Articles

Cyclosporine Impairs Vasodilation Without Increased Sympathetic Activity in Humans

C. Michael Stein, Huaibing He, Theodore Pincus, Alastair J.J. Wood
https://doi.org/10.1161/01.HYP.26.4.705
Hypertension. 1995;26:705-710
Originally published October 1, 1995

Jump to

Abstract

Abstract Hypertension and nephrotoxicity frequently complicate treatment with cyclosporine; two suggested mechanisms are increased sympathetic activity and altered vascular reactivity. It is difficult to assess these mechanisms in patients receiving cyclosporine after transplantation because of the accompanying major physiological alterations. Therefore, we studied 12 patients with rheumatoid arthritis twice—while they were taking and not taking cyclosporine. We measured vascular response in the dorsal hand vein using the linear variable differential transformer technique. Cyclosporine treatment significantly attenuated vasodilation induced by 60 ng/min isoproterenol (no cyclosporine, 19.8±3.5% versus cyclosporine, 7.9±2.2%; P=.02) and prostaglandin E1 at 1000 pg/min (no cyclosporine, 72.6±10.2% versus cyclosporine, 45.6±9.0%) and 2000 pg/min (no cyclosporine, 100.8±14.7% versus cyclosporine, 68.6±8.0%; F=5.47, P=.047). However, neither vascular response to phenylephrine or nitroglycerin nor sympathetic activity assessed by measurement of norepinephrine spillover with a radioisotope dilution technique was affected by cyclosporine (no cyclosporine, 516.1±47.9 ng/min versus cyclosporine, 476.6±51.8 ng/min; P=.42). Cyclosporine impaired venodilation in response to two agonists that act through adenylate cyclase without altering α-agonist–induced venoconstriction or sympathetic activity. Therefore, in humans impaired vasodilation rather than sympathetic activation or enhanced vasoconstriction may be an important mechanism for the alterations of vascular tone that occur after long-term cyclosporine administration.

Cyclosporine has become a standard component of the immunosuppressive regimen in both solid organ and bone marrow transplantation. More recently, cyclosporine has also been used in the treatment of several autoimmune diseases.1 The major factor limiting the use of cyclosporine has been the development of nephrotoxicity and/or hypertension in a variable but high proportion of patients.1 The mechanisms by which cyclosporine treatment results in increased blood pressure and nephrotoxicity are unclear2 3 but are thought to be the result of increased cytosolic calcium with enhanced arteriolar smooth muscle responsiveness in both renal and systemic vasculature.4 5 6 Several pathophysiological mechanisms have been proposed, including enhanced sympathetic activity with consequent vasoconstriction,6 7 cyclosporine-induced release of neurohormonal vasoconstrictors,8 9 10 11 and cyclosporine-induced alterations in vascular sensitivity.12 13

Several studies in animals5 9 14 15 and a study in patients who had undergone cardiac transplantation7 have demonstrated increased sympathetic activity after cyclosporine treatment, suggesting that cyclosporine may induce hypertension and nephrotoxicity by means of sympathetically mediated vasoconstriction. However, the results have not been uniform.16 17 In addition to increased sympathetic activity, altered vascular sensitivity to agonists has been suggested as a possible mechanism to explain cyclosporine-induced vasoconstriction.12 13 A direct vasoconstricting effect of cyclosporine is not thought to play a major role,18 19 and animal studies and studies in isolated human vasculature have suggested that cyclosporine resulted in both enhanced vasoconstrictor responses and attenuated vasodilator responses.20 21 22 The relevance of these findings to the effect of cyclosporine on vascular smooth muscle responses in vivo in humans is unknown.

The purpose of this study was to measure the effects of cyclosporine on vascular smooth muscle response in vivo and to determine the role of sympathetic nervous system activation on this response in humans in the absence of organ transplantation.

Methods

Subjects

Approval for the study was obtained from the Vanderbilt Committee for the Protection of Human Subjects, and subjects gave written informed consent. The subjects studied were taking part in a clinical trial in which refractory rheumatoid arthritis was treated with the addition of either cyclosporine or placebo to a standard regimen consisting of weekly methotrexate with or without low-dose prednisone and/or a nonsteroidal anti-inflammatory drug. Subjects taking part in the present study were studied either before and 1 month after starting cyclosporine, or while receiving and 1 month after discontinuing cyclosporine. Subjects began therapy with a cyclosporine dose of 2.5 mg/kg per day; the dose was increased or decreased according to clinical response, serum creatinine concentration, blood pressure, and side effects. The maximal cyclosporine dose allowed within the protocol was 5.0 mg/kg per day. Dose adjustments were made so that serum creatinine concentration did not increase by more than 30% from the baseline value for each individual subject and so that diastolic pressure did not exceed 90 mm Hg. Medications other than cyclosporine were not altered between the two study days.

