(Hypertension. 1997;29:570-575.)
© 1997 American Heart Association, Inc.
Articles |
Cyclosporin A Increases Nitric Oxide Activity In Vivo
the Departments of Nephrology and Hypertension (E.S.G.S., H.A.K., T.J.R.) and of Hematology (F.G. de G.), University Hospital Utrecht (Netherlands), and Cardiovascular Research, University Hospital, Bern, Switzerland (T.F.L.)A
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Abstract |
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The use of cyclosporine is complicated by its vasoconstrictive actions. In vitro cyclosporine has been associated with both decreased endothelium-dependent vasodilatation and increased nitric oxide activity. We studied the interaction between cyclosporine and endothelium-derived nitric oxide in seven healthy volunteers. Using venous-occlusion plethysmography, we measured forearm blood flow during intra-arterial infusion of serotonin, which in the concentrations used is a selective agonist of endothelial nitric oxide release, or NG-monomethyl-L-arginine, a specific inhibitor of nitric oxide synthase, during coinfusion of saline or cyclosporine (75 µg/min), respectively. During coinfusion of cyclosporine, forearm blood flow increased on maximal serotonin infusion from 2.9 (SE, 0.2) to 8.1 (0.9) mL/100 mL per minute in forearm tissue, which was significantly higher than the increase during saline coinfusion (3.0 [0.3] to 6.0 [0.5]; P<.05). Cyclosporine infusion during a "free" nitric oxide system had no effect on basal forearm blood flow, but it significantly decreased forearm blood flow (21.7 [2.8]%; P<.05) during fixed nitric oxide activity. These data suggest that acute administration of cyclosporine enhances both basal and receptor-stimulated nitric oxide activity. The mechanism is not clear but may include cyclosporine-induced shear stress as well as direct effects of cyclosporine. The latter was supported by our observation that gene expression of the enzyme nitric oxide synthase III was enhanced by approximately 50% after coincubation with cyclosporine. In conclusion, the present observation demonstrates that nitric oxide constitutes an important regulating mechanism that protects against cyclosporine-associated vasoconstriction in vivo.
Key Words: cyclosporine • nitric oxide • serotonin • nitric oxide synthase
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Introduction |
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Cyclosporine has greatly improved morbidity and mortality in transplantation patients over the last decade; however, its use is often accompanied by unwanted side effects, such as hypertension, an increased incidence of thromboembolic complications,1 and deterioration of renal function. The endothelium, and more specifically, endothelium-derived NO production, has been shown to be crucial in the maintenance of a state of basal vasodilatation,2 preventing platelet adhesion and aggregation3 and antagonizing vasoconstrictor tone in the renal afferent arterioles.4 Research has focused on the possible role of impaired NO activity in cyclosporine-induced side effects.5 6 7 8 9 10 11 12 13 14 15 16 Thus, in organ chambers, impaired endothelium-dependent vasodilatation has been observed during either acute (in vitro) or chronic (in vivo) cyclosporine administration.5 6 7 8 9 10 11 12 13 14 15 16 However, in these organ chamber experiments, impaired endothelium-dependent vasodilatation can be a consequence of either decreased endothelium-dependent vasodilator activity5 6 7 8 9 11 12 13 14 15 or increased vasoconstrictor activity.10 16 Interestingly, cyclosporine was associated with mildly enhanced gene transcription for NOS-III as well as significantly increased NO activity in rat kidney cells in vitro.17 Hence, if cyclosporine induces both vasoconstriction and increased NO activity, one could hypothesize that NO serves as an intrinsic counterregulatory mechanism that protects the vessel wall from cyclosporine-induced vasoconstriction.
