosine (0.1 and 1 mmol/L). When both vasodilators had been applied, a 30-minute recovery period was allowed, and application of sodium nitroprusside and adenosine to the cranial window was repeated during combined application of ODQ (10 µmol/L) and SOD (100 U/mL). The cranial window was treated with ODQ plus SOD for 20 minutes before and during application of vasodilators. The purpose of these experiments was to determine whether the inhibitory effect of ODQ on vasodilator responses to sodium nitroprusside is dependent on generation of superoxide anion.
Drugs
Acetylcholine chloride, adenosine, L-NNA, sodium
nitroprusside, 8-bromo-cGMP monophosphate sodium salt, and SOD were
obtained from Sigma Chemical Co. ODQ was obtained from Tocris Cookson.
Aliquots of ODQ (3x10-2 mol/L) were prepared
by dissolving the drug in dimethyl sulfoxide and were stored at
-20°C. Subsequent dilutions of ODQ were made in saline. The vehicle
for ODQ (eg, 0.03% dimethyl sulfoxide at 10 µmol/L ODQ) had no
effect on cerebral arteriolar diameter. All other drugs were dissolved
and diluted in saline.
Statistical Analysis
To examine effects of inhibitors on baseline vessel
diameter, paired t tests were used on absolute values (not
percent change). For comparison of percent change data in the absence
and presence of inhibitors, statistical analysis
was also performed with Wilcoxon's test. All values are
expressed as mean±SE. A value of P<.05 was considered
significant.
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Results |
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Cerebral Vasodilator Responses to Acetylcholine and Sodium Nitroprusside
The control diameter of mouse pial arterioles was 29±1 µm (n=28). Baseline arteriolar diameter was stable throughout time-control experiments (31±3 versus 32±4 µm). Acetylcholine, an endothelium-dependent vasodilator, produced concentration-dependent dilator responses of cerebral arterioles that were reproducible. Acetylcholine (1 and 10 µmol/L) dilated cerebral arterioles by 12±2% and 24±3% during the first application and 10±3% and 21±2%, respectively, during the second application. Cerebral vasodilatation in response to acetylcholine was markedly inhibited by L-NNA (100 µmol/L) (P<.05; Fig 1
). Baseline diameter of cerebral arterioles was
26±1 µm in the absence and 25±1 µm in the presence of
L-NNA. This finding confirms previous reports21 22 23 24 that
dilatation of mouse cerebral arterioles in response to acetylcholine is
dependent on production of nitric oxide.
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Sodium nitroprusside produced concentration-dependent dilator responses
of cerebral arterioles that were reproducible. Nitroprusside (0.1 and
1 µmol/L) dilated cerebral arterioles by 12±2% and 35±3%
during the first application and 18±3% and 34±3%, respectively,
during the second application. In contrast, cerebral vasodilator
responses to sodium nitroprusside were augmented by L-NNA
(P<.05; Fig 1
). Thus, L-NNA selectively inhibits
endothelium-dependent nitric oxide–mediated
vasodilator responses of cerebral arterioles in mice.
Effect of ODQ on Cerebral Vasodilator Responses
Increases in the diameter of cerebral arterioles in response to
acetylcholine and sodium nitroprusside were reduced by 60% to 80% in
the presence of 3 µmol/L ODQ (Fig 2). Cerebral
vasodilator responses to adenosine, which were found to be
reproducible in time-control experiments (data not shown), were
unaffected by 3 µmol/L ODQ. Adenosine (0.1 and 1
mmol/L) dilated cerebral arterioles by 18±3% and 33±7% in the
absence of ODQ and 19±4% and 30±7%, respectively, in the presence
of 3 µmol/L ODQ. The baseline diameter of cerebral arterioles
was 38±3 µm in the absence and 39±4 µm in the presence
of 3 µmol/L ODQ.
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Increases in the diameter of cerebral arterioles in response to
acetylcholine and sodium nitroprusside were reduced (by 80% to 90%)
in the presence of 10 µmol/L ODQ (Fig 3).
Cerebral vasodilator responses to 8-bromo-cGMP were unaffected by
10 µmol/L ODQ (Fig 4). The baseline diameter of
cerebral arterioles was 25±2 µm in the absence and 24±2
µm in the presence of 10 µmol/L ODQ. Thus, consistent
with an inhibitory effect on production of cGMP by
soluble guanylyl cyclase, ODQ selectively inhibits cerebral vasodilator
responses mediated by endogenous or exogenous nitric oxide.