Subjects were asked to refrain from smoking and consuming caffeinated drinks for 24 hours before each study day. The evening before each study day subjects were admitted to the Vanderbilt Clinical Research Center. They took their evening dose of cyclosporine at 7 pm but omitted the evening dose of other medications. Subjects remained supine and fasted from midnight. At approximately 6:30 am an intravenous cannula was placed in an antecubital vein of both arms, and 2 hours later norepinephrine spillover was measured as described below.

Norepinephrine Spillover

[3H]Norepinephrine (norepinephrine levo-[ring-2,5,6-3H], 43.7 to 56.9 Ci/mmol, DuPont-NEN) was infused into the arm contralateral to the arm from which venous blood samples would later be drawn. An initial loading dose of 25 μCi [3H]norepinephrine was administered over 2 minutes, followed by a constant infusion of 0.8 μCi/min. The [3H]norepinephrine was prepared for human administration by the Vanderbilt Hospital Radiopharmacy, and appropriate sterility and pyrogen testing were performed. Immediately before use [3H]norepinephrine was diluted to a concentration of 2 μCi/mL in normal saline, with 1 mg/mL ascorbic acid added to the infusion solution. Venous blood samples were drawn for determination of the rate of norepinephrine release into plasma (norepinephrine spillover) after 30 and 40 minutes of the [3H]norepinephrine infusion. Blood was collected in cooled tubes with EGTA and reduced glutathione (Amersham Corp), placed on ice, and centrifuged at 4°C. Plasma was stored at −20°C until assayed as described below. Samples of the [3H]norepinephrine infusion solution were collected, stored, and later assayed as described for the blood samples to allow determination of the actual rate of [3H]norepinephrine infusion. Norepinephrine spillover was determined in 11 subjects. One subject declined to perform this part of the study.

Dorsal Hand Vein Technique

After completion of the measurement of norepinephrine spillover subjects were allowed to eat a standardized light breakfast. Vein sensitivity was measured in the dorsal hand vein 1 hour later. Heart rate was determined from an electrocardiogram recorded during the administration of each dose of drug. Blood pressure was monitored at 5-minute intervals with an automated Dinamap blood pressure monitoring device. Blood pressure and heart rate values obtained during the 30-minute equilibration period, before infusion of any vasoactive drugs, were averaged for each subject and compared on the two study days. The change in the diameter of a dorsal hand vein was measured with the use of the linear variable differential transformer technique as modified by Aellig23 and widely used previously by ourselves24 and others.25 26 Experiments were performed at the same time of day and by the same experimenter in the same room maintained at constant temperature. Subjects rested supine on a comfortable bed. The left arm was placed on a support sloping upwards at an angle of 30° to 45° with the hand above the level of the heart to ensure complete emptying of the superficial veins. A 23-gauge butterfly needle was inserted into a suitable dorsal hand vein and kept patent with saline at a flow rate of 0.67 mL/min. To allow for recovery of the vein after insertion of the needle, at least 30 minutes were allowed to elapse before a linear variable differential transformer (model MHR 100, Schaevitz Engineering) was mounted on the back of the hand with its moveable central core centered over the vein 1 cm proximal to the needle tip.

The linear variable differential transformer measured the change in vein diameter in response to venoconstricting or venodilating agents delivered through the butterfly needle while a sphygmomanometer cuff was inflated to induce venous filling. The deflection caused by the venous distension with the cuff inflated to 45 mm Hg and with saline flowing at a rate of 0.67 mL/min was taken as the baseline maximal venous distension. Drug infusions were started after three stable baseline maximal readings had been obtained. All drugs were infused through the needle, and infusions at each dose lasted for at least 5 minutes, with a sphygmomanometer cuff inflated to 45 mm Hg for the last 2 minutes of the infusion or until the response was stable. Drugs were administered by syringe infusion pumps (Harvard Apparatus) via three-way stopcocks with increasing doses of drug given sequentially. By varying the drug concentration we kept the total flow rate through the needle constant at 0.67 mL/min throughout the experiment at all drug doses.

The α1-adrenergic agonist phenylephrine (ESI Pharmaceuticals) was administered in sequentially increasing doses (5 to 2500 ng/min), and a full dose-response curve was constructed. The dose that caused approximately 70% constriction of the hand vein was determined for each subject. This phenylephrine dose was then maintained to produce preconstriction for the subsequent study of venorelaxant drugs. The phenylephrine venoconstriction was stable for the duration of the experiment. For measurement of vascular response to a β-agonist, isoproterenol (Isuprel, Winthrop Pharmaceuticals) was infused at a dose of 60 ng/min, and the response of the hand vein was determined. We have previously found this isoproterenol dose to induce venodilation without systemic effects. After a washout period of 10 minutes and after a stable response to the preconstricting phenylephrine dose had been obtained, venodilation in response to the non–β receptor–mediated vasodilator glyceryltrinitrate (50 ng/min, Tridil, DuPont Pharmaceuticals) was determined. After a second washout period of 10 minutes followed by stable phenylephrine preconstriction, two doses of prostaglandin E1 (PGE1, 1000 and 2000 pg/min; Alprostadil, Upjohn) were administered sequentially and venodilation was measured.