To evaluate this hypothesis in humans, we first studied the effects of cyclosporine on forearm vasomotion during both "free" and clamped NO systems. We clamped endogenous NO activity by blocking it with the selective NO blocker L-NMMA. Subsequently, L-NMMA–induced vasoconstriction was neutralized by infusion of incremental doses of the exogenous NO donor SNP until baseline FBF was restored. This setup allows differentiation of cyclosporine-mediated modulation of endogenous NO activity (ie, before NO inhibition) from cyclosporine-mediated effects through NO-independent mechanisms (ie, after NO inhibition). Second, we studied the effects of cyclosporine coinfusion on receptor-mediated NO activity in the forearm vascular resistance bed using serotonin, which previously has been shown to be a selective agonist of endothelial NO release.18 Third, to further evaluate possible mechanisms involved in the interaction between cyclosporine and NOS, we simulated the effect of short-term exposure of human endothelial cells to peak therapeutic levels of cyclosporine in vitro to determine changes in endothelial NOS-III mRNA.
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Methods |
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Subjects
Studies were performed in seven healthy volunteers (six males). Mean age was 24.7 (SE, 0.7) years; body mass index, 23.0 (1.1) kg/m2; and arterial pressure, 80 (3) mm Hg. Forearm volume averaged 1257 (57) mL. None of the subjects had signs of overt arterial disease on physical examination and electrocardiography. Subjects did not smoke nor had they used medication the previous 2 months. Twelve hours before the study, all subjects refrained from drinking alcohol or caffeine-containing beverages. The study protocol was approved by the Utrecht University Hospital Ethics Committee for study in human beings. Subjects gave written informed consent after the protocol was explained. The procedures followed were in accordance with institutional guidelines.
Protocol
Experiments were performed in a quiet room kept at a constant temperature of 22° to 24°C. During the experiments, the subjects were supine with both forearms resting slightly above heart level. A 22-gauge needle (Arrow) was inserted into the brachial artery of the nondominant arm after local anesthesia. FBF in both arms was measured at 15-second intervals by R wave–triggered venous-occlusion plethysmography with mercury-in-Silastic strain gauges18 (EC-4 plethysmograph, Hokanson Inc). The upper arm collecting cuffs were inflated to 45 mm Hg. During FBF measurement, both hands were excluded from the circulation by small wrist cuffs, which were inflated 40 mm Hg above systolic pressure. Baseline measurements started 45 minutes after cannulation of the brachial artery when FBF had stabilized. Between infusions, wrist cuffs were deflated, allowing at least 20 minutes for FBF to recover before each subsequent infusion. Infusions of serotonin (Sigma Chemical Co), SNP (Merck), cyclosporine (Sandimmune, Sandoz), and L-NMMA (Sigma) were given into the brachial artery. All drugs were dissolved in 0.9% saline. All solutions were prepared aseptically from sterile stock solutions or ampoules on the day of the study and were stored at 4°C until use.
Fig 1
shows the infusion protocol. Serotonin (block A) was administered in a cumulative dose infusion of 0.1 (dose 1), 0.3 (dose 2), and 1.0 (dose 3) ng/kg per minute as described previously.18 Serotonin induced a rapid and transient vasodilatation followed by persistent vasodilatation at low concentrations. The persistent vasodilatation is due to NO release.18 Since steady-state persistent vasodilatation was reached after about 3.5 minutes, each serotonin dose was infused for 5 minutes. SNP (block B) was administered in a cumulative dose infusion of 1 (dose 1), 10 (dose 2), 30 (dose 3), and 100 (dose 4) ng/kg per minute.18 Steady-state FBF during SNP infusion was obtained after approximately 1.5 minutes. FBF measurements were therefore performed from 1.5 through 3 minutes of infusion. We alternated the order of the infusion blocks of serotonin and SNP (ie, A/D and B/E) (see Fig 1 legend) to avoid bias from carryover effects. Since cyclosporine may have long-lasting actions, the remaining blocks were not alternated. Saline infusion (block C1) served as a time control within one infusion block. Next, cyclosporine was infused locally into the brachial artery at a rate of 75 µg/min for 15 minutes (block C2). Subsequently, the cumulative dose infusions of serotonin (block D) and SNP (block E) were repeated in random order during coinfusion of cyclosporine. During the sixth and final infusion period, first endogenous NO production was blocked by L-NMMA infusion at a rate of 8 µmol/min; then, SNP was coinfused in incremental doses until baseline FBF had been restored (block F1). During the 15-minute break between blocks F1 and F2, L-NMMA and SNP infusions were continued. In block F2, we infused cyclosporine during NO clamp to study whether modulation of endogenous NO is involved in antagonism of the vascular effects of cyclosporine. Before and after infusion block C2, blood samples were drawn from the brachial artery of the infused arm as well as the antecubital veins of both the infused and noninfused arms for determination of cyclosporine and endothelin-1 levels.
