(Hypertension. 1998;32:849-855.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Role of Nitric Oxide in Cyclosporine A–Induced Hypertension
From the Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Dr Gibson K. Oriji, Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Dr, MSC 1754, Bldg 10, Room 8C103, Bethesda, MD 20892-1754.
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Abstract |
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Abstract—Cyclosporine A (CsA) is an immunosuppressive agent that also causes hypertension. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and isolated rat aortic rings. Male rats weighing 250 to 300 g were given either CsA (25 mg · kg-1 · d-1) in olive oil or vehicle by intraperitoneal injection for 7 days. CsA administration produced a 42% increase (P<0.001) in mean arterial pressure (MAP) that reached a plateau after 3 days. Conversely, the levels of both nitrate/nitrite, metabolites of nitric oxide (NO), and cGMP, which mediates NO action, decreased by 50% (P<0.001) and 35% (P<0.001), respectively, in the urine. Thoracic aortic rings from rats treated with CsA and precontracted with endothelin (10-9 mol/L) showed a 35% increase (P<0.001) in tension, whereas endothelium-dependent relaxation induced by acetylcholine (ACh, 10-9 mol/L) was inhibited 65% (P<0.001) compared with that in untreated rats. This response was similar to that of endothelium-denuded aortic rings from untreated rats in which ACh-induced relaxation was completely abolished (P<0.001), but relaxation induced by S-nitroso-N-acetylpenicillamine (SNAP, 10-8 mol/L) was unaffected (P<0.001). ACh-induced formation of both nitrate/nitrite and cGMP by both denuded and CsA-treated aortic rings was inhibited 95% (P<0.001) and 65% (P<0.001), respectively, compared with intact aortic rings. The effects of CsA were reversed both in vivo and in vitro by pretreatment with L-arginine (10 mg · kg-1 · d-1 IP), the precursor of NO. There were no changes in MAP and tension in rats treated with L-arginine alone. In summary, CsA inhibits endothelial NO activity, with resulting increases in MAP and tension, and this inhibition can be overcome by parenteral administration of L-arginine.
Key Words: cyclosporine • arginine • endothelin • acetylcholine • nitrates • rats • aortic rings
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Introduction |
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Cyclosporine A (CsA) is a potent immunosuppressive agent that is associated with the development of arterial hypertension.1 2 Numerous articles have reported data that support many possible causes for the hypertension, but none have really clarified the mechanism.3 As a result, effective treatment of CsA-induced hypertension remains empiric.
Therefore, this study aimed to answer the following questions: (1) What vasoactive system abnormalities, if any, accompany CsA-induced hypertension in the whole animal? (2) Are similar abnormalities found in isolated aortic rings from CsA-treated animals? (3) Does direct measurement of the vasoactive substance(s) produced by the rings provide evidence of the abnormality? (4) Can CsA toxicity be overcome by administration of an agent that should remedy the abnormality? By performing complementary studies in the whole animal, isolated aortic rings, and the fluid that bathed those rings, we found that CsA toxicity is associated with an inhibition of nitric oxide (NO) activity that can be overcome by pretreatment with L-arginine (L-Arg).
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Methods |
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Animals
Male Sprague-Dawley rats weighing 250 to 300 g were housed in individual metabolic cages with free access to water and rat chow (batch 5001 from Purina Mills Inc).
Effects of CsA, L-Arg, Bosentan, and BQ-123 on Blood
Pressure
After 3 days of acclimatization, the rats were divided randomly
into 8 groups and treated with (1) CsA (25 mg/kg) in 1 mL of olive oil;
(2) olive oil (1 mL); (3) L-Arg (10 mg/kg); (4) bosentan (25 mg/kg), an
endothelin (ET)A/B receptor
antagonist; (5) BQ-123 (0.1 mg/kg), an
ETA receptor antagonist; (6) bosentan
(25 mg/kg) plus CsA (25 mg/kg); (7) BQ-123 (0.1 mg/kg) plus CsA (25
mg/kg); or (8) L-Arg (10 mg/kg) plus CsA (25 mg/kg); each drug was
given via a separate intraperitoneal injection
daily for 7 days (n=6 for each group). In a preliminary study, we found
that daily injections of CsA (25 mg/kg) produced hypertension that was
only partially prevented by injections of either BQ-123 (0.1 mg/kg) or
bosentan (25 mg/kg), whereas doses of 50 mg/kg bosentan caused
progressive toxicity with severe anorexia, weight loss, and death
(Figure 2
). Not all groups of rats were studied at the same time.