Catecholamine Assay

Norepinephrine concentrations were measured by high-performance liquid chromatography and electrochemical detection, with 3,4-dihydroxybenzylamine as the internal standard as we have described previously.27 28 The chromatographic effluent coinciding with the norepinephrine peak was collected and counted by liquid scintillation. This allowed determination of plasma [3H]norepinephrine concentration without interference from tritiated metabolites. The intraday and interday coefficients of variation were 7.8% and 7.6%, respectively. Calculations for the determination of norepinephrine kinetics using the isotope dilution method as described by Esler et al29 30 and previously used by ourselves28 were performed as follows, with V and V* representing the concentrations of endogenous and tritiated norepinephrine, respectively: Systemic Clearance (norepinephrine clearance from the whole body)=[3H]Norepinephrine Infusion Rate/V*, and Systemic Spillover (the rate at which norepinephrine entered plasma for the whole body)=Systemic Clearance×V.

Data Analysis

Values obtained after 30 and 40 minutes of [3H]norepinephrine infusion were similar, and their mean was used as the measure of norepinephrine spillover on each study day. Venoconstriction induced by phenylephrine was expressed as the percentage reduction in vein diameter from baseline maximal dilation measured during infusion of saline alone before the infusion of any vasoactive drugs. Venodilation was expressed as the percent reversal of the phenylephrine-induced constriction. Individual phenylephrine dose-response curves were analyzed with a sigmoid Emax model (Fig Perfect, Biosoft), and the dose of phenylephrine (ED50) required to produce 50% of the maximal response (Emax) was determined. All measures of potency (eg, ED50) were log transformed before statistical analysis and are expressed as geometric means with 95% confidence intervals (CIs). All other data are expressed as mean±SEM. A two-tailed t test for paired or unpaired observations or repeated-measures ANOVA, as appropriate, was used to compare data obtained from subjects with and without exposure to cyclosporine, with a value of P<.05 being the minimal level of significance accepted.

Results

Subject Characteristics

Twelve subjects (7 women, 5 men) aged 29 to 70 years (mean age, 55.9±3.3 years) were studied. Six subjects were studied before and 4 weeks after cyclosporine had been added to their treatment regimen, and 6 subjects were studied after receiving cyclosporine for 6 to 12 months and 4 weeks after discontinuing cyclosporine. When subjects on cyclosporine were studied, they were receiving a dose ranging from 1.5 to 4.5 mg/kg per day (mean, 2.8±0.2 mg/kg per day), with a mean trough whole blood cyclosporine concentration of 104.8±12.0 ng/mL. Subjects were receiving 11.3±0.8 mg/wk methotrexate, 6.1±0.8 mg/d prednisone, and a nonsteroidal anti-inflammatory drug. No subject was receiving antihypertensive treatment, other vasoactive drugs, or drugs known to alter sympathetic activity. Medications other than cyclosporine were not altered between the two study days.

The effects of cyclosporine on heart rate, blood pressure, and plasma renin activity were measured. Diastolic pressure was significantly higher when subjects were receiving cyclosporine (69.8±1.9 versus 65.7±2.4 mm Hg, P=.03), but systolic pressure and resting heart rate were not different. Supine plasma renin activity (1.7±0.77 [no cyclosporine] versus 1.3±0.31 ng/mL per hour [cyclosporine]) was not different on the two study days (P=.6).

Vascular Responses

Vascular reactivity in the dorsal hand vein was measured in 9 subjects. This was not performed in 3 subjects because of technical difficulties in 1 subject, frequent baseline ventricular ectopic beats in 1 subject, and the presence of ventricular ectopic beats after phenylephrine infusion in 1 subject. This arrhythmia was clinically insignificant and thought to be unrelated to the phenylephrine infusion, but because of the potential for aggravation of the arrhythmia by the subsequent administration of isoproterenol, the study was abandoned.