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Laboratory Parameters
Cyclosporine in whole blood was assayed by high-performance liquid chromatography. Endothelin-1 was determined by radioimmunoassay (Nichols Institute) as described in detail previously.19 Endothelin-1 recovery throughout the extraction was 85%. Reported concentrations (picomoles per liter) are corrected for procedural losses. The detection limit of the assay was 0.4 pmol/L.
NOS-III Gene Regulation
Human umbilical vein endothelial cells (second passage) from five donors were incubated for 2 hours with cyclosporine in a concentration of 2.0 mg/L Dulbecco's modified Eagle's medium or a similar quantity of saline per liter in Dulbecco's modified Eagle's medium. Total RNA was isolated from these cells with TRIzol reagent (GIBCO) according to the manufacturer's instructions. cDNA was produced from this RNA by reverse transcription (RT) (Superscrip) of 4 µg total RNA from each sample. cDNA encoding human endothelial NOS was amplified by PCR with the two primers (designed by Oligo 4.0 Primer Design Software, National Biosciences Inc) 5'-TCTCACCTTCTTCCTGGACATACA-3' and 5'-AGCCCTTTGCTCTCAATGTCATGC-3', and cDNA encoding GAPDH was amplified with the primers 5'-CAGGAATTCGGTGAAGGTCGGAGTCAACGG-3' and 5'-AGTGGATCCGGTCATGAGTCCTTCCACGAT-3'(MWG Biotech). PCR for NOS-III and GAPDH (denaturing at 94°C for 30 seconds; annealing at 62°C for 30 seconds; extension at 72°C for 1.5 minutes) was performed at 10, 15, 20, 25, 30, 35, 40, and 45 cycles. Specific amplification of NOS-III and GAPDH with these primers should yield products of 537 and 517 bp, respectively. The optical density of the products was measured in the exponential phase of the PCR, which was at 35 cycles for NOS-III and 25 cycles for GAPDH. The optical density ratio for NOS-III/GAPDH was compared between cDNA from control and cyclosporine-treated cells. Control PCR was performed with RNA without RT to exclude contamination with genomic DNA. PCR products were separated by 1% agarose gel electrophoresis, visualized, and analyzed with a gel documentation system (Molecular Analyst, Bio-Rad). To confirm the specificity of the amplified RT-PCR products, we performed high-stringency Southern analysis using 32P-labeled cDNA probes for NOS-III and GAPDH.
Analysis
During each infusion step, the final six FBF values from both the measurement and control arms were used for calculation of both mean FBF and the mean ratio of FBF between the measurement and control arms (M/C ratio20 ) for each individual infusion step. These results are expressed as mean (SE). Repeated measures ANOVA was used for evaluation of statistically significant alterations in FBF during the infusions (serotonin, SNP, L-NMMA, and cyclosporine) and for evaluation of statistically significant differences between the response curves before and during clamping (Fig 2) and between the dose-response curves before and during coinfusion of cyclosporine (Fig 3). If variance ratios reached statistical significance, differences between the means were analyzed with the Student-Newman-Keuls test for a value of P<.05.