However, an appropriate control group was always studied
simultaneously with every treated group.
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Measurement of Blood Pressure
Mean arterial pressure (MAP) was measured at the
same time each day with the tail-cuff method using a model 229 Blood
Pressure Amplifier/Pump from IITC Inc.
Collection of Urine
Urine was collected into 0.2 mL of 6N-HCl for the 24-hour period
immediately after the last treatment and stored at -70°C until assay
for NO, cGMP, and prostacyclin (PGI2) or their
metabolites.
Preparation of Aortic Rings
On day 7 of treatment, rats were anesthetized by
injection of sodium pentobarbital (40 mg/kg IP), and the thoracic aorta
was removed and prepared as previously
described.4 The aortic rings were stimulated
every 20 minutes with KCl (50 mmol/L) until reproducible
contractions were obtained. All subsequent contractile responses in
each vessel were expressed as a percentage of the last contractile
response to KCl, and all data are expressed as mean±SEM.
In Vivo Effects of CsA on Tension
Aortic rings were prepared from intact rings from animals given
either CsA (n=4) or vehicle (n=6) and from either intact (n=6) or
denuded (n=4) rings from untreated rats. Later, rings were prepared
from rats given either CsA plus L-Arg or L-Arg alone (n=6 for each).
The doses of drugs or vehicle were the same as those listed above. ET
(10-9 mol/L) was added, and the rings were
allowed to contract for 120 minutes without washing out of the agonist.
Another set of rings was prepared as above, either acetylcholine (ACh;
10-9 mol/L) or
S-nitroso-N-acetylpenicillamine (SNAP;
10-8 mol/L) was added 30 minutes after the ET
(10-9 mol/L), and the reaction was observed for
90 more minutes without washing out of either agonist.
In Vitro Effects of CsA on Tension
Aortic rings from a group of untreated control rats were used to
study the in vitro effects of CsA on tension and the production
of nitrate/nitrite
(NO2/NO3), cGMP, and 6
keto-PGF1
. After a 30-minute equilibration
period, CsA (10-9 mol/L) was added to the bath,
and the aortic ring was allowed to contract for 120 minutes. Bath fluid
was harvested 90 minutes after the addition of CsA and stored at
-70°C until assay for NO, cGMP, and PGI2 or
their metabolites.
Measurement of NO, cGMP, and PGI2
NO was quantified by measurement of its metabolites
nitrate/nitrite using Greiss reagent with sodium nitrite as a
standard.5 cGMP was assayed via a
radioimmunoassay kit (NEX 133, Du Pont).
PGI2 was assayed via a radioimmunoassay kit for
its metabolite 6 keto-PGF1 (Kit 515,
Amersham).
Statistical Analysis
All data were generated with paired controls. Values are
expressed as mean±SEM. Two-way ANOVA was used for comparisons within
experiments. A value of P<0.05 was considered
significant.
Drugs and Chemicals
CsA (Sandimmune) was a gift from Sandoz Inc (East
Hanover, NJ), and bosentan was a gift from Hoffmann La Roche (Basel,
Switzerland). Endothelin, BQ-123, ACh, SNAP, and L-Arg were all
purchased from Calbiochem Inc.
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Results |
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Effects of Daily Intraperitoneal Injection of CsA for 7 Days on MAP
In CsA-treated rats, MAP began to increase on day 1 and increased rapidly through day 3, after which it reached a plateau from which it often increased further on day 7. Basal MAP averaged 120±4 mm Hg. By day 3, MAP had increased to 160±3 mm Hg in CsA-treated rats compared with 126±3 mm Hg in untreated rats (P<0.001) (Figure 1
). On day
3, MAP in CsA-treated rats was 42% higher than in untreated rats.
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Effects of Daily Intraperitoneal Injection of
BQ-123 or Bosentan on CsA-Induced Hypertension
In preliminary experiments, we sought to determine whether
ET was the cause of CsA-induced hypertension. Despite the fact that
either 0.1 mg/kg BQ-123 or 25 mg/kg bosentan prevented the hypertension
produced by daily injection of 100 ng/kg of ET, those same doses of
either BQ-123 or bosentan failed to prevent CsA-induced hypertension
(Figure 2
).