Since much of the animal data suggested that a major effect of cyclosporine was to increase sensitivity to vasoconstrictors, we studied the effects of the α1-adrenergic agonist phenylephrine administered in sequentially increasing doses while subjects were receiving and not receiving cyclosporine. A representative log dose–response curve to phenylephrine in a single subject studied while receiving and not receiving cyclosporine is shown in Fig 1⇓. Sensitivity to phenylephrine as determined by ED50 and Emax was not altered by cyclosporine treatment. The geometric mean phenylephrine ED50 (241.6 ng/min; 95% CI, 119.9 to 485.3 ng/min) and Emax (86.8±6.7%) while subjects were receiving and not receiving cyclosporine (ED50, 205.1 ng/min; 95% CI, 101.6 to 413.0 ng/min; Emax, 87.3±4.6%) were not different (P=.77 and P=.96, respectively).

Figure 1.
Figure 1.

Line graph of representative log dose response shows increasing vasoconstriction to increasing doses of phenylephrine in a single subject studied while receiving (▴) and not receiving (▪) cyclosporine.

To examine vascular sensitivity to vasodilators and determine the specificity of any alterations observed, we measured venodilation in response to isoproterenol, PGE1, and nitroglycerin in the phenylephrine-preconstricted dorsal hand vein. The degree of preconstriction induced with phenylephrine (no cyclosporine, 73.0±4.6% versus cyclosporine, 76.8±5.0%) and the preconstricting dose of phenylephrine (no cyclosporine, 1074 ng/min; 95% CI, 658 to 1758 ng/min versus cyclosporine, 1350 ng/min; 95% CI, 1130 to 1611 ng/min) did not differ on the two study days. Responses to only one or two doses of the respective vasodilators were determined because of the constraints imposed by the length of time subjects with rheumatoid arthritis were able to remain supine without moving and the time required for washout periods between the different agonists.

Venodilation induced by 60 ng/min isoproterenol was less when subjects were taking cyclosporine (7.9±2.2%) than when they were not (19.8±3.5%, P=.02; Fig 2⇓). As was observed with isoproterenol, venodilation in response to PGE1 was reduced when subjects were receiving cyclosporine (1000 pg/min PGE1, 72.6±10.2% [no cyclosporine] versus 45.6±9.0% [cyclosporine]; 2000 pg/min PGE1, 100.8±14.7% [no cyclosporine] versus 68.6±8.0% [cyclosporine]) (F=5.47, P=.047; Fig 3⇓). To determine the specificity of these alterations we determined the response to nitroglycerin, which acts through guanylate cyclase. There was no difference in the vascular response to 50 ng/min nitroglycerin whether or not subjects were receiving cyclosporine (50 ng/min nitroglycerin, 45.8±8.9% [no cyclosporine] versus 36.8±5.0% [cyclosporine]; P=.32).

Figure 2.
Figure 2.

Bar graph shows mean±SEM venodilation in response to 60 ng/min isoproterenol (ISO) in nine subjects studied while receiving and not receiving cyclosporine.

Figure 3.
Figure 3.

Plot shows mean±SEM venodilation in response to prostaglandin E1 (PGE1) at 1000 and 2000 pg/min in nine subjects studied while receiving (▴) and not receiving (▪) cyclosporine (CSA).

We analyzed separately the two subject subgroups—one (n=4) studied before and 1 month after cyclosporine; the other (n=5) studied after receiving cyclosporine for 6 to 12 months and 1 month after discontinuing cyclosporine. The only significant difference was that vasodilator responses to isoproterenol on the control day (no cyclosporine) differed between the group studied before receiving cyclosporine (27.7±5.5%) and the group studied after having received cyclosporine (13.6±1.7%, P=.03), implying that the impairment of vasodilation in response to isoproterenol by cyclosporine may be prolonged.

Sympathetic Activity

Because sympathetic tone can alter vascular responsiveness and because of the evidence suggesting that cyclosporine increased sympathetic activity, norepinephrine spillover was measured. Cyclosporine administration did not affect norepinephrine spillover (cyclosporine, 476.6±51.8 ng/min versus no cyclosporine, 516.1±47.9 ng/min; P=.42, Fig 4⇓), indicating that the observed alterations in vascular sensitivity to vasodilators when subjects were receiving cyclosporine were not due to increased sympathetic tone.

Figure 4.
Figure 4.

Bar graph shows mean±SEM norepinephrine spillover in 11 subjects studied while receiving and not receiving cyclosporine.

