(Hypertension. 1996;27:228-234.)
© 1996 American Heart Association, Inc.
Articles |
Indigo Carmine Inhibits Endothelium-Dependent and -Independent Vasodilation
From the Department of Anesthesiology, Oregon Health Sciences University and Anesthesiology Service, Veterans Affairs Medical Center, Portland, Ore.
Correspondence to Kyoung S.K. Chang, MD, PhD, Department of Anesthesiology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201. E-mail changk@ohsu.edu.
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Abstract |
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Abstract To investigate the potential mechanisms by which indigo carmine produces hypertension, we tested the hypothesis that indigo carmine inhibits endothelium-dependent vasodilation and determined the possible site of the inhibition (endothelium versus smooth muscle). Using isolated rat thoracic aortic rings that were precontracted with phenylephrine, we examined vasodilatory responses to acetylcholine, histamine, and Ca2+ ionophore A23187 (in endothelium-intact rings) and sodium nitroprusside and isoproterenol (in endothelium-denuded rings) in the presence and absence of indigo carmine. In addition, the effects of methylene blue on the acetylcholine- and sodium nitroprusside–induced vasodilation were compared with those of indigo carmine. Indigo carmine (10-6, 10-5, and 10-4 mol/L) significantly inhibited receptor- and non–receptor-mediated endothelium-dependent vasorelaxation. Indigo carmine (10-4 mol/L) also inhibited endothelium-independent vasorelaxation induced by sodium nitroprusside (an activator of vascular smooth muscle soluble guanylyl cyclase), although to a lesser extent than vasodilation from acetylcholine, histamine, and Ca2+ ionophore A23187. In contrast, indigo carmine (10-4 mol/L) had no effect on the vasodilation induced by isoproterenol (an activator of adenylyl cyclase), indicating that indigo carmine selectively inhibits nitric oxide–mediated responses. Methylene blue, a known inhibitor of soluble guanylyl cyclase, inhibited both acetylcholine- and sodium nitroprusside–induced vasorelaxation. The inhibition was also greater in the acetylcholine- than the sodium nitroprusside–induced vasodilation. These results suggest that indigo carmine, like methylene blue, may inhibit endothelium-dependent relaxation by a mechanism that involves two levels. The major action of indigo carmine appears to be at the level of nitric oxide generation and/or release from the endothelial cell. In addition, indigo carmine appears to inhibit vascular smooth muscle guanylyl cyclase. Thus, indigo carmine may elevate blood pressure by interfering with these nitric oxide–mediated vasodilatory mechanisms.
Key Words: acetylcholine • aorta • endothelium-derived factor • indigo carmine • nitroprusside • rats • vasodilation
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Indigo carmine (sodium indigotin disulfonate), a blue dye that is often administered intravenously to determine patency of the urinary collecting system, has been reported to cause mild to severe hypertension in some patients.1 2 3 4 The hypertension associated with IC was attributed to an increase in total peripheral resistance either due to direct activation of
-adrenergic receptors or indirectly through the release of
catecholamines.1 4 In addition, IC may have
serotonin-like effects as a result of its structural
similarity to serotonin.3 Vascular endothelium plays an important role in the regulation of vascular smooth muscle tone by releasing vasodilatory and/or vasoconstricting substances.5 6 One of the most powerful substances released from endothelium is EDRF, now identified as NO.7 8 NO plays a major role in maintaining resting vascular tone, and lack of NO production has been implicated as a cause of vasospasm and hypertension.6 NO is released under basal conditions and in response to a wide range of vasodilators.9 10 Inhibition of NO synthesis increases blood pressure.11 Thus, IC may elevate blood pressure by interfering with these NO-mediated vasodilatory