(Hypertension. 1996;27:1346-1352.)
© 1996 American Heart Association, Inc.
Articles |
Carbenoxolone Damages Endothelium and Enhances Vasoconstrictor Action in Aortic Rings
From the Departments of Medicine (M.E.U., L.G.W., R.K.D., B.M.E.), Pathology (D.J.H.-M.), and Pharmacology (B.M.E.), Medical University of South Carolina and Ralph H. Johnson Veterans Administration Hospital, Charleston.
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Abstract |
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Abstract Carbenoxolone causes hypertension indirectly by inhibition of 11ß-hydroxysteroid dehydrogenase and consequent elevation of intracellular glucocorticoid levels and enhancement of vasoconstrictor action. We performed the present study to determine whether carbenoxolone also enhances vascular tone directly by mechanisms independent of glucocorticoids and other systemic influences. Exposure of rat aortic rings to 10 to 100 µmol/L carbenoxolone in aerated Krebs-Henseleit buffer for 24 hours resulted in concentration-dependent increases in angiotensin II (Ang II) (100 nmol/L)–stimulated contractions and significant shifting of the phenylephrine cumulative contraction curve to the left but not increases in KCl (120 mmol/L)–stimulated contractions. Maximal enhancement of Ang II contraction was 39%. In contrast, brief (15-minute) exposure to 100 µmol/L carbenoxolone did not alter Ang II contractions. Mechanical denudation of the endothelium obviated enhancement of Ang II contractions by carbenoxolone, suggesting interaction of carbenoxolone with the endothelium. Endothelium-dependent relaxation of precontracted rings to acetylcholine or ATP was reduced by more than 90% by 24-hour pretreatment with 100 µmol/L carbenoxolone but not with 100 µmol/L deoxycorticosterone acetate (a mineralocorticoid) or 100 µmol/L glycyrrhizic acid (a natural 11ß-hydroxysteroid dehydrogenase inhibitor). Vascular smooth muscle relaxation with sodium nitroprusside was not inhibited by carbenoxolone. Incubation of cultured endothelial cells with 100 µmol/L carbenoxolone for 24 hours did not inhibit nitric oxide synthase activity, as measured by conversion of [3H]L-arginine to [3H]L-citrulline. Electron micrography demonstrated that endothelial cell ultrastructure but not vascular smooth muscle cell ultrastructure was abnormal after incubation of rings for 24 hours with 100 µmol/L carbenoxolone. These studies suggest that carbenoxolone concentrations higher than 10 µmol/L enhance vasoconstrictor action via selective toxicity to the endothelium and elimination of endothelium-dependent relaxation.
Key Words: carbenoxolone • endothelium • muscle, smooth, vascular • vasoconstriction • receptors, adrenergic • angiotensin II
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Introduction |
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Compounds that inhibit the enzyme 11ß-hydroxysteroid dehydrogenase cause hypertension. These include glycyrrhizic acid and glycyrrhetinic acid, natural compounds found in licorice and tobacco, and carbenoxolone, the semisynthetic hemisuccinate derivative of glycyrrhetinic acid. Carbenoxolone has been used as a treatment for peptic ulcer disease. It has been hypothesized that 11ß-hydroxysteroid dehydrogenase allows certain tissues to be mineralocorticoid targets.1 Although type 1 adrenocorticosteroid receptors have equal binding affinity for the glucocorticoid cortisol and the mineralocorticoid aldosterone and although circulating glucocorticoid concentrations exceed circulating mineralocorticoid concentrations by 1000-fold, glucocorticoids (but not mineralocorticoids) are metabolized to less active compounds by 11ß-hydroxysteroid dehydrogenase in certain tissues such as the kidney. Consequently, mineralocorticoids can gain access to type 1 receptors. In the setting of 11ß-hydroxysteroid dehydrogenase inhibition, however, glucocorticoids may flood type 1 receptors and result in excess sodium reabsorption, expansion of extracellular fluid volume, and hypertension.