Effects of ET on Either Denuded or Intact Aortic Rings and on
Aortic Rings of Rats Treated With Either Olive Oil or CsA
To explore the cause of this hypertension, we performed
experiments with aortic rings. The maximum tension developed in
response to ET increased rapidly to a plateau by 30 minutes, remained
at that level through 70 minutes, and then declined slowly. Maximum
tension in rings from CsA-treated rats (206±7%) was not significantly
different from that in rings denuded of endothelium
from untreated rats (212±6%). These values were on average 35±5%
(P<0.001) higher than those in intact rings from either
untreated rats (160±6%) or vehicle-treated rats (160±6%) (Figure 3).
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Effects of ACh or SNAP on ET-Induced Contractions in Either Denuded
or Intact Aortic Rings and on Aortic Rings of Rats Treated With Either
Olive Oil or CsA
Thirty minutes after administration of ET, when the ET-induced
contraction was maximal, addition of either ACh or SNAP produced a
rapid 99.9% (P<0.001) decrease in contractile tension in
both intact and vehicle-treated aortic rings, but ACh produced only a
minimal effect in either denuded or CsA-treated aortic rings; the
effect of SNAP was similar to that seen in intact aortic rings (Figure 4). ACh-induced formation of both
nitrate/nitrite and cGMP in both denuded and CsA-treated aortic rings
was inhibited compared with that in intact aortic rings (data not
shown).
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Acute Effects of Either CsA on Tension, Level of Nitrate/Nitrite,
cGMP, and 6-Keto PGF1 in the Organ Bath
When CsA was added acutely to intact aortic rings from untreated
rats, tension increased from 0% to 105±1% of KCl tension
(P<0.01). Concomitantly, nitrate/nitrite production
decreased 83±4% (23±1 versus 3.8±0.01 nmol/L per milliliter), cGMP
production decreased 90±1% (12.1±1.2 versus 0.0 pmol/L per
milliliter), and PGI2 production
increased 40-fold (299±11 versus 3878±65 pg/mL; P<0.01
for each) (Figure 5).
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Because all our data suggested that CsA was inhibiting endothelial NO production, we sought to determine whether added L-Arg could mitigate these effects. In a preliminary experiment, we found that once-daily injections of either 2.5 or 5 mg/kg L-Arg had no effect on CsA-induced hypertension, whereas 10 mg/kg prevented the hypertension and 25 mg/kg reduced blood pressure below the baseline level (data not shown).
Daily injections of L-Arg (10 mg/kg) completely prevented CsA-induced
hypertension, whereas daily injections of L-Arg alone had no effect on
MAP (Figure 1).
Effects of ET on Aortic Rings of Rats Treated With L-Arg and
CsA
Daily administration of L-Arg to rats abolished the CsA-induced
increases in maximum tension of aortic rings to ET and normalized the
response of aortic rings from rats given either L-Arg or vehicle alone
(Figure 6).
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Effects of ACh or SNAP on ET-Induced Contractions in Aortic Rings
of Rats Treated With L-Arg and CsA
Daily administration of L-Arg to rats restored ACh-induced
relaxation in aortic rings from rats treated with CsA to that of rings
from rats treated with either L-Arg or vehicle alone (Figure 7). SNAP-induced relaxation in aortic
rings from rats was unaffected by any of the treatments (Figure 7).
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Effects of Daily Intraperitoneal Injection (7
Days) of CsA, L-Arg, or L-Arg+CsA on Levels of Nitrate/Nitrite and cGMP
in Urine
Daily administration of L-Arg to rats prevented CsA-induced
decreases of both nitrate/nitrite (Figure 8A) and cGMP (Figure 8B) in urine, so
that levels were not different from those seen in rats given either
L-Arg or vehicle alone.