mechanisms. NO is produced in endothelial cells from the amino acid L-arginine by a constitutive enzyme, NO synthase, which is Ca2+-, calmodulin-, and NADPH-dependent.12 Intracellular free Ca2+ concentration is probably the major factor involved in the activation of NO synthase in endothelial cells.13 14 Intracellular Ca2+ can be increased in the endothelial cells by agonist-receptor interaction through both extracellular Ca2+ influx and Ca2+ release from intracellular stores (eg, ACh, histamine) or by nonreceptor mechanisms that involve direct Ca2+ transport through the cell membrane (eg, Ca2+ ionophore A23187).15 16 17 18 NO thus formed in endothelial cells causes vasodilation by stimulating vascular smooth muscle soluble guanylyl cyclase and elevating cGMP levels.19 Inhibition of any site in this L-arginine–NO–guanylyl cyclase pathway can cause an impairment of endothelium-dependent vasodilation and hypertension. The goals of the present study were (1) to examine whether IC inhibits endothelium-dependent vasodilation and (2) to determine whether the site of the inhibition is at the endothelium or at the vascular smooth muscle soluble guanylyl cyclase level. We attempted to answer these questions by using endothelium-dependent (ACh, histamine, A23187) and endothelium-independent (SNP) vasodilators. Further, by using different receptor- and non-receptor–activating agents, we tested whether the inhibition involves specific endothelial receptors or is distal to receptor sites.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The protocol was approved by the Institutional Animal Care and Use Committee of the Oregon Health Sciences University. The method used for the in vitro study of rat thoracic aortic rings has been described in detail.20 Briefly, thoracic aorta was removed from male Sprague-Dawley rats (body weight, 250 to 300 g; Simonsen Laboratories, Gilroy, Calif) that were anesthetized with isoflurane. Rings approximately 3 mm wide were then cut, mounted between two stainless steel wires, and placed in a 20-mL organ bath containing a modified K-H solution of the following composition (mmol/L): KCl 4.75, KH2PO4 1.19, MgSO4 1.19, CaCl2 1.25, NaCl 119, NaHCO3 25, and glucose 11, pH 7.4. The solution was continuously aerated with a gas mixture of 95% O2/5% CO2 and maintained at 37°C. Rings were equilibrated for 60 to 90 minutes with resting tension of 2 g. Preliminary length-tension experiments suggested that 2 g was the optimal resting tension for these vessels. Isometric tensions were recorded with force-displacement transducers (model FT 03, Grass Instruments) and recorded on a polygraph (model 7, Grass Instruments). Some of the rings were denuded of endothelium according to the protocol. The endothelium was removed by insertion of a small forceps into the lumen of the ring and gentle rolling of the ring for a few seconds. Three to four rings from the same aorta were studied simultaneously. Since for each experimental condition only one ring was used from each animal, the numbers of experiments (n) and the numbers of animals used are the same. A total of 75 animals were used.
Concentration Responses of Endothelium-Dependent
and -Independent Vasodilators in the Presence of IC
After 60 to 90
minutes of equilibration, active tone was induced
with EC50 of phenylephrine as determined
previously (10-7 mol/L for
endothelium-intact rings and
5x10-8 mol/L for
endothelium-denuded rings).21 22
The functional integrity of endothelium was confirmed
by observation of a minimum of 40% relaxation in response to ACh
10-5 mol/L. Lack of relaxation in
response to ACh in the denuded preparation was taken to indicate
effective functional removal of endothelium. After ACh
testing, the bathing solution was changed several times until tension
returned to the baseline 2-g resting tension.
To determine the site(s) of IC inhibition in the NO-dependent vasodilatory cascade, the relaxation responses to various endothelium-dependent and endothelium-independent vasodilators were tested in the presence and absence of IC.