Although it contains less than the kidney, the vasculature also contains 11ß-hydroxysteroid dehydrogenase.2 3 Since glucocorticoids potentiate vascular constrictor responses to a number of pressor hormones such as norepinephrine and angiotensin II (Ang II),4 5 6 7 it is possible that inhibition of 11ß-hydroxysteroid dehydrogenase results in increased glucocorticoid levels in vascular smooth muscle and further potentiation of vasoconstrictor action. In fact, oral treatment with carbenoxolone or skin treatment with glycyrrhetinic acid resulted in increased dermal constriction to endogenous pressors, and carbenoxolone treatment resulted in increased blood pressure responses and heightened forearm blood flow reductions to exogenous norepinephrine.8 9
Recent studies have suggested that carbenoxolone may alter vascular tone by mechanisms independent of 11ß-hydroxysteroid dehydrogenase or glucocorticoid levels. Short-term exposure of aortic rings to carbenoxolone resulted in alterations in endothelium-dependent relaxation,10 and carbenoxolone treatment of aortic rings from adrenalectomized animals (which lack circulating corticosteroids) resulted in potentiation of norepinephrine-stimulated vasoconstriction.11 Therefore, we hypothesized that carbenoxolone, in addition to its indirect enhancement of vascular smooth muscle tone via alterations in glucocorticoid metabolism, directly enhances vascular responses to pressor hormones via attenuation of endothelium-dependent relaxation. We performed contraction studies after exposure of endothelium-denuded and endothelium-intact rings to carbenoxolone ex vivo. We used this ex vivo experimental system to avoid secondary systemic effects of carbenoxolone.
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Methods |
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Aortic Ring Contractions
Aortic ring segments were obtained from Sprague-Dawley rats by procedures approved by the Institutional Animal Care and Utilization Committee of the Medical University of South Carolina. Thoracic aortas were cleaned of fat and adventitia and cut into rings 5 mm in length. Rings were treated with the desired agents for the desired time periods in Krebs-Henseleit bicarbonate buffer bubbled with 95% O2/5% CO2 to pH 7.4 at room temperature in an Erlenmeyer flask. Rings were then attached to an isometric force-displacement transducer under 2 g of tension and equilibrated for 1 hour in the same buffer at 37°C. Effectors and inhibitors in 10-µL volumes were added simultaneously to control and experimental rings in side-by-side 10-mL organ chambers to achieve the desired final concentrations. Cumulative contractions to phenylephrine were achieved by administration of increasing concentrations of phenylephrine when the contraction from the previous concentration had plateaued. Contraction intensity was expressed as grams tension per milligram dry weight of aorta. Maintenance of vascular segments ex vivo for prolonged periods of time has been described previously.12 13
Nitric Oxide Synthase Activity
Confluent endothelial cells in triplicate in 12-
or 24-well plates were washed twice with phosphate-buffered saline
and then exposed to 1 mL of [3H]L-arginine (3
µCi/mL) for 20 minutes. Reactions were terminated after various
stimulations by washing cells with ice-cold calcium-free buffer
containing 5 mmol/L EDTA and adding 1 mL of 0.3 mol/L perchloric acid.
Nitric oxide (NO) synthase activity was measured as the conversion of
[3H]L-arginine to
[3H]L-citrulline after separation of these
amino acids by ion-exchange chromatography.
Vascular Ultrastructure
Aortic rings were fixed in 2.5% glutaraldehyde
in phosphate-buffered saline for 1.5 hours after the desired
treatment. After fixation, rings were rinsed in phosphate-buffered
saline and post-fixed in 2% aqueous osmium tetroxide. The rings
were then rinsed in distilled water, dehydrated in a graded series of
ethanols, cleared in propylene oxide, and infiltrated and embedded in
Embed 812. Half-micron-thick sections were obtained and stained
in toluidine blue for evaluation. Representative areas
were used to obtain 70-nm-thin sections that were stained with
uranyl acetate and lead citrate. Micrographs of thin section profiles
were obtained with an electron microscope (JEOL 100S).
