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LOCAL CONTROL OF CIRCULATION
Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112
Submitted 8 October 2002 ; accepted in final form 2 April 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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-aminolevulinic acid
(-ALA), constricted arterioles with intact endothelium pretreated with
phenylephrine; these effects were abolished by removal of the endothelium. CO-
and -ALA-induced vasoconstrictions were converted to dilations by
pretreatment with an inhibitor of NO synthase,
N
-nitro-L-arginine methyl ester, or with
N-nitro-L-arginine methyl ester and an
NO donor, sodium nitroprusside. Furthermore, CO-induced vasoconstriction was
prevented by pretreatment with the NO synthase substrate
L-arginine. This study shows that exogenous, as well as
endogenously formed, CO can promote endothelium-dependent vasoconstriction in
isolated gracilis muscle arterioles. Because CO-induced vasoconstriction is
abolished by NO synthase blockade and by L-arginine, CO most likely
promotes endothelium-dependent vasoconstriction by inhibiting endothelial NO
formation.
heme oxygenase; nitric oxide; vascular tone; -aminolevulinic acid
Despite the popular characterization of CO as a vasodilator, there has been evidence to suggest that CO can inhibit the NO system (6) and, accordingly, may also exert a vasoconstrictive influence on vascular tone (6). Biochemical studies have shown that CO inhibits NO formation by binding to NO synthase (1, 9, 14, 25). In addition, a recent report suggested that, in isolated renal resistance vessels, physiological concentrations of CO (23) can suppress the activity of endothelial NO synthase (21). Therefore, the possibility exists that although CO promotes a vasodilatory influence by acting directly on vascular smooth muscle, it may simultaneously exert a vasoconstrictive influence by inhibiting formation of endothelium-derived NO.
The present study tests the hypothesis that CO promotes endothelium- and NO synthase-dependent vasoconstriction. For this purpose, experiments were conducted using pressurized first-order gracilis muscle rat arterioles with or without intact endothelium and arterioles with NO synthase blockade. In these preparations, we examined the effects of exogenous and endogenous CO on arteriolar diameter.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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CO gas was purchased from Air Liquide (Harvey, LA), -aminolevulinic
acid (-ALA) from Frontier Scientific (Logan, UT),
N-nitro-L-arginine methyl ester
(L-NAME), L-arginine hydrochloride, sodium nitroprusside
(SNP), phenylephrine, and acetylcholine from Sigma Aldrich (St. Louis, MO),
and all other chemicals from Fisher Scientific (Houston, TX).
L-NAME, SNP, phenylephrine, L-arginine, and
acetylcholine were dissolved in modified Krebs buffer immediately before use.
CO-saturated solution (1 mmol/l) was prepared by bubbling ice-cold modified
Krebs buffer with CO gas for 20 min. The final concentration of CO in the
microvessel chamber (0.1-100 µmol/l) was achieved by predilution with
ice-cold modified Krebs buffer in the infusion syringe (for 0.1, 1, and 10
µmol/l) and final dilution with superfusion buffer (modified Krebs buffer
at 37°C). Stock and final microvessel chamber concentrations of CO were
confirmed by combining samples with freshly lysed rat blood and then
calculating from the resulting carboxyhemoglobin content (model OSM3,
Radiometer, Westlake, OH). The composition of modified Krebs buffer was
(mmol/l) 118.5 NaCl, 4.7 KCl, 1.4 CaCl2, 1.2
KH2PO4, 1.1 MgSO4, 25.0 NaHCO3,
and 11.1 dextrose.
Animals
Use of male Sprague-Dawley rats (250-300 g, n = 70; Harlan, Indianapolis, IN) in these studies was approved by the Institutional Animal Care and Use Committee. Rats were housed in a controlled environment and had free access to commercial rat chow and tap water.