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Discussion |
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There are several important findings of this study: (1) CsA administration to rats increased MAP and concomitantly decreased levels of both nitrate/nitrite and cGMP in urine. (2) ET antagonists were only partially able to block CsA-induced hypertension. (3) ET-induced tension was increased in aortic rings from CsA-treated rats compared with controls and was the same as that of normal rings denuded of endothelium. (4) Aortic rings from CsA-treated rats did not relax in response to ACh. (5) Aortic rings from CsA-treated rats relaxed normally in response to SNAP. (6) All the effects of CsA, both in vivo and in vitro, were reversed by daily intraperitoneal injections of L-Arg.
The finding that CsA administration causes hypertension in both humans and laboratory animals is well established.1 2 A number of possible explanations for the hypertension have been proposed, but none has been definitive. Over the years, data have been presented suggesting that CsA causes time- and dose-dependent endothelial cell injury in vitro,6 that CsA augments the in vitro contractile response to nerve stimulation,7 and that chronic CsA affects both endothelium-dependent vasodilation and vascular smooth muscle contraction depending on the stimulus applied.8
More recently, the possibility that ET is involved in CsA-induced nephrotoxicity and hypertension has gained interest because of the following observations: (1) CsA-induced glomerular hypoperfusion is associated with a remarkable increase in urinary ET9 and in some cases in plasma ET10; (2) CsA stimulates ET production by several types of renal and nonrenal cells11,12; and (3) CsA-related glomerular hypoperfusion/filtration and exaggerated cellular proliferation can be ameliorated by agents that block ET actions, such as anti-ET antibodies13 or selective ET antagonists.14 However, in our own studies in rats, we were unable to prevent CsA-induced hypertension by administration of ET antagonists (ie, either BQ-123 or bosentan).
Our finding that CsA-induced hypertension is accompanied by
decreases in urinary
NO2/NO3 and cGMP suggested
that a vasodilator pathway was suppressed, most likely NO. It is very
unlikely that the major effector of CsA-induced hypertension is a
product of cyclooxygenase, ie, either the
vasodilator PGI2 or a vasoconstrictor such as
PGF2, because indomethacin did
not alter the level of CsA-induced hypertension in preliminary
experiments (data not shown). Acute exposure of aortic rings to CsA,
increased PGI2 release (Figure 5), and
L-Arg reversed the CsA-suppressed endothelium-dependent
relaxation of ACh, but pretreatment with indomethacin
did not reverse the suppressed ACh
endothelium-dependent relaxation in aortic rings
treated with CsA (data not shown). This observation is similar to the
findings of Kim et al.15 L-Arg completely
corrected CsA-induced hypertension, therefore suggesting that
perturbations in a pathway other than NO were the principal cause of
the hypertension.
We chose ET as our model vasoconstrictor because of its prolonged duration of action. We found that CsA-treated aortic rings developed greater tension in response to ET than untreated rings. This effect is not specific to the agonist ET because angiotensin II also produced greater increases in tension in aortic rings from CsA-treated rats than it did in rings from controls (data not shown). Similar findings have been reported by a number of authors using rat thoracic aorta or tail artery and various agonists.15 16 17 18 We found that the increased tension was the same as that developed in normal rings denuded of endothelium. This suggested that chronic CsA administration impaired the vasodilating action of the endothelium. To test this hypothesis, we used ACh, an endothelium-dependent vasodilator. CsA prevented the vasodilator response to ACh to the same degree that denuding a normal aortic ring of endothelium abolishes ACh-induced vasodilation. To extend this observation on endothelial dysfunction, we also used SNAP, an NO donor, that causes endothelium-independent relaxation of rat aortic rings.19 20 CsA did not suppress the vasodilator response to SNAP. Our finding that CsA impairs the vasodilator response of rat aortic rings agrees with the findings of many studies.8 18 21 22