Discussion

Our findings that cyclosporine treatment altered vascular responsiveness in vivo in humans are new. Previous studies in animals have found that cyclosporine treatment altered vasodilation and vasoconstriction in response to several agonists.12 20 21 31 Cyclosporine itself had a small direct vasoconstrictor effect,18 19 but enhanced agonist-mediated vasoconstriction was thought to be more important. In addition to increased vasoconstriction, decreased vasodilator responses to acetylcholine, PGI2, and nitroprusside21 were found in the isolated perfused kidneys of rabbits previously exposed to cyclosporine, and cyclosporine-treated rats demonstrated an attenuated hypotensive response to prostacyclin and nitroprusside.12

In contrast to what would be predicted from the animal experiments described above, Richards and colleagues,22 32 examining the effects of cyclosporine on isolated human vasculature, found that norepinephrine sensitivity was decreased rather than increased and that vasodilation in response to sodium nitroprusside was enhanced rather than impaired. Studies examining the effects of cyclosporine on vascular responses in intact animals or on isolated vascular tissue have important limitations. The responses in isolated vascular tissue or intact animals exposed to high concentrations of cyclosporine for a short time may differ and may not accurately predict the effects of long-term exposure to pharmacological doses of cyclosporine. Furthermore, there is interspecies variability in the effects of cyclosporine on homeostatic mechanisms that regulate vascular tone.33 34 35 36 It is clear from the preceding studies with their varying conclusions that accurate determination of the specific effects of cyclosporine on human vascular responses requires that the effect of the drug on vascular responses be studied in vivo in humans.

In the present study, in which subjects received therapeutic doses of cyclosporine, vascular response was studied in vivo. We found that cyclosporine did not alter sensitivity to α-adrenoceptor–mediated vasoconstriction but that vasodilation in response to isoproterenol, a β-adrenoceptor agonist, and to PGE1, acting through prostaglandin receptors, was impaired. PGE1 and isoproterenol both stimulate adenylate cyclase but through different receptors. It is therefore of interest that the response to nitroglycerin, which acts through guanylate cyclase, was not significantly altered, suggesting that responses mediated through guanylate cyclase may be less susceptible to inhibition by cyclosporine. The study had 80% power to detect a reduction in nitroglycerin-mediated vasorelaxation of a magnitude similar to that seen with isoproterenol. Obviously, we cannot exclude the possibility that a smaller difference in nitroglycerin response might exist. Cyclosporine-induced impairment of endothelium-dependent relaxation has been reported in vitro in both animal31 and human22 vasculature, and cyclosporine may therefore result in attenuation of vasodilation mediated by several mechanisms without specificity for adenylate cyclase–mediated responses.

A blunted vascular response to isoproterenol has also previously been noted in patients with essential hypertension,25 37 suggesting that the treatment of normotensive patients with cyclosporine may alter β-adrenoceptor–mediated vascular responses in a fashion similar to that previously noted to occur in patients with essential hypertension. The impairment of vasodilation in response to PGE1 observed in cyclosporine-treated patients, in addition to suggesting that the site of the abnormality may be the effector system rather than the receptors, is also of interest because altered prostanoid biosynthesis by cyclosporine has been extensively investigated as a cause of cyclosporine-induced hypertension and nephrotoxicity.35 Previous studies showing that the deleterious effect of cyclosporine and nonsteroidal anti-inflammatory drugs on renal function was synergistic suggested that endogenous vasodilating prostaglandins were important in the maintenance of renal function in patients receiving cyclosporine.38 Our findings suggest that in addition to alterations in prostanoid synthesis, decreased response to vasodilating prostaglandins may contribute to these additive effects.

The time course of recovery of vascular response after cyclosporine treatment is unknown, but the subject subgroup analysis, which suggested that responses to isoproterenol had not completely returned to control values after 1 month, indicates that recovery may be slow. However, the numbers in each subgroup are too small to allow a definitive conclusion. A delayed recovery would be in keeping with clinical studies showing a relatively rapid onset (within weeks) of nephrotoxicity after treatment with cyclosporine and a relatively slow recovery (over months) after discontinuation of cyclosporine.33

Since sympathetic activity is a major determinant of vascular tone, both sympathetic and vascular responses should ideally be measured to allow more meaningful interpretation of any observed alteration in vascular response. Under carefully controlled conditions, using each subject as his or her own control, we found that cyclosporine did not alter sympathetic activity. This contrasts with several studies in animals suggesting that cyclosporine resulted in sympathetic activation.5 9 14 15 39 Two previous studies that examined the effect of long-term cyclosporine administration on sympathetic activity in humans in vivo reached different conclusions. Scherrer and colleagues7 reported increased muscle sympathetic nerve activity in patients receiving cyclosporine after heart transplantation compared with a control group that did not receive cyclosporine. In contrast, Kaye and colleagues17 also studied patients who received cyclosporine after cardiac transplantation and compared them with healthy control subjects but did not find an increase in either muscle sympathetic nerve activity or norepinephrine spillover. The effects of cardiac disease, concomitant medications, hypertension, volume changes, and the transplantation process itself make it difficult to interpret the effects of cyclosporine in these previous studies and may account for their conflicting conclusions.