Endothelium-dependent vasodilation. Rings with intact endothelium were contracted submaximally as before with EC50 of phenylephrine. ACh (10-8 to 10-4 mol/L) or histamine (10-7 to 10-3 mol/L) was then added to the bath to obtain control cumulative concentration-relaxation response curves. After control curves for these vasodilators in the individual rings were obtained, the rings were treated with either a single concentration of IC (10-6, 10-5, or 10-4 mol/L) or an equal volume of added distilled water (time control) for 10 minutes. The experiment was repeated to obtain second concentration-response curves for these vasodilators in the presence of IC or vehicle. The rings were then washed several times with normal K-H solution for 60 to 90 minutes until the tension returned to the baseline 2-g resting tension. The third concentration-relaxation response curves were obtained to determine whether the preparation had recovered from the exposure of IC. In each experiment, one ring was designated as a time control throughout all the experimental protocol, thus confirming the stability of vasodilatory responses to ACh or histamine and contractile responses to phenylephrine. In the case of A23187 (10-8 to 3x10-6 mol/L), our preliminary experiments demonstrated that the preparation did not fully recover from A23187 treatment even with extensive washings (up to 2 hours). Therefore, the first control dose response for A23187 before IC treatment was not obtained. From the beginning, one ring was used as control and other rings were treated with various concentrations of IC (10-6, 10-5, and 10-4 mol/L). In separate experiments, to rule out possible involvement of prostacyclin and other prostanoid-mediated responses by some of the vasodilators used (eg, ACh), aortic rings with intact endothelium were studied in K-H solution containing indomethacin 10-5 mol/L, an inhibitor of cyclooxygenase.23
Endothelium-independent vasodilation. The same protocol described for ACh and histamine as above were used to study responses in endothelium-denuded rings. In this experiment, the vasodilatory responses to SNP (10-9 to 10-7 mol/L) and isoproterenol (10-8 to 10-5 mol/L) were studied with and without IC.
Effect of methylene blue on endothelium-dependent and endothelium-independent vasodilation. To compare the effects of IC with those of methylene blue, rings with and without endothelium were incubated with methylene blue (10-6 and 10-5 mol/L) for 10 minutes. The rest of the protocol was the same as above.
Drugs
The following drugs were used: ACh chloride,
L-phenylephrine hydrochloride,
indomethacin, histamine, (-)isoproterenol, IC,
methylene blue, SNP, Ca2+ ionophore A23187, and DMSO. All
drugs were purchased from Sigma Chemical Co and prepared in distilled
water just before use except for indomethacin and
A23187, which were dissolved in absolute ethanol and DMSO,
respectively. The stock solutions of indomethacin and
A23187 in ethanol and in DMSO were diluted with distilled water. Final
bath concentrations of vehicles (ethanol and DMSO), at concentrations
of 0.0001% to 0.01%, did not produce a measurable response during
preliminary testing in aortic rings with and without
endothelium.
Data Analysis
Relaxation responses produced with increasing
concentrations of
various vasodilators were expressed as the percentage relaxation from
the contractile state elicited by EC50 of
phenylephrine. All data are expressed as mean±SEM.
Statistical analysis of the data was performed with one-way
ANOVA between experimental groups (eg, comparison between responses
from IC–treated rings and those of appropriate time control). When
three or more groups of data were compared, significant differences
were determined by the Scheffé F test. Data analysis
within groups (eg, comparison between before and after IC treatment
within each group) were performed with ANOVA for repeated measures.
P<.05 was considered statistically significant.
All statistical analyses were performed with StatView 11 software (Abacus Concepts Inc).
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Tension Evoked by Phenylephrine and IC
Because the response to phenylephrine was increased (without a change in maximal contraction) in endothelium-denuded rings relative to endothelium-intact rings,21 22 EC50 of phenylephrine was chosen to precontract the preparations (10-7 mol/L for endothelium-intact rings and 5x10-8 mol/L for endothelium-denuded rings) (Table 1
). Thus, a similar baseline
tension was obtained with
phenylephrine in all groups of rings before IC treatment
whether endothelium was intact or removed (Table 1).