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Effects of Cyclosporine Before and After Infusion of an NO Inhibitor
Acute infusion of cyclosporine (75 µg/min) during 15 minutes did not significantly alter FBF (Fig 2B
; M/C ratio unaltered). L-NMMA infusion (8 µmol/min) decreased FBF by 36.2 (4.0)% (from 3.1 [0.2] to 1.9 [0.3] mL/100 mL per minute in forearm tissue; P<.05). Coinfusion of nitroprusside (median dose, 3.0 ng/kg per minute) successfully restored baseline FBF (before L-NMMA, 3.1 [0.2] mL/100 mL forearm tissue per minute; after titration, 3.0 [0.2]) (Fig 2A). After the 15-minute break between blocks F1 and F2, FBF remained at "restored" baseline level, hence demonstrating the stability of the NO clamp (Fig 2B). Coinfusion of cyclosporine after NO activity was clamped in this manner caused a significant decrease in FBF of 21.7 (2.8)% compared with baseline (FBF after 5 minutes, 2.5 [0.2] mL/100 mL forearm tissue per minute; after 10 minutes, 2.5 [0.3]; both P<.05 versus baseline FBF before cyclosporine). In agreement, M/C ratios on cyclosporine infusion were significantly lower during NO clamp than at baseline conditions (Fig 2B).
Effects of Serotonin Infusion
On cumulative dose infusion of serotonin during saline coinfusion, mean FBF increased significantly, from 3.0 (0.3) to 3.8 (0.3), 4.6 (0.4) (P<.05 versus baseline), and 6.0 (0.5) (P<.05 versus baseline) mL/100 mL forearm tissue per minute. Cumulative dose infusion of serotonin during cyclosporine coinfusion caused a significant further increase of FBF compared with saline coinfusion, from 2.9 (0.2) to 4.2 (0.5), 6.3 (0.7), and 8.1 (0.9) mL/100 mL forearm tissue per minute (all P<.05 versus baseline), resulting in a significant upward shift of the dose-response curve of M/C ratios during cyclosporine compared with during saline coinfusion (P<.05, Fig 3B).
Effects of SNP Infusion
Administration of a cumulative dose infusion of the exogenous NO donor SNP caused similar increments in FBF during saline coinfusion (from 2.7 [0.3] to 3.9 [0.5], 8.6 [1.0] [P<.05 versus baseline], 11.5 [1.5] [P<.05 versus baseline], and 17.9 [2.3] [P<.05 versus baseline] mL/100 mL forearm tissue per minute) and during cyclosporine coinfusion (from 3.2 [0.3] to 4.3 [0.6], 9.2 [1.2] [P<.05 versus baseline], 13.1 [1.8] [P<.05 versus baseline], and 18.8 [2.0] [P<.05 versus baseline] mL/100 mL forearm tissue per minute) (Fig 3A).
Effects of Cyclosporine on Local Endothelin-1 Levels
Venous antecubital whole blood cyclosporine levels after 15 minutes of cyclosporine infusion were 2.07 (0.24) and 0.08 (0.02) mg/L in the infused and noninfused arms, respectively. Arterial and venous endothelin-1 levels were 1.78 (0.17) and 1.83 (0.14) pmol/L before cyclosporine infusion and 1.74 (0.16) and 2.03 (0.26) after cyclosporine infusion (arterial versus venous and before versus after cyclosporine infusion not significantly different).
Effects of Cyclosporine on NOS-III mRNA In Vitro
The optical density ratio for NOS-III/GAPDH increased from 1.16 (0.13) during incubation with saline to 1.79 (0.16) during incubation with cyclosporine (P<.05) (Fig 4).
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Discussion |
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In the present study, we show for the first time in humans that cyclosporine causes vasoconstriction after inhibition of the endogenous NO system, whereas it has no effect during a "free" NO system. This provides evidence for increased basal NO release during cyclosporine administration. In addition, the cyclosporine-induced upward shift in the dose-response curve for serotonin, a selective agonist of NO release, also demonstrates a cyclosporine-mediated increase in receptor-mediated NO activity.