Studies of the effects of cyclosporine on vascular response in vivo in humans are necessarily complex, partly because the most common indication for treatment with cyclosporine—transplantation—itself causes major physiological disturbances. The attendant alterations in disease status, fluid balance, blood pressure, and other drug therapy make measurement of the effects of cyclosporine on physiological responses difficult. In addition, since cyclosporine is now standard therapy for patients undergoing organ transplantation, it is impossible to match these patients to a similar control group not receiving cyclosporine. Our study design, which examined subjects receiving cyclosporine for the treatment of rheumatoid arthritis, has overcome many of the problems inherent in the previous studies that involved the study of patients undergoing organ transplantation.

Ideally, one would want to study the effects of cyclosporine on sympathetic activity and vascular reactivity in patients who are receiving no other medications. However, this is difficult because cyclosporine is too toxic to administer chronically to healthy volunteers. On the other hand, the patient population receiving cyclosporine therapeutically has significant concomitant disease that requires treatment with several therapeutic agents. Therefore, to avoid the potential confounding effects of concomitant medications seen in previous studies that examined the effect of cyclosporine on sympathetic activity in humans,7 17 we controlled for this variable by examining the same subjects twice—once while they were receiving cyclosporine and once while they were not receiving it—while maintaining other medications unchanged throughout, thus excluding that variable.

Ideally, vascular responsiveness would be studied in resistance vessels; however, the invasive nature of this type of study makes it poorly suited to the types of patients who are receiving cyclosporine. The dorsal hand vein technique has the advantage of allowing the study of vascular smooth muscle response in vivo in a noninvasive fashion. Alterations in vascular sensitivity seen using the dorsal hand vein model have been reflected in alterations in vascular responsiveness at other sites in both normotensive and hypertensive subjects using a wide range of agonists in several clinical situations.25 40 41 Therefore, the alterations in vascular sensitivity observed in the dorsal hand vein in the present study may reflect similar changes in other vascular tissues.

Two techniques, direct measurement of muscle sympathetic nerve traffic and measurement of norepinephrine release into plasma (norepinephrine spillover), are commonly used to measure sympathetic activity. Since the amount of norepinephrine released per quantum of nerve traffic may be altered by physiological or pharmacological effects mediated through presynaptic receptors,28 determination of norepinephrine spillover is, in most situations, a more relevant measure, and muscle sympathetic nerve activity is most useful in defining the site of abnormality in norepinephrine spillover. Our finding that sympathetic activity, as determined by norepinephrine spillover, was not increased by cyclosporine is in keeping with the findings of Kaye and colleagues,17 who found no evidence of cyclosporine-induced sympathetic activation as determined by measurement of both muscle sympathetic nerve activity and norepinephrine spillover.

The necessary complexity of the study, the population of subjects studied, the concomitant medications they were receiving, and the techniques used are all factors that may restrict the generalizability of our findings to a wider group of patients receiving cyclosporine for other indications. Nevertheless, the demonstration of unaltered sympathetic activity in the present study and another study in which transplant recipients were studied17 does not support excess sympathetic activation as a mechanism for increased vascular resistance in cyclosporine therapy. On the other hand, therapeutic interventions selected to reverse the inhibitory effects of cyclosporine on vasodilation may be worth exploring.

The present study demonstrates that cyclosporine administered to humans in pharmacological doses resulted in impaired vasodilation in response to isoproterenol and PGE1 without altering vasoconstriction in response to the α1-adrenergic agonist phenylephrine and without altering sympathetic activity. Therefore, in humans impaired vasodilation rather than enhanced sympathetic activity or vasoconstriction may be important in the pathogenesis of the vascular complications associated with the use of cyclosporine.

Acknowledgments

Michael Stein was supported in part by a Merck Sharp & Dohme International Fellowship in Clinical Pharmacology and is the recipient of a Pharmaceutical Manufacturers of America Clinical Pharmacology Faculty Development Award. This work was also supported by a Grant-in-Aid from the American Heart Association and US Public Health Service grants GM 31304, GM 07569, and GM 5M01-RR00095.

Footnotes

  • Parts of this work have been presented in abstract form (Clin Res. 1994;42:252A).

  • Received May 11, 1995.
  • Revision received June 1, 1995.
  • Accepted June 30, 1995.