Also, there was no significant difference in the
phenylephrine-evoked baseline tone within each
experimental group of rings before and after treatment with IC except
in rings with intact endothelium that were treated with
10-4 mol/L (Table 1). Under the latter
conditions, the phenylephrine response was significantly
enhanced. In this case, the concentration of phenylephrine
was decreased to 3x10-8 mol/L to match a
tension developed by phenylephrine before IC treatment
(1450±145 mg). IC itself caused small but significant contraction both
in endothelium-intact and
endothelium-denuded rings (
3% to 6% of 1.2- to
1.3-g tension evoked by EC50 of phenylephrine
in endothelium-intact rings), which was
greater in the endothelium-intact rings (Table 2). The
contraction occurred at
10-5 mol/L in
endothelium-intact rings and at
10-4 mol/L in
endothelium-denuded rings.
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Endothelium-Dependent Vasodilation
In aortic rings with
intact endothelium
precontracted with phenylephrine, ACh and
histamine produced concentration-dependent relaxations (Figs 1
and 2) that were similar among all
experimental groups of rings before IC treatment (time-control
rings and rings to be treated) (Figs 1A and 2A).
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IC 10-5 and
10-4 mol/L significantly inhibited
vasodilation induced by ACh and histamine with a shift of
dose-response curves to the right and downward (Figs 1B
and
2B). IC
10-6 mol/L inhibited vasodilation induced
by low concentrations (3x10-7 and
10-6 mol/L for ACh and
10-5 and
10-4 mol/L for histamine) without
affecting responses to high concentrations of these agents (Figs
1B and 2B). Responses to ACh and histamine
completely recovered from IC after
the washout procedures (Figs 1C and 2C).
Time-control responses to
ACh and histamine (first, second, and third times) were stable (Figs
1D and 2D). Since time-control responses to ACh
or histamine during IC
exposure were not different from pre–IC responses to these agents,
comparisons were made between appropriate time-control and
IC–treated groups unless otherwise stated.
Vasodilation induced
by the non–receptor-mediated
endothelium-dependent agent A23187
(10-8 to
3x10-6 mol/L) was also significantly
inhibited by IC at concentrations of 10-5
and 10-4 mol/L, with lesser inhibition
with 10-6 mol/L (Fig 3A).
Once the preparation was exposed to A23187, responses were diminished
to 30% to 40% of the original response despite extensive washings.
Nevertheless, complete recovery from the IC effect still can be seen
(Fig 3B).
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Indomethacin had no effect on the inhibition of ACh-induced vasodilation by IC (data not shown).
Endothelium-Independent Vasodilation
SNP produced a
dose-dependent vasodilation that was similar
among the experimental groups of rings before IC treatment (Fig
4A). IC inhibited the SNP-induced vasodilation to a
lesser extent than vasodilation to ACh, histamine, or A23187 (Fig
4B).
Whereas low concentrations of IC (10-6
and 10-5 mol/L) had no effect on the
SNP-induced vasodilation, high concentrations
(10-4 mol/L) caused significant
inhibition. SNP responses completely recovered from IC exposure after
the washout (Fig 4C). Time-control responses to SNP were stable
(Fig 4D). IC had no effect on the isoproterenol-induced
endothelium-independent vasodilation (Fig 5).