Preservation of vasodilator responses to 8-bromo-cGMP suggests that ODQ
does not inhibit responses to cGMP in cerebral vascular muscle.
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Effect of ODQ Plus SOD on Cerebral Vasodilator Responses
Increases in diameter of cerebral arterioles in response to sodium
nitroprusside were markedly reduced in the presence of ODQ (10
µmol/L) plus SOD (100 U/mL) (Fig 5). Cerebral
vasodilator responses to adenosine were unaffected by ODQ plus
SOD (data not shown). The baseline diameter of cerebral arterioles was
28±2 µm in the absence and 28±2 µm in the presence of
ODQ plus SOD.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We studied cerebral vasodilator mechanisms in anesthetized and artificially ventilated mice, in which systemic arterial pressure and end-tidal CO2 were continually monitored and blood pH and gas concentrations were controlled. The major finding is that nitric oxide–mediated dilatation of cerebral arterioles in vivo is profoundly inhibited by ODQ, an inhibitor of activity of soluble guanylyl cyclase. Furthermore, cerebral dilator responses to adenosine and 8-bromo-cGMP were preserved in the presence of ODQ, indicating that inhibition by ODQ was selective for dilatation mediated by the nitric oxide/soluble guanylyl cyclase mechanism.
Responses to Acetylcholine
Relaxation of cerebral arteries and arterioles in response to
acetylcholine is endothelium
dependent.25 26 In the present experiments,
acetylcholine produced concentration-dependent increases in diameter of
cerebral arterioles of the mouse in vivo. Vasodilator responses to
acetylcholine were markedly inhibited during administration of L-NNA,
an inhibitor of nitric oxide synthase. This result confirms
previous studies which suggested that dilatation of cerebral arterioles
in the mouse21 22 23 24 and other species27 28 29 30 is
dependent on formation of nitric oxide. Recent studies suggest that
nitric oxide also mediates endothelium-dependent
relaxation in human cerebral arteries.31 32 Because the
vast majority of the response to acetylcholine in the mouse was
inhibited by L-NNA, endothelium-derived nitric oxide
mediates most, if not all, of the dilator response to acetylcholine in
these vessels.
Sodium nitroprusside, a nitric oxide donor, also caused concentration-dependent dilatation of cerebral arterioles. Consistent with previous findings in several species, dilator responses of cerebral arterioles to nitroprusside were not inhibited by L-NNA.27 28 29 Thus, inhibitory effects of L-NNA on responses to acetylcholine were selective.
Effects of ODQ on Cerebral Vasodilator
Responses
ODQ inhibited cerebral vasodilator responses to both
acetylcholine, which causes formation of endogenous nitric
oxide, and sodium nitroprusside, which is a donor of nitric oxide. At a
concentration of 10 µmol/L, ODQ almost completely inhibited
nitric oxide–mediated dilator responses, consistent with an
inhibitory effect of ODQ on soluble guanylyl cyclase
activity in the cerebral circulation in vivo. Thus, the data suggest
that nitric oxide–mediated dilatation of mouse cerebral arterioles
occurs predominantly, if not exclusively, through generation of cGMP in
vascular muscle, and probably not through direct effects of nitric
oxide on potassium channels in vascular muscle.4 The
finding that inhibition of dilator responses to acetylcholine was
virtually complete in the presence of ODQ also suggests that there is
little or no contribution by a non–nitric oxide,
endothelium-derived hyperpolarizing factor in the
response to acetylcholine.
Adenosine is known to produce marked relaxation of cerebral blood vessels. Adenosine activates adenylate cyclase and increases cAMP, a vasodilator, in cerebral vascular muscle.33 Relaxation of cerebral vessels in response to adenosine is endothelium-independent and not dependent on formation of nitric oxide.28 34 35 Consistent with these findings, we observed that dilatation of cerebral arterioles in response to adenosine was unaffected by ODQ. This finding indicates that inhibition by ODQ of responses mediated by the soluble guanylyl cyclase/cGMP system was selective.
Cerebral dilator responses to 8-bromo-cGMP, a stable analogue of cGMP, were also not altered in the presence of ODQ. This finding suggests that ODQ produces its effect by inhibiting production of, but not responsiveness to, cGMP.