References

  1. ↵
    Kahan BD. Cyclosporine. N Engl J Med. 1989;321:1725-1738.
    OpenUrlCrossRefPubMed
  2. ↵
    Luke RG. Mechanism of cyclosporine induced hypertension. Am J Hypertens. 1991;4:468-471.
    OpenUrlPubMed
  3. ↵
    Myers BD. Cyclosporine nephrotoxicity. Kidney Int. 1986;30:964-974.
    OpenUrlPubMed
  4. ↵
    Sullivan BA, Hak LJ, Finn WF. Cyclosporine nephrotoxicity: studies in laboratory animals. Transplant Proc. 1985;17:145-154.
    OpenUrlPubMed
  5. ↵
    Murray BM, Paller MS, Ferris TF. Effect of cyclosporine administration on renal hemodynamics in conscious rats. Kidney Int. 1985;28:767-774.
    OpenUrlPubMed
  6. ↵
    Mark AL. Cyclosporine, sympathetic activity and hypertension. N Engl J Med. 1990;323:748-750.
    OpenUrlPubMed
  7. ↵
    Scherrer U, Vissing SF, Morgan BJ, Rollins JA, Tindall RSA, Ring S, Hanson P, Mohanty PK, Victor RG. Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med. 1990;323:693-699.
    OpenUrlCrossRefPubMed
  8. ↵
    Pfeilschifter J, Ruegg UT. Cyclosporin A augments angiotensin II-stimulated rise in intracellular free calcium in vascular smooth muscle cells. Biochem J. 1987;248:883-887.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Chiu PJS, Vemulapalli S, Sabin C, Rivelli M, Bernardino V, Sybertz EJ. Sympathoadrenal stimulation not endothelin plays a role in the acute pressor response to cyclosporine in anesthetized rats. J Pharmacol Exp Ther. 1992;261:994-999.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Kon V, Sugiura M, Inagami T, Harvie BR, Ichikawa I, Hoover RL. Role of endothelin in cyclosporine-induced glomerular dysfunction. Kidney Int. 1990;37:1487-1491.
    OpenUrlCrossRefPubMed
  11. ↵
    Coffman TM, Carr DR, Yarger WE, Klotman PE. Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity. Transplantation. 1987;43:282-285.
    OpenUrlPubMed
  12. ↵
    Rego A, Vargas R, Cathapermal S, Kuwahara M, Foegh ML, Ramwell PW. Systemic vascular effects of cyclosporin A treatment in normotensive rats. J Pharmacol Exp Ther. 1991;259:905-915.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Lamb FS, Webb RC. Cyclosporine augments reactivity of isolated blood vessels. Life Sci. 1987;40:2571-2578.
    OpenUrlCrossRefPubMed
  14. ↵
    Lyson T, Morgan BJ, Ermel LD, Victor RG. Comparative effect of FK 506 and cyclosporine on sympathetic nerve activity and blood pressure. Hypertension. 1991;18:388.
    OpenUrl
  15. ↵
    Moss NG, Powell SL, Falk RJ. Intravenous cyclosporine activates afferent and efferent renal nerves and causes sodium retention in innervated kidneys in rats. Proc Natl Acad Sci U S A. 1985;82:8222-8226.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Carrier M, Tronc F, Stewart D, Pelletier LC. Dose dependent effect of cyclosporin on renal arterial resistance in dogs. Am J Physiol. 1991;261:H1791-H1796.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Kaye D, Thompson J, Jennings G, Esler M. Cyclosporine therapy after cardiac transplantation causes hypertension and renal vasoconstriction without sympathetic activation. Circulation. 1993;88:1101-1109.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Carrier M, Pelletier CR, Pelletier LC. Effect of direct injection of cyclosporine on the arterial vessels of the isolated hindlimb in the dog. Can J Cardiol. 1991;7:91-95.
    OpenUrlPubMed
  19. ↵
    Tronc F, Carrier M, Pelletier CL. Mechanism of hind limb vasoconstriction due to cyclosporin in the dog. Circ Res. 1992;71:1159-1164.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Rego A, Vargas R, Suarez KR, Foegh ML, Ramwell PW. Mechanism of cyclosporine potentiation of vasoconstriction of the isolated rat mesenteric arterial bed: role of extracellular calcium. J Pharmacol Exp Ther. 1990;254:799-808.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Cairns HS, Fairbanks LD, Westwick J, Neild GH. Cyclosporine therapy in vivo attenuates the response to vasodilators in the isolated perfused kidney of the rabbit. Br J Pharmacol. 1989;98:463-468.
    OpenUrlPubMed
  22. ↵
    Richards NT, Poston L, Hilton PJ. Cyclosporine A inhibits endothelium-dependent, prostanoid-induced relaxation in human subcutaneous resistance vessels. J Hypertens. 1990;8:159-163.
    OpenUrlCrossRefPubMed
  23. ↵
    Aellig WH. A new technique for recording compliance of human hand veins. Br J Clin Pharmacol. 1981;11:237-243.