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Effect of Methylene Blue on ACh- and SNP-Induced
Vasodilation
Methylene blue inhibited both vasodilation induced by ACh
and that
induced by SNP (Fig 6A and 6B). Methylene blue
had much
less effect on SNP-induced than on ACh-induced vasodilation.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The principal finding of this study is that IC inhibits NO-mediated endothelium-dependent and -independent vasodilation in rat aortic vascular smooth muscle. IC inhibited both receptor- and non–receptor-mediated endothelium-dependent vasodilation induced by ACh, histamine, and A23187 and endothelium-independent vasodilation induced by SNP. Agents like ACh, histamine, and A23187 produce vasodilation through the endothelial synthesis and release of NO, which activates vascular smooth muscle soluble guanylyl cyclase to produce an increase of cGMP concentration.15 16 19 SNP produces vasodilation by activation of soluble guanylyl cyclase after its breakdown to NO.24 Thus, the site of action for NO is soluble guanylyl cyclase, whether it is released endogenously from endothelial cell activation by receptor-mediated (ACh, histamine) or non–receptor-mediated (A23187) agents or is produced intracellularly in the smooth muscle cells from metabolism of the nitrovasodilator SNP.24 Our findings that IC had less influence on SNP than on the endothelium-mediated agents ACh, histamine, and A23187 suggest that IC may have a predominantly inhibitory action on the NO-generating and/or NO-releasing mechanisms in the endothelium, with a minor action at the level of vascular smooth muscle guanylyl cyclase. Although our present results suggest the major site of action on the endothelium, the mechanisms by which IC elicits such an effect in the endothelium are unclear at present. On the basis of the known mechanism of NO synthesis and release, possibilities include (1) an interference with receptor activation and signal transduction, (2) a reduction of intracellular calcium availability, (3) direct inhibition of NO synthase, and (4) interactions with NO itself. NO synthesis in vascular endothelium results from an activation of constitutive NO synthase that depends primarily on the intracellular Ca2+ concentration.13 14 An increase in intracellular Ca2+ in the endothelial cells can be achieved by extracellular Ca2+ influx and/or Ca2+ release from intracellular stores. Drugs such as ACh and histamine, which act via endothelial membrane receptors, increase the intracellular Ca2+ concentration through extracellular Ca2+ influx and Ca2+ release from intracellular stores.17 18 A23187 bypasses receptor-mediated processes by directly transporting Ca2+ across the cell membrane.25 Our present results suggest that it is unlikely that IC inhibits endothelium-dependent vasodilation by interacting with specific endothelial receptors (muscarinic or histaminergic receptors), on the basis of two observations. First, the vasodilation induced by activation of two entirely different receptor systems was inhibited to a similar extent by IC. Second, the vasodilation from A23187 that bypasses receptor effects was also inhibited to a degree similar to that from the receptor-mediated agents, consistent with an inhibition distal to the receptors and intracellular Ca2+ availability. Since the SNP response was inhibited less than the ACh, histamine, and A23187 responses, the inhibition may involve sites distal to the Ca2+ availability in the endothelium and proximal to guanylyl cyclase, including NO synthase.
The inhibition by IC was similar to that of methylene blue, a known
inhibitor of soluble guanylyl cyclase. Methylene blue
inhibits both ACh- and nitrovasodilator-induced
relaxation.26 27 28 IC may have a
mechanism of action similar
to that of methylene blue. Although methylene blue is known to inhibit
a soluble guanylyl cyclase, it has been reported that methylene blue
has more potent inhibitory activity on
endothelium-dependent vasodilation than on
vasodilation induced by
nitrovasodilators.26 27 28 The latter
observations are consistent with the results of our present
study (Fig 6). Methylene blue can inactivate NO via
superoxide generation29 and also acts as a direct
inhibitor of NO synthase.30 31 These
additional actions of methylene blue on the inhibition of NO synthesis
and NO destruction may explain the greater inhibitory
action on ACh-induced vasodilation than on SNP-induced
vasodilation. Methylene blue can affect iron-containing
enzymes,32 easily oxidizing ferrous hemoprotein to the
ferric form.33 The mechanism of inhibition of guanylyl
cyclase, an iron-containing enzyme, by methylene blue may involve
oxidation of the hemoprotein linked to guanylyl cyclase.34
Recently, it was reported that NO synthase is a cytochrome P-450–type
hemoprotein.35 Thus, NO synthase may also be inhibited by
methylene blue oxidation of hemoprotein. IC, as an electron mediator,
can oxidize or reduce iron-containing enzymes.36 Thus,
it is possible that IC, like methylene blue, may act on the hemoprotein
of soluble guanylyl cyclase and NO synthase, resulting in an
inactivation of both enzymes. It is unknown, however, whether IC, like
methylene blue, can generate superoxide radicals that destroy NO. On
the basis of its known redox properties,36 IC, like
methylene blue, may generate superoxide radicals during its
auto-oxidation. Our observations that the inhibition by IC was
promptly reversed suggests a direct chemical interaction with NO as a
major mechanism rather than an enzyme inhibition, which would be
expected to last longer.