ODQ did not significantly alter the baseline diameter of cerebral
arterioles in these experiments. This finding might seem surprising
since previous studies have reported that inhibitors of
nitric oxide synthase reduce cerebral blood flow. It should be noted,
however, that inhibitors of nitric oxide synthase have been
reported to have no effect28 or to produce only modest
constriction of cerebral arterioles when applied topically in a cranial
window in most studies. Reductions in diameter of cerebral (pial)
arterioles less than 100 µm are not generally more than
10%.21 27 29 36 37 In the present experiments, we
studied pial arterioles less than 40 µm in diameter. Diameter of
these arterioles tended to decrease (change in diameter of 
4%) in
response to the highest concentration of ODQ or L-NNA, but this effect
was not statistically significant. The present data are
consistent with previous studies of pial arterioles in
mice.21 24 38 Overall, our data seem consistent
with the concept that the influence of basal production of
nitric oxide in small pial arterioles is modest.
Mechanism of Inhibition by ODQ
To our knowledge, the present study is the first to examine
effects of ODQ on vasodilator responses in brain, or any vascular bed,
in vivo. ODQ selectively inhibits soluble guanylyl cyclase in vitro in
brain14 15 and several tissue
preparations.16 17 18 19 20 It has been reported that ODQ does not
generate superoxide anions and does not inhibit nitric oxide
synthase.14 Inhibitory effects of ODQ appear
to involve inhibition at the heme site of soluble guanylyl
cyclase.18 We found that inhibitory effects of
ODQ were not altered by SOD. In contrast, inhibitory
effects of methylene blue and LY 83583 on cerebral arterioles are
prevented by SOD.8 11 The apparent selectivity of action
by ODQ may make it a preferred inhibitor of soluble
guanylyl cyclase over previously used inhibitors such as
methylene blue and LY 83583, which have several actions independent of
inhibition of soluble guanylyl cyclase. These actions include
generation of superoxide anion8 9 10 11 and inhibition of
nitric oxide synthase.12 13
In the present study we found that coadministration of SOD with ODQ did not reduce the inhibitory effect of ODQ against nitric oxide–mediated vasodilatation. This finding suggests that ODQ does not inhibit soluble guanylyl cyclase in vivo by generating superoxide anions. This finding supports previous findings in vitro that effects of ODQ are not mediated by generation of superoxide anion.14
Selective and potent inhibition of soluble guanylyl cyclase by ODQ enables direct effects of nitric oxide to be distinguished from effects dependent on cGMP production.16 Because dilator responses to acetylcholine and nitroprusside were virtually abolished in the presence of ODQ, there appears to be little or no role for non–cGMP-mediated dilator effects of nitric oxide in mouse cerebral arterioles.
Study of Mouse Cerebral Vascular Responses In
Vivo
The use of anesthetized mice to examine responses of
cerebral arterioles was pioneered and used extensively by Rosenblum and
Zweifach.39 This approach was expanded recently to include
routine monitoring of end-tidal CO2 and
arterial blood pressure.40 In the present
study we used the latter approach to examine responses of cerebral
arterioles in anesthetized mice. Small-volume and
high-frequency artificial ventilation, combined with continuous
sampling of end-tidal CO2, enables accurate estimation and
regulation of arterial CO2 and pH levels in
mice, which have insufficient blood volume to allow multiple blood
sampling for analysis of arterial blood gases.
Using this approach, we obtained appropriate arterial blood
gas and pH levels in each animal used in the study. These techniques
should provide more optimal monitoring and control of
cardiovascular parameters and are useful in
studies in which genetically altered murine models are
used.22 23 24 38
In conclusion, nitric oxide–mediated dilatation of cerebral arterioles in vivo is profoundly inhibited by ODQ, an agent reported to inhibit activity of soluble guanylyl cyclase. ODQ selectively inhibits cerebral dilator responses that are dependent on the production of cGMP by soluble guanylyl cyclase but did not affect vasodilatation to a cGMP analogue. Finally, unlike previously used inhibitors of soluble guanylyl cyclase, the inhibitory effect of ODQ does not involve generation of superoxide anions.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-38901 and NS-24621 and by a Grant-in-Aid from the American Heart Association (95014510). Dr Faraci is an Established Investigator of the American Heart Association. Dr Sobey is the recipient of a C.J. Martin Fellowship from the National Health and Medical Research Council of Australia and a Michael J. Brody Fellowship in Basic Cardiovascular Research from the University of Iowa. The authors thank Drs Donald Heistad and Kathryn Lamping for critical review of the manuscript and Cynthia Lynch for technical assistance.
Received September 30, 1996; revision received December 18, 1996; accepted January 9, 1997.
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