    OpenUrlPubMed
  24. ↵
    Stein M, Deegan R, Wood AJJ. Chronic exposure to beta2 receptor agonist specifically desensitizes beta receptor-mediated venodilation. Clin Pharmacol Ther. 1993;54:187-193.
    OpenUrlPubMed
  25. ↵
    Feldman RD. Defective venous beta-adrenergic response in borderline hypertensive subjects is corrected by a low sodium diet. J Clin Invest. 1990;85:647-652.
  26. ↵
    Eichler HG, Ford GA, Blaschke TF, Swislocki A, Hoffman BB. Responsiveness of superficial hand veins to phenylephrine in essential hypertension: alpha adrenergic blockade during prazocin therapy. J Clin Invest. 1989;83:108-112.
  27. ↵
    He HB, Deegan RJ, Wood M, Wood AJJ. Optimization of HPLC assay for catecholamines: determination of ideal mobile phase composition and elimination of species-dependent differences in extraction recovery of DHBA. J Chromatogr. 1992;574:213-218.
    OpenUrlPubMed
  28. ↵
    Stein M, Deegan R, He H, Wood AJJ. Beta adrenergic receptor-mediated release of norepinephrine in the human forearm. Clin Pharmacol Ther. 1993;54:58-64.
    OpenUrlPubMed
  29. ↵
    Esler M, Leonard P, O’Dea K, Jackman G, Jennings G, Korner P. Biochemical quantification of sympathetic nervous activity in humans using radiotracer methodology: fallibility of plasma noradrenaline measurements. J Cardiovasc Pharmacol. 1982;4:S152-S157.
  30. ↵
    Esler M, Jennings G, Korner P, Willett I, Dudley F, Hasking G, Anderson W, Lambert G. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension. 1988;11:3-20.
    OpenUrlFREE Full Text
  31. ↵
    Roullet J, Xue H, McCarron DA, Holcomb S, Bennett WM. Vascular mechanisms of cyclosporin-induced hypertension in the rat. J Clin Invest. 1994;93:2244-2250.
  32. ↵
    Richards NT, Poston L, Hilton PJ. Cyclosporine A inhibits relaxation but does not induce vasoconstriction in human subcutaneous resistance vessels. J Hypertens. 1989;7:1-3.
    OpenUrlCrossRefPubMed
  33. ↵
    Sturrock NDC, Struthers AD. Hormonal and other mechanisms involved in the pathogenesis of cyclosporin-induced nephrotoxicity and hypertension in man. Clin Sci. 1994;86:1-9.
    OpenUrlPubMed
  34. ↵
    Lustig S, Stern N, Eggena P, Tuck ML, Lee DBN. Effect of cyclosporin on blood pressure and renin-aldosterone axis in rats. Am J Physiol. 1987;253:H1596-H1600.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    Mason J. Pharmacology of cyclosporine (Sandimmune), VII: Pathophysiology and toxicology of cyclosporine in humans and animals. Pharmacol Rev. 1989;42:423-434.
    OpenUrl
  36. ↵
    Bantle JP, Boudreau RJ, Ferris TF. Suppression of plasma renin activity by cyclosporine. Am J Med. 1987;83:59-64.
    OpenUrlCrossRefPubMed
  37. ↵
    Naslund T, Silbertstein DJ, Merrell WJ, Nadeau JH, Wood AJJ. Low sodium intake corrects abnormality in beta-receptor mediated arterial vasodilation in patients with hypertension: correlation with beta-receptor function in vitro. Clin Pharmacol Ther. 1990;48:87-95.
    OpenUrlCrossRefPubMed
  38. ↵
    Altman RD, Perez GO, Sfakianakis GN. Interaction of cyclosporine A and nonsteroidal anti-inflammatory drugs on renal function in patients with rheumatoid arthritis. Am J Med. 1992;93:395-402.
    OpenUrl
  39. ↵
    Lyson T, McMullan DM, Ermel LD, Morgan BJ, Victor RG. Mechanism of cyclosporine-induced sympathetic activation and acute hypertension in rats. Hypertension. 1994;23:667-675.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Ford GA, Hoffmann BB, Vestal RE, Blaschke TF. Age related changes in adenosine and beta-adrenoceptor responsiveness of vascular smooth muscle in man. Br J Clin Pharmacol. 1992;33:83-87.
    OpenUrlPubMed
  41. ↵
    Vincent J, Blaschke TF, Hoffmann BB. Vascular reactivity to phenylephrine and angiotensin II: comparison of direct venous and systemic vascular responses. Clin Pharmacol Ther. 1992;51:68-75.
    OpenUrlPubMed
View Abstract

This Issue

Jump to

Article Tools

Share this Article

  • Email
  • Cyclosporine Impairs Vasodilation Without Increased Sympathetic Activity in Humans
    C. Michael Stein, Huaibing He, Theodore Pincus and Alastair J.J. Wood
    Hypertension. 1995;26:705-710, originally published October 1, 1995
    https://doi.org/10.1161/01.HYP.26.4.705
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...