Some investigators have reported findings similar to our own in narrowly defined aspects of the problem, but they have not integrated them into a comprehensive explanation of CsA-induced hypertension; for example, Gallego et al23 showed that chronically administered CsA-induced endothelial dysfunction in rings of rat femoral artery and a decrease in ACh-induced endothelium-dependent relaxation, which was corrected by incubation of the rat arteries with L-Arg,23 results that were similar to our findings. Where we differ is that while Gallego et al concentrated on Ca2+ uptake, we showed that NO2/NO3, surrogates for NO production and cGMP, which mediates NO action, were decreased in both urine and aortic rings of animals treated with CsA and that chronic L-Arg administration reversed both in vivo and in vitro effects of CsA. Bloom et al24 showed that acutely administered CsA decreased NO metabolism in isolated perfused hydronephrotic rat kidneys. Khalil et al25 reported that injection of CsA directly into the coronary arteries of dogs caused vasoconstriction through "myogenic and endothelium-dependent mechanisms." Sudhir et al26 reported that acute injection of CsA "impairs release of endothelium-derived relaxing factors in epicardial and resistance coronary arteries" of dogs. Richards et al27 showed that incubation with CsA in human subcutaneous resistance vessels inhibited endothelium-dependent relaxation, as assessed by the ACh response. Marumo et al28 reported that acutely administered CsA inhibits NO synthase induction in rat aortic smooth muscle cells. Chan and coworkers29 suggested that CsA-induced vascular dysfunction is due to direct vasoconstriction, while Galle et al30 suggested that an interaction between CsA and oxidized lipoprotein was necessary. Amore et al31 reported that with chronically administered CsA, increased NO synthase activity and induced nephrotoxicity were prevented by L-Arg administration. To highlight the continuing controversy, O'Neil et al32 reported that NO response was preserved in the coronary arteries of patients treated with cyclosporin; Massoudy et al33 reported that concentrations of NO measured amperometrically in coronary effluent are well preserved in CsA-treated heart after ischemia. Lopez-Ongil et al34 showed that NO synthesis is moderately enhanced in endothelial cells in culture exposed to CsA for 24 hours, and Stroes et al35 reported that acute infusion of CsA into human forearm vessels increased NO activity, but their supporting molecular biological data were from isolated human umbilical vein cells exposed to CsA for only 2 hours. Our study integrates data from chronically treated whole animals, their isolated aortic rings, and the vasoactive substances the rings produce.
What are the acute effects of CsA? We found that a single exposure to CsA significantly increased tension and PGI2 production while appearance of NO metabolites and cGMP were nearly abolished. CsA did not suppress endothelium-independent relaxation. This implied that CsA does not seriously damage the endothelium or block the production of all vasoactive substances; rather, it appears to interfere specifically with the NO pathway.
There are at least 3 possible explanations for the reduced vasodilator response to ACh in CsA-treated rats: (1) an abnormality of ACh receptor/signal transduction, (2) an abnormality in NO formation, or (3) NO degradation. The first hypothesis seems improbable since administration of L-Arg restored both ACh-induced vasodilation and the activity of NO. The second and third hypotheses that CsA may induce an abnormality in NO formation or degradation, respectively, seem much more likely. Such an abnormality or degradation could occur at any one of the steps in the pathway. At present, it is difficult to assess directly many of these steps in vivo. Therefore, since NO can be synthesized from L-Arg by endothelial cells in culture,36 we used L-Arg, a substrate for NO, in this study.
L-Arg administration completely prevented the hypertension in CsA-treated rats and normalized the urinary excretion of both NO2/NO3 and cGMP. L-Arg completely normalized the excessive tension in response to ET that occurred in CsA-treated rats and it restored completely the vasodilatory response to ACh. Both Gallego et al,23 who used rat femoral artery strips, and Kim et al,15 who used rat thoracic aortic rings, found only partial restoration of ACh-induced vasodilation after preincubation of the aortic rings of CsA-treated rats with L-Arg. Both Gallego et al23 and Kim et al15 incubated the aortic rings with L-Arg and did not study the effects of L-Arg on MAP, whereas we administered L-Arg by intraperitoneal injection in the whole animal and studied changes in both MAP and tension. The reasons for the differences between their results and ours are unclear, but they may relate to differences in dosage or experimental design. In any case, we found that all the effects of CsA were reversed completely, both in vivo and in vitro, by treatment with L-Arg.
The finding that L-Arg administration can correct the hypertension and vascular toxicity of CsA administration suggests possible therapy for patients who must take CsA as an immunosuppressive agent. It also suggests further experiments to define the precise mechanism by which CsA impairs the NO pathway.
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Acknowledgments |
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The authors wish to thank John Tate, Shalese Madison, and Erika Felix for their excellent technical assistance and Carol Smith for typing the references.
Received June 19, 1998; first decision July 6, 1998; accepted July 17, 1998.
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References |
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