Cyclosporine infusion alone did not significantly alter basal FBF in healthy control subjects. This is in agreement with in vitro human data,21 which showed that incubation of subcutaneous resistance vessels with cyclosporine did not cause vasoconstriction. However, cyclosporine has been shown to exert divergent effects on vascular tone, including increased endothelium-independent and -dependent vasoconstriction10 16 as well as decreased endothelium-dependent vasodilatation.5 6 7 8 9 11 12 13 14 15 In view of this diversity of cyclosporine-induced vascular effects, the absence of direct hemodynamic effects of cyclosporine cannot simply be translated into an unaltered activity of the NO system. In contrast, the combination of no cyclosporine-induced effect on vascular tone with increased cyclosporine-associated NO activity in vitro17 may suggest that NO serves as an intrinsic mechanism that protects the vessel wall from cyclosporine-induced vasoconstriction.
To study this hypothesis, we minimized potential confounding factors. First, we infused cyclosporine locally to avoid the increased sympathetic drive that has been demonstrated after systemic cyclosporine administration.22 Second, we administered cyclosporine acutely to prevent a potential influence of cyclosporine-induced structural alterations. Finally and most importantly, we infused cyclosporine both during a "free" NO system and after inhibition of NO activity. With the use of this clamp technique (see "Methods"), the effects of cyclosporine on endogenous NO activity can be determined by comparison of vascular responses to cyclosporine infusion both before and after NOS inhibition. Whereas cyclosporine alone had no effect on FBF, it caused a significant decrease in FBF after clamping of endogenous NO activity. These data suggest an increase in NO activity on cyclosporine infusion, which protects against the vasoconstrictive effects of cyclosporine. This intrinsic mechanism of modulation in NO activity, by which the blood vessels can respond to vasoconstrictive stimuli, is not unique for cyclosporine-induced vasoconstriction. In this respect, a modulatory role of NO in vasoconstriction has also been demonstrated in animal models for other vasoconstrictive agents, such as angiotensin II23 and norepinephrine.24 Also, in individuals with heart failure, increased NO activity has been proposed as a counterregulatory vasodilator mechanism for the invariably increased neurohumoral activation of these individuals.25 Hence, these data lend further support to the concept that NO acts as an attenuating agent in counteracting vasoconstriction in general.26
Cyclosporine also significantly enhanced receptor-mediated NO release, as indicated by the upward shift of the serotonin dose-response curve. Earlier studies in animal models5 6 7 8 9 10 11 12 13 14 15 16 and in humans21 have described an impaired endothelium-dependent vasodilatation on stimulation with agonists after cyclosporine administration. However, several differences in the experimental setup deserve closer attention. First, extrapolation of in vitro studies under static conditions, such as organ chambers, to human studies, with continuous exposure to cyclic strain, is hazardous because shear stress is the main regulating mechanism of NO activity.26 Second, in the present study, clinically relevant doses were used, compared with the high supraphysiological doses used in most animal models (ranging from 5 to 60 mg/kg per day).5 6 7 8 9 10 11 12 13 14 15 16 Third, most studies used acetylcholine as an agonist,5 6 7 8 9 10 11 12 13 14 15 16 21 which has been shown to induce multiple vascular effects, such as release of NO, vasodilative prostaglandins, endothelium-derived hyperpolarizing factor, and vasoconstrictive prostaglandins.20 27 28 In contrast, serotonin-induced vasodilatation, used in the present study, is abolished by L-NMMA infusion, hence providing evidence that NO is the sole agent responsible for the vasodilative effect.18 This effect has been shown to be mediated through the serotonin type 1c+d and type 3 receptors (5-HT1c+d and 5-HT3).29
Short-term regulation of NO formation is predominantly mediated by increases in intracellular calcium concentration.30 Cyclosporine gives rise to increased intracellular calcium through multiple pathways, including a possible direct interaction with a plasma membrane calcium transporter as well as reduced calcium reuptake into cellular organelles concerned with calcium sequestration.31 An increased intracellular calcium content has been shown to enhance the response to calcium-mobilizing ligands, including serotonin.32 This may at least partly explain the enhanced NO activity on serotonin stimulation. An additional mechanism of increased NO formation during cyclosporine may involve shear stress. The cyclosporine-induced vasoconstriction observed during NO clamping will result in increased wall tension. Since the latter is the most important stimulus for operative basal NO activity,26 increased shear stress will invariably elicit a counterregulatory NO response. In addition to these acute effects, cyclosporine may also exert direct effects on gene regulation. The latter is supported by the present data, which show enhanced gene expression of NOS-III.