Materials
All chemicals and reagents were obtained from Sigma Chemical Co
except the following: [3H]L-arginine (New
England Nuclear), rats (Harlan Sprague Dawley, Indianapolis, Ind),
ion-exchange resin (Bio-Rad), Ang II (Peninsula Laboratories),
Embed 812 (EM Sciences), and pulmonary artery
endothelial cells (American Type Culture Collection).
Aortic endothelial cells were kindly provided by Dr
W.C. O'Neill, Emory University School of Medicine, Atlanta, Ga.
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Results |
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Effects on Vasoconstrictor Action
Ring contraction studies were performed after rings had been exposed to carbenoxolone ex vivo. As demonstrated in Fig 1
, exposure of rings to 100 µmol/L carbenoxolone for
24 hours resulted in significant enhancement of contractions to 100
nmol/L Ang II (39% greater than control) but no enhancement of KCl
contractions. Incubation with 50 µmol/L carbenoxolone also enhanced
Ang II contractions (0.34±0.13 [control] versus 0.73±0.09
[carbenoxolone] g tension/mg dry aortic weight, n=4,
P<.01), but 10 µmol/L carbenoxolone was ineffective
(0.58±0.12 [control] versus 0.53±0.08 [carbenoxolone], n=4,
P=NS). Fifteen-minute exposure of rings to 100 µmol/L
carbenoxolone did not increase contractile responses to 100 nmol/L Ang
II (0.39±0.11 [control] versus 0.25±0.08 [carbenoxolone], n=4).
To determine whether the effect of carbenoxolone on vascular reactivity
was specific for Ang II, we repeated studies with the
1-adrenergic agonist phenylephrine. Unlike
Ang II, whose contractions desensitize on repeated
exposure,14 phenylephrine can be repetitively
administered to generate cumulative contraction curves. Exposure of
rings ex vivo to 0 or 100 µmol/L carbenoxolone for 24 hours resulted
in maximal contractions (to 10 µmol/L phenylephrine) that
were not different (1.52±0.30 [control] versus 1.71±0.21
[carbenoxolone], P=NS). However, carbenoxolone
significantly potentiated phenylephrine contractions (ie,
shifted the cumulative contraction curve to the left) (Fig 2). In summary, these studies demonstrate that prolonged
incubations with carbenoxolone concentrations higher than 10 µmol/L
result in enhanced vasoconstriction to at least two distinct pressor
hormones.
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Role of Endothelium
Since a previous study suggested that carbenoxolone affected
endothelial cell function,10 we performed
studies to determine whether carbenoxolone would enhance Ang II
contractions in the absence of endothelium. After rings
were exposed to 0 or 100 µmol/L carbenoxolone for 24 hours,
endothelium was removed from all rings with a
cotton-tipped applicator. Absence of endothelium
was confirmed by assessing the degree of relaxation to 1 µmol/L
acetylcholine (an agent that causes release of NO from
endothelial cells) after precontraction with 1 µmol/L
phenylephrine. In both control and
carbenoxolone-treated rings, acetylcholine-mediated relaxation
was less than 10% after physical manipulation of
endothelium. In contrast to the results of experiments
with intact endothelium, carbenoxolone did not enhance
Ang II contractions in the absence of endothelium
(0.60±0.07 [control] versus 0.56±0.05 [carbenoxolone] g
tension/mg dry aortic weight, n=7, P=NS). It should be noted
that Ang II contractions tended to be greater in the absence of
endothelium than in its presence.
Since enhancement of Ang II–stimulated contractions by carbenoxolone
was not observed after endothelium was removed, the
effects of carbenoxolone on endothelium-dependent
relaxation were investigated. Fig 3 shows a
representative tracing of contractions and relaxations
of rings from a single aorta treated with 0 or 100 µmol/L
carbenoxolone for 24 hours ex vivo. Contractions to 100 nmol/L Ang II
but not to 120 mmol/L KCl were greater in carbenoxolone-treated
rings than in control rings, as demonstrated in Fig 1
.