Microvascular Preparation
Rats were anesthetized with a single dose of thiobutabarbital sodium (Inactin, 140 mg/kg ip) and heparinized (1,000 U/kg iv). The gracilis anticus muscles were removed, and segments of the first-order gracilis muscle arterioles were isolated as previously described (19). Individual arteriolar segments were cannulated at both ends with glass micropipettes in a water-jacketed vessel chamber (18 ml volume; Instrument Shop, New York Medical College, Valhalla, NY). Silicone tubing (Masterflex, Cole-Parmer, Vernon Hills, IL) connected the distal micropipette to a stopcock and the proximal micropipette to a reservoir containing modified Krebs buffer. The height of the reservoir was adjusted to 108.8 cm above the level of the arteriole to achieve 80 mmHg intraluminal pressure. The vessel chamber was superfused continuously via a nonrecirculating system (Masterflex L/S pump, Cole-Parmer) with oxygenated (14% O2 -5% CO2-balance N2) modified Krebs buffer (5 ml/min) at 37°C (Isotemp 2100 immersion circulator, Fisher Scientific). For internal diameter measurements, the vessel chamber was mounted on the stage of a microscope (Micromaster, Fisher Scientific) that was fitted with a video camera (video microscope package, Fisher Scientific) leading to a video caliper (Texas A & M University, College Station, TX) and a television-videocassette recorder (Zenith, Sears). With this setup, a magnified image of the arteriolar segment was viewed on the television screen, and internal diameter was measured throughout the experiment by manual adjustment of the white guides superimposed by the video caliper.
Mounted vessels were allowed to stabilize for 60 min before initiation of
the experiments. Only vessels that developed an active tone during the
stabilization period were used for the studies. Pretreatment drugs (i.e.,
phenylephrine, L-NAME, SNP, or L-arginine) were included
in the superfusion buffer. CO-saturated solution (1 mmol/l) or -ALA
stock solution (80 mmol/l) was added directly to the microvessel chamber and
then continuously infused (model M361, Sage, Boston, MA) into the superfusion
buffer to quickly achieve and maintain the desired concentration of CO
(0.1-100 µmol/l) or -ALA (80 µmol/l) in the chamber without
interruption of chamber superfusion.
Experimental Design
Arterioles with intact endothelium. The following experiments were
designed to study endothelium-dependent effects of exogenous and endogenously
formed CO on arteriolar diameter. The arteriolar endothelium was left intact,
and microvessels were pretreated with a vasoconstrictor, phenylephrine (100
nmol/l); phenylephrine treatment was continued throughout the remainder of the
experiment. This concentration of phenylephrine (100 nmol/l) was used to match
the internal diameter of denuded and L-NAME-pretreated vessels.
After 25 min of pretreatment, CO (0.1-100 µmol/l) or -ALA (80
µmol/l) was administered, and internal diameter was monitored for 20 min.
Recently, it has been reported that small amounts of CO release NO (0.01
µmol CO/l) and promote vasodilation (0.1 µmol CO/l), but physiological
concentrations of CO (1-10 µmol/l) inhibit NO synthesis and release in
isolated renal resistance vessels
(21). To explore this
potentially bimodal response, we examined the effects of exogenous CO at
0.1-100 µmol/l in arterioles with intact endothelium. Endogenous free heme
levels are estimated to be 
0.5 µmol/l
(6). Eight -ALA
molecules are used for the synthesis of one heme molecule, and we used 80
µmol/l -ALA to enhance heme synthesis. At the end of the experiment,
the presence of functional endothelium was confirmed by studying the
vasodilatory responses to acetylcholine (1 µmol/l).
Arterioles denuded of endothelium. The following experiments were
designed to study the endothelium-independent effects of exogenous and
endogenously formed CO on arteriolar diameter. After the stabilization period,
the arteriolar endothelium was removed by perfusion of 2 ml of air through the
lumen, as previously described
(19). After an additional
40-min stabilization period, CO (50 µmol/l) or -ALA (80 µmol/l)
was administered, and internal diameter was monitored for 20 min. At the end
of the experiments, the absence of functional endothelium was confirmed by the
lack of vasodilatory response to acetylcholine (1 µmol/l).
Arterioles with NO synthase blockade. Experiments were designed to
study the NO system-independent effects of exogenous and endogenously formed
CO on arteriolar diameter. The microvessel endothelium was left intact. After
the stabilization period, microvessels were exposed to an inhibitor of NO
synthase, L-NAME (1 mmol/l). Exposure to the inhibitor was
continued throughout the remainder of the experiment. Previous experiments
have found that this concentration of L-NAME was required to cause
maximal constriction of isolated gracilis muscle arterioles (unpublished
observations), suggesting maximal achievable blockade of the NO system. After
55 min of pretreatment, CO (50 µmol/l) or -ALA (80 µmol/l) was
administered, and internal diameter was monitored for 20 min.