An increase in NO activity may theoretically reflect both increased NOS-III activity, which is expressed in the endothelium of the vessel wall, and increased NOS-II activity, which may also be present in vascular smooth muscle cells and macrophages in the vessel wall. Serotonin induces an increase in intracellular calcium, which secondarily activates NOS activity.30 NOS-II is a calcium-independent enzyme and as such is not influenced by serotonin stimulation. NOS-III is a calcium-dependent enzyme and is activated on serotonin stimulation. Additionally, cyclosporine has been shown to inhibit rather than stimulate both the activity33 and expression34 of NOS-II. Hence, the present observation of a cyclosporine-mediated increase in NO activity strongly supports an effect on NOS-III.
The vasoconstriction induced by cyclosporine after NOS inhibition may be related to several mechanisms. Both in vitro35 and in vivo36 studies have suggested that endothelin-1 may at least partly be responsible for this vasoconstriction. In contrast, in the present study, cyclosporine administration was not associated with a significant increase in endothelin-1 production in the forearm. However, since endothelin-1 is primarily secreted abluminally,37 one cannot conclude from the present observation that endothelin does not contribute to cyclosporine-induced vasoconstriction. Definitive exclusion of endothelin-1 as the responsible vasoconstrictor awaits further studies with endothelin antagonists. Other vasoconstrictor mechanisms include release of other endothelium-derived constricting factors, such as thromboxane,1 and/or a cyclosporine-induced increase in intracellular calcium, which potentiates the effect of other vasoactive constrictor peptides.32 38
Limitations of the present study include the duration of cyclosporine administration and the population studied. Since cyclosporine was infused acutely, extrapolation of the present conclusions to the clinical setting of long-term cyclosporine administration needs confirmation. Second, we evaluated the effects in healthy control subjects with an intact NO system. Effects may differ in individuals that receive cyclosporine for heart or kidney transplantation. In such individuals, endothelium-dependent NO activity may be impaired by, for instance, hyperlipidemia and hypertension,18 thus perhaps making these patients more susceptible to the vasoconstrictive effects of cyclosporine.
In conclusion, the present observation of cyclosporine-induced vasoconstriction and a simultaneous increase in endothelial NO release offers an intrinsic regulatory mechanism by which the vessel wall can respond to acute, cyclosporine-induced vasoconstriction in humans. Therefore, decreased NO activity is less likely to be involved in the vasoconstrictive actions of cyclosporine.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Dutch Kidney Foundation (No. C 93.1300). Ton Rabelink is sponsored by a fellowship of the Royal Dutch Academy of Sciences (KNAW). We gratefully acknowledge Barry Oemar for advice on laboratory techniques, Aalt van Dijk for determination of cyclosporine levels, and Thea van Dam for technical assistance.
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Footnotes |
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Reprint requests to T.J. Rabelink, MD, PhD, Department of Nephrology and Hypertension, Room F03.226, Heidelberglaan 100, 3584 CX the Netherlands.
Received July 29, 1996;
first decision August 27, 1996;
first decision September 11, 1996;
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