Endothelium-dependent relaxation (to 1 µmol/L
acetylcholine and to 100 µmol/L ATP) from
phenylephrine-mediated precontraction was greater than
80% in the control rings but less than 10% in the treated rings. Fig 4 summarizes these data from rings from a number of
rats. Fig 5 demonstrates that loss of
endothelium-dependent relaxation was concentration
dependent from 10 to 100 µmol/L carbenoxolone. For determination of
whether carbenoxolone affected the ability of vascular smooth muscle to
relax, rings treated with 0 or 100 µmol/L carbenoxolone for 24 hours
were precontracted with 1 µmol/L phenylephrine and then
exposed to 100 µmol/L sodium nitroprusside, an agent that elaborates
NO in vascular smooth muscle. Relaxation to sodium nitroprusside was
greater than 90% in both groups of rings (data not shown).
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To determine whether the loss of
endothelium-dependent relaxation after incubation
with carbenoxolone could be related to depletion of the substrate for
NO synthase, we repeated some of the studies described above in the
presence of the NO precursor L-arginine. Rings were
incubated with 0 or 10 mmol/L L-arginine for 1 hour before
the addition of 100 µmol/L carbenoxolone for an additional 24 hours.
Fig 6 demonstrates that preincubation with
L-arginine prevented a portion of
carbenoxolone-mediated loss of
endothelium-dependent relaxation.
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Since the triterpenoid carbenoxolone is similar in structure to steroid hormones, we performed studies to determine whether other triterpenoids or adrenocorticosteroid hormones also inhibit endothelium-dependent relaxation. We were unable to dissolve glycyrrhetinic acid in buffer at the desired concentrations and therefore were unable to evaluate its effects. Incubation with either the mineralocorticoid deoxycorticosterone acetate or the naturally occurring triterpenoid glycyrrhizic acid at 100 µmol/L for 24 hours did not significantly inhibit relaxation of precontracted rings to 1 µmol/L acetylcholine (71±5% [control] versus 70±6% [glycyrrhizic acid] versus 53±7% [deoxycorticosterone acetate], n=5, P=NS).
We performed an additional study to determine whether inhibition of endothelium-dependent relaxation by an agent different from carbenoxolone would also enhance Ang II contractions. Rings were incubated for 15 minutes with 0 or 100 µmol/L of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), and contractions to 100 nmol/L Ang II were measured. L-NAME treatment, like carbenoxolone treatment, enhanced Ang II contractions (0.45±0.11 [control] versus 0.87±0.11 [L-NAME] g tension/mg dry aortic weight, P<.01 by paired t test).
Effects on NO Synthase Activity
The results described above are consistent with the
possibility that endothelial cell function but not
vascular smooth muscle cell function is impaired by carbenoxolone.
Therefore, we performed studies to determine the effect of
carbenoxolone on NO synthase activity. Confluent bovine
pulmonary artery endothelial cells and bovine
aortic endothelial cells were treated with 0 or 100
µmol/L carbenoxolone for 24 hours. Then, conversion of
[3H]L-arginine to
[3H]L-citrulline as a measure of NO synthase
activity was determined in the basal state and in response to ionomycin
(maximal) and ATP (receptor-mediated). After 24-hour treatment with
carbenoxolone, endothelial cells in culture were not
grossly altered by carbenoxolone, as assessed by visual inspection. NO
synthase activity was stimulated by ATP and ionomycin, but this
stimulation was similar in control and carbenoxolone-treated cells
(Fig 7).
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Effects on Endothelial Ultrastructure
Although endothelial cell structure and NO
synthase activity were normal in culture, endothelial
integrity in rings exposed to carbenoxolone ex vivo may have been
compromised. Aortic rings were fixed after various treatments and time
periods ex vivo, and vascular ultrastructure was examined with electron
microscopy. Rings fixed immediately after isolation (Fig 8A) revealed intact endothelial lining
separated from smooth muscle cells and connective tissues by a
continuous basal lamina. Endothelial cells were
characterized by numerous micropinocytotic vesicles at the
plasmalemma surfaces and intact intercellular junctional
complexes. Rings treated with 100 µmol/L carbenoxolone for 24 hours
ex vivo in aerated buffer (Fig 8B) exhibited focal sites of
endothelial damage, whereas the smooth muscle
components of the rings appeared unaffected.