Although the endothelium releases two major vasodilators, NO and prostacyclin, our present ACh results indicate that IC does not affect the prostacyclin-mediated vasodilation, since the inhibition of ACh-induced vasodilation by IC was still present after the cyclooxygenase activity was blocked by indomethacin. This view was further supported by the observation that the concentration of IC (10-4 mol/L) that inhibited the vasodilation induced by SNP, an activator of soluble guanylyl cyclase, had no effect on the vasodilation induced by isoproterenol, an activator of adenylyl cyclase. This suggests that IC selectively inhibits NO-mediated vasodilation.
IC itself caused small but significant contractions, which were greater
with an intact endothelium (Table 2). This may be due
in part to inhibition of the effects of spontaneously released NO by
IC. In addition, IC augmented phenylephrine-evoked tone
in aortic rings containing endothelium (Table 1). This
supports the view that IC inhibits basal release of NO from
endothelium in addition to the release of NO by
receptor- and non–receptor-mediated
endothelium-dependent vasodilators. Basal release
of NO modulates the contractile responses to many vasoconstrictors,
including phenylephrine.10 Although IC caused
a greater contraction in rings containing endothelium,
it also caused a slight contraction in rings of aorta lacking
endothelial cells. This may be due to direct
-adrenergic receptor stimulation or indirect release of
catecholamines, as was previously suggested for
IC,4 and/or to blockade of basal unstimulated guanylyl
cyclase activity if IC can enter cells. In the present study,
methylene blue, like IC, produced a contraction that was greater in
endothelium-containing rings than in
endothelium-absent rings, consistent with
observations by others.27 37
Low concentrations of IC that inhibit the endothelium-dependent relaxation by ACh, histamine, and A23187 are within the range clinically used (10-6 and 10-5 mol/L; 0.46 and 4.6 µg/mL). Methylene blue, which inhibits both soluble guanylyl cyclase and NO synthase, has been shown to cause a short-lived hypertension in a dose-dependent manner in the rat model.38 Inhibition of NO synthase with NG-monomethyl-L-arginine also causes an increase in blood pressure.11 Although we cannot extrapolate in vitro data directly to in vivo conditions, hypertension associated with intravenous administration of IC is consistent with inhibitory actions on NO-generating mechanisms. High concentrations of IC (10-4 mol/L; 46 µg/mL) also inhibit SNP-induced relaxation. However, such high concentrations are not likely during the clinical administration of IC.
In summary, IC inhibits endothelium-dependent vasorelaxation induced by ACh, histamine, and A23187 and endothelium-independent vasorelaxation induced by SNP in rings of rat aorta. The inhibition was selective for agents that produce vasorelaxation in association with NO production and a rise in cGMP. Cyclooxygenase activity does not appear to contribute. IC has significantly less inhibitory effect with SNP vasodilation than with endothelium-dependent vasodilation by ACh, histamine, and A23187, indicating that IC may inhibit the NO-generating mechanism in the endothelium more than soluble guanylyl cyclase activity. The site of the inhibitory effect on endothelial NO production is probably distal to plasma membrane receptors and cytosolic Ca2+ availability. Therefore, the most likely site of action is at the NO synthase and/or NO stability level. The possibility that IC produces its inhibitory effects on endothelium-dependent vasorelaxation by interfering with NO synthase (and/or NO destruction) and soluble guanylyl cyclase warrants further investigation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by the American Heart Association, Oregon Affiliate, and by the Medical Research Foundation of Oregon. We thank John Hromco for his technical assistance and Becki Stephenson for her secretarial assistance.
Received June 20, 1995; first decision August 22, 1995; accepted November 14, 1995.
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TopAbstractIntroductionMethods Results Discussion References |
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