Arterioles with "NO clamp." The following experiments were designed to identify the NO synthase-independent effects of exogenous CO on arteriolar diameter. The microvessel endothelium was left intact. After the stabilization period, arterioles were pretreated with L-NAME (1 mmol/l) to block NO synthase activity and with an NO donor, SNP (10-30 nmol/l), to maintain internal diameter at before-pretreatment levels (NO clamp). Exposure to the clamp was continued throughout the remainder of the experiment. With this design, we achieved maximal blockade of NO synthase while maintaining the activity of the vascular NO signaling system by replacing endogenous NO with an NO donor. After a 55-min pretreatment period, CO (50 µmol/l) was administered, and internal diameter was monitored for 20 min.
Arterioles pretreated with L-arginine. The following experiments were designed to study the L-arginine-dependent effects of exogenous CO on arteriolar diameter. The microvessel endothelium was left intact. After the stabilization period, arterioles were pretreated with a vasoconstrictor, phenylephrine (100 nmol/l), and the substrate for NO synthesis, L-arginine (1 mmol/l). This pretreatment regimen was continued throughout the remainder of the experiment. With this design, we provided excess substrate for NO synthesis. After 60 min of pretreatment, CO (50 µmol/l) was administered, and internal diameter was monitored for 20 min.
Statistics
Values are means ± SE. Data showing time-related vascular responses were analyzed by analysis of variance, and further post hoc comparisons were made by performing orthogonal contrasts (18) using a statistical package (SYSTAT) when appropriate. Data showing concentration-related vascular responses to exogenous CO were analyzed by t-tests. P < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In arterioles with intact endothelium
(Fig. 1A), exogenous
CO (50 µmol/l) promoted a sustained vasoconstriction (from 85 ± 5 to
66 ± 4 µm, n = 8, P < 0.05). Removal of the
endothelium (Fig. 1B)
abolished the vasoconstrictor response to CO (from 111 ± 9 to 117
± 9 µm, n = 8, P > 0.05).
Figure 2 shows
concentration-dependent responses to exogenous CO in arterioles with intact
endothelium measured as the average of the last four measurements (1
measurement/min) at the end of the 20-min exposure.
Figure 2 shows that CO promoted
concentration-dependent vasoconstriction that was evident at 1 µmol/l
(
max = -6 ± 1 µm, n = 5, P <
0.05 vs. vehicle) and maximum at 50 µmol/l (max = -17
± 3 µm, n = 8, P < 0.05 vs. vehicle). In
arterioles with intact endothelium (Fig.
3A), pretreatment with an NO synthase inhibitor,
L-NAME (1 mmol/l), converted CO-induced vasoconstriction to
vasodilation (from 91 ± 14 to 128 ± 11 µm, n = 6,
P < 0.05). Similarly, in arterioles subjected to NO clamp
(Fig. 3B), i.e.,
pretreated with an NO synthase inhibitor (1 mmol L-NAME/l) and an
NO donor (10-30 nmol SNP/l), CO caused vasodilation (from 115 ± 10 to
123 ± 9 µm, n = 6, P < 0.05). The heme
synthesis precursor -ALA (80 µmol/l) promoted vasoconstriction in
arterioles with intact endothelium (max = -9 ± 1
µm, n = 6, P < 0.05;
Fig. 4). -ALA-induced
vasoconstriction was converted to vasodilation by removal of the endothelium
(max = 7 ± 1 µm, n = 4, P <
0.05) and pretreatment with an inhibitor of NO synthase, L-NAME (1
mmol/l; max = 7 ± 1 µm, n = 4, P
< 0.05). In arterioles with intact endothelium
(Fig. 5B),
pretreatment with the NO synthase substrate L-arginine (1 mmol/l)
prevented CO-induced vasoconstriction (from 100 ± 6 to 95 ± 6
µm, n = 7, P > 0.05).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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CO is commonly characterized as a vasodilatory regulator of vascular tone, inasmuch as CO has been shown to relax vascular smooth muscle (2, 3, 6, 22, 24). In addition, numerous studies have reported that exogenously applied and endogenously formed CO promoted dilation of different vascular beds (2, 3, 6, 22, 24). With regard to these findings, we have similarly observed that heme-derived CO dilated isolated gracilis muscle arterioles pretreated with an inhibitor of NO synthase (10). However, a commonly overlooked effect of CO is inhibition of NO synthesis by binding to the NO synthase (1, 9, 14, 25). Seminal findings by White and Marletta (25) and Klatt et al. (9) led to the recognition of NO synthase as a cytochrome P-450-type hemoprotein. More recently, it has been reported that small amounts of CO release NO (21), but physiological concentrations of CO (23) inhibit NO synthesis in isolated renal resistance vessels (21).