Endothelial cells frequently revealed damaged
mitochondrial profiles, multivesicular bodies, and secondary
lysosomes. To explore the possibility that the prolonged
aeration, independent of carbenoxolone, might have compromised
endothelial structural integrity, we examined rings
after 24 hours of ex vivo aeration in the absence of carbenoxolone (Fig 8C). These rings, like those acutely fixed (Fig 8A), revealed intact
endothelial cell lining with normal intercellular
complexes and numerous pinocytotic vesicles. Smooth muscle components
were also normal.
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Discussion |
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These studies demonstrate that prolonged exposure of blood vessels to carbenoxolone at concentrations higher than 10 µmol/L causes selective endothelial damage. Enhanced responses to vasoconstrictors, maintained relaxation to sodium nitroprusside, and normal vascular smooth muscle ultrastructure suggest that vascular smooth muscle integrity and action were not affected by 24-hour incubation with carbenoxolone. Similarly, there are clinical hypertensive states in which endothelium is selectively damaged but underlying vascular smooth muscle is not, eg, eclampsia and preeclampsia. It is unclear why 100 µmol/L carbenoxolone was toxic to endothelial cells in rings but not to endothelial cells in culture, but this fortuitous set of circumstances contributed to our eliminating NO synthase as the target of carbenoxolone action. Structural or functional changes in endothelial cells resulting from multiple passage in culture or different attachment surfaces for endothelial cells in culture and for endothelium in vivo may explain why cultured cells were more resistant to the deleterious effects of carbenoxolone. Maintained endothelium-dependent relaxation and normal endothelial ultrastructural appearance in rings aerated ex vivo for 24 hours in the absence of carbenoxolone imply that the ex vivo conditions themselves were not toxic to the endothelium. A number of reports describe toxicities of carbenoxolone,15 and a repeated theme with this drug is loss of cell membrane integrity as evidenced by acute renal tubular necrosis in patients on oral carbenoxolone therapy16 17 and membrane leakage after ex vivo exposure of leukocytes,18 hepatic lysosomes,19 and artificial lecithin:cholesterol liposomes20 to 10 to 100 µmol/L carbenoxolone. It should be noted that the concentration range of carbenoxolone (10 to 100 µmol/L) that caused membrane leakage in those studies is identical to the carbenoxolone concentration range that eliminated endothelium-dependent relaxation in the present study.
The mechanisms of endothelial damage from carbenoxolone
are unknown. A single study has suggested that short-term exposure
to 100 to 300 µmol/L carbenoxolone causes release of NO from the
endothelium.10 It is possible that this
release was the earliest manifestation of carbenoxolone-mediated
endothelium toxicity, with leak of NO to the underlying
vascular smooth muscle. More prolonged carbenoxolone exposure, as in
the present study, might have resulted in enough
endothelial damage to deplete existing NO and eliminate
the ability of the endothelium to form additional NO.
Partial restoration of endothelium-dependent
relaxation with an excess of L-arginine (Fig 6) suggests
that L-arginine depletion is playing a role in the loss of
endothelium-dependent relaxation upon carbenoxolone
exposure and that endothelial damage is not total.
In a study similar to the present study, vascular segments were exposed to carbenoxolone ex vivo for assessment of the direct effects of carbenoxolone on vascular reactivity.11 However, findings similar to ours were not reported because of the following methodological differences: rings were mechanically deendothelialized before carbenoxolone exposure; carbenoxolone exposure was only 2 to 5 hours; and the carbenoxolone concentration used was 10 µmol/L, which is at the threshold for the effects observed in the present study.