Our present study shows that exogenous CO promotes concentration-dependent vasoconstriction in isolated rat arterioles with intact endothelium. Because the vasoconstrictive effect of CO was abolished by removal of the endothelium, we reasoned that CO might 1) stimulate release of an endothelium-derived constricting factor or 2) inhibit release of an endothelium-derived relaxing factor. Because previous studies suggested that CO interferes with NO synthesis (1, 9, 14, 25), we examined the effects of exogenous CO in arterioles with intact endothelium pretreated with an inhibitor of NO synthase. Consistent with our previous reports (10), we have found that pretreatment with L-NAME converted CO-induced vasoconstriction to vasodilation. These data suggest that CO-induced endothelium-dependent vasoconstriction is most likely due to interference with the vasodilatory effects of the endothelial NO system.
Although previous studies have shown that CO directly inhibits NO synthase (1, 9, 14, 25), a recent report suggested that endogenous CO may also promote hypertension by serving as a partial agonist/antagonist for soluble guanylate cyclase (4). In that case, in arterioles pretreated simultaneously with an NO synthase inhibitor and an NO donor (i.e., NO clamp), CO should promote vasoconstriction. However, we found that CO promotes vasodilation in vessels subjected to the NO clamp. Nevertheless, the response was marginally attenuated compared with arterioles pretreated only with the NO synthase inhibitor. Although this attenuation may in part be due to CO interfering with NO-induced vasodilatory mechanisms, we did not find vasoconstriction in these arterioles subjected to NO clamp; this feature strongly suggests that CO-induced vasoconstriction does not arise primarily from inhibition of soluble guanylate cyclase activity.
The major source of endogenous CO production is the enzymatic degradation
of heme by heme oxygenase
(20). -ALA is a
precursor for heme synthesis: eight -ALA molecules are required for the
synthesis of one molecule of heme
(15,
17). In the heme synthetic
cascade, -ALA formation is the primary point of regulation
(15,
17). Provision of exogenous
-ALA drives heme synthesis
(11) and, consequently,
increases substrate availability for heme oxygenase. Radiolabeled -ALA
has been shown to generate radiolabeled CO in a reaction that is mediated by
heme oxygenase (11). Because
heme oxygenase activity appears to be regulated by substrate availability
(6,
16), provision of -ALA
increases heme oxygenase activity and, consequently, endogenous CO formation
(12,
26) in a
concentration-dependent manner
(12), and the iron released
during heme degradation is available to be recycled into the formation of new
monomeric heme (17). Our
previous studies (6,
10) used heme preparations to
provide substrate for heme oxygenase
(6,
16). However, heme contains
iron, and its use may potentially contribute to detrimental iron loading of
the tissues. To minimize the chances of these unwanted effects, we decided to
use the heme synthesis precursor -ALA to drive heme synthesis and,
consequently, drive the endogenous formation of CO. In the present study, we
observed that the -ALA promoted effects that were similar to those of
exogenous CO. In arterioles with intact endothelium, -ALA promoted
vasoconstriction, and this vasoconstrictive effect was converted to
vasodilation by removal of the endothelium or pretreatment with an inhibitor
of NO synthase. The highly unique actions of this well-established heme
precursor, in conjunction with the highly unique actions of exogenously formed
CO, strongly suggest that -ALA drives CO formation in these isolated
microvessels and that its vasoconstrictive actions arise from the subsequent
generation of CO by inhibiting the vasodilatory effects of the NO system.
A previous study using isolated NO synthase suggested that excess substrate (L-arginine) levels decrease the affinity of CO binding to NO synthase (1, 14) by binding close to the heme and/or altering the confirmation of the distal heme pocket and, hence, constraining CO binding to the heme moiety (1, 14). To investigate whether L-arginine protects against CO-induced vasoconstriction, we conducted experiments on arterioles with intact endothelium pretreated with L-arginine. We found that, in isolated gracilis muscle arterioles, pretreatment with L-arginine (1 mmol/l) abolished CO-induced vasoconstriction. These data show that L-arginine can protect against CO-induced vasoconstriction, which further supports the notion that CO might promote vasoconstriction by inhibiting endothelial NO synthase.
The vasodilatory effects of exogenous CO and -ALA in arterioles
pretreated with L-NAME appear to reflect their actions on vascular
smooth muscle. Our findings show that the vasodilatory effects of CO may
dominate in the absence of NO synthase activity when the endothelium is
present. However, our findings also show that exogenous CO, at the examined
concentration, has little vasodilatory action in the absence of endothelium.
Because L-NAME-pretreated and endothelium-denuded vessels should
lack NO synthase activity, the difference in CO-induced responses suggests
that perhaps other endothelium-dependent systems may be involved. NO has been
suggested to interact with other vasoactive mediators produced in the vascular
endothelium, such as endothelin and prostaglandins. Many of these systems may
be altered when NO synthesis is blocked. CO has also been suggested to
interact with some of these other endothelium-dependent vasoactive mediators
(6). In the face of these
observations, the possibility exists that, in L-NAME-pretreated
vessels, increased release of an endothelium-dependent vasodilator or
decreased release of an endothelium-dependent vasoconstrictor may contribute
to the vasodilatory effects of CO. However, exploration of such potential
interactions is beyond the scope of the present study.
A recent study (21) reported that small amounts of CO release NO (0.01 µmol CO/l) and promote vasodilation (0.1 µmol CO/l), but physiological concentrations of CO (1-10 µmol/l) inhibit NO synthesis and release in isolated renal resistance vessels. In our preparation, we found that CO at 0.1 µmol/l did not produce statistically significant changes in arteriolar diameter compared with the matched unbubbled ice-cold vehicle controls. At larger concentrations, exogenous CO promoted concentration-dependent vasoconstriction of arterioles with intact endothelium that was evident at 1 µmol/l and maximal at 50 µmol/l. Because tissue contents of CO were reported to be 1-50 pmol/mg fresh weight (23), which roughly translates to 1-50 µmol/l, it appears that CO can affect NO synthase activity at "physiological" concentrations.
It also appears that the inhibitory effect of CO on endothelial NO synthase may become more pronounced during certain pathophysiological conditions when heme oxygenase expression and/or endogenous CO formation is increased. Specifically, induction of heme oxygenase-1 has been shown to attenuate muscarinic agonist-induced NO release (21) and vasodilation (7) in isolated renal resistance vessels. We recently reported that vascular heme oxygenase-1 levels were increased in Dahl-Rapp salt-sensitive rats with salt-induced hypertension (5). Skeletal muscle arterioles isolated from these hypertensive rats showed abolished endothelium-dependent vasodilatory responses, which were completely restored by acute in vitro treatment with an inhibitor of endogenous CO formation (5). Therefore, it appears that endogenous levels of CO are able to inhibit endothelial NO synthase activity under physiological conditions, but this inhibitory effect becomes more severe during certain pathophysiological conditions when endogenous CO formation is increased.
In summary, our data show that, in isolated gracilis muscle arterioles with
intact endothelium, CO and a heme synthesis precursor, -ALA, promote
endothelium-dependent vasoconstriction. In arterioles pretreated with an
inhibitor of NO synthase, as well as in arterioles pretreated with an
inhibitor of NO synthase and an NO donor, CO promotes vasodilation.
Furthermore, pretreatment with the NO synthase substrate abolishes CO-induced
vasoconstriction. These data suggest that, in isolated arterioles, exogenous
and endogenously formed CO can promote endothelium-dependent vasoconstriction,
most likely by inhibiting endothelial NO synthesis.
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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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P < 0.05 relative to
control (before 