The ability of carbenoxolone but not related compounds to disrupt endothelial function is of interest. It has been suggested that carbenoxolone and other triterpenoids act as corticosteroids.21 22 However, in our studies, neither the mineralocorticoid deoxycorticosterone acetate nor the triterpenoid glycyrrhizic acid significantly reduced endothelium-dependent relaxation as carbenoxolone did. Although these results appear to imply a degree of specificity for carbenoxolone among the steroids in inhibiting endothelium-dependent relaxation, cautions in interpretation are necessary. Just as glycyrrhetinic acid is a far stronger inhibitor of 11ß-hydroxysteroid dehydrogenase than glycyrrhizic acid,23 glycyrrhetinic acid may have been as efficacious as carbenoxolone in inhibiting endothelium-dependent relaxation, whereas glycyrrhizic acid was not. We could not test glycyrrhetinic acid in the present study because of lack of solubility. In addition, we did not examine endothelial ultrastructure after deoxycorticosterone acetate or glycyrrhizic acid exposure as it was after carbenoxolone exposure.
A secondary result of the present study is that contractions to Ang II are enhanced by reductions in NO production, whether this reduction is mediated by the NO synthase inhibitor L-NAME or by toxicity to endothelium. Similarly, Ang II contractions were heightened in rabbit aortic segments after physical denudation of endothelium or after treatment with NO synthase inhibitors,24 and Ang II did not cause contraction of isolated rabbit afferent arterioles unless an NO synthase inhibitor was present.25 These results suggest either that there is chronic vasodilator tone mediated by the spontaneous elaboration of NO in the vasculature or that Ang II stimulates the formation and/or release of NO. The latter possibility is strengthened by the fact that endothelial NO synthase is calcium dependent and that Ang II causes increases in intracellular calcium concentration.26 Other studies have demonstrated that NO synthase inhibition in intact animals causes hypertension that is Ang II dependent.27 28
The role of endothelial toxicity and loss of NO
elaboration in carbenoxolone-mediated hypertension is unknown at
present. Carbenoxolone may foster hypertension by multiple
mechanisms. It is possible that carbenoxolone, over a wide range of
concentrations, inhibits 11ß-hydroxysteroid dehydrogenase in
vascular smooth muscle, increases intracellular glucocorticoid
concentrations, and accentuates vasoconstrictor action. These
corticosteroids may be formed locally in the blood
vessel29 30 31 or may reach the vascular smooth muscle after
synthesis in the adrenal cortex. At concentrations of carbenoxolone
higher than 10 µmol/L, however, loss of endothelial
cell integrity and endothelium-dependent relaxation
may also contribute to increased vascular tone. If incubation of rings
with glucocorticoid (eg, corticosterone) and carbenoxolone together
were to enhance vasoconstrictor action more than incubation with
carbenoxolone alone, support for both endothelial and
smooth muscle loci of carbenoxolone action would be forthcoming.
Although cultured cells and isolated rings are extremely useful assay
systems because systemic influences can be eliminated, differences in
these isolated preparations from blood vessels in the in vivo setting
necessitate repetition of the present study after treatment of
intact animals with carbenoxolone. We will perform these studies in the
near future. Carbenoxolone concentrations that result in loss of
endothelium-dependent relaxation (Fig 5) are
relevant to blood concentrations of carbenoxolone attained in vivo. One
to 2 hours after oral ingestion of 100 mg carbenoxolone in humans, a
blood level of 20 to 30 µmol/L is attained.32 Greater
and more sustained blood levels might result from ingestion of a higher
dose or during clinical states in which protein binding or
metabolism of carbenoxolone are reduced (hypoproteinemia,
hepatic dysfunction).
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Acknowledgments |
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Support for this research was obtained from a Grant-in-Aid from the American Heart Association, South Carolina Affiliate, and a Biomedical Research Grant from the Medical University of South Carolina. Ultrastructural data were obtained with the Medical University of South Carolina Electron Microscopy University Shared Instrument Resource. The authors thank Jana J. Fine and Gregory D. Miller for expert technical assistance.
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Footnotes |
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Reprint requests to Michael E. Ullian, Medical University of South Carolina, Division of Nephrology, Clinical Sciences Building 829, 171 Ashley Ave, Charleston, SC 29425. E-mail michael_ ullian@smtpgw-musc.edu.
Received October 10, 1995; first decision November 14, 1995; accepted February 12, 1996.
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