Cyclosporine A modulates baroreceptor function in kidney transplant recipients

https://doi.org/10.1016/S0167-5273(98)00368-4Get rights and content

Abstract

Cyclosporine has been described to increase the sympathetic tone. Alterations in sympathetic tone may contribute to baroreceptor dysfunction. Therefore, in this study baroreceptor function in 20 kidney transplant recipients was investigated under both low and high cyclosporine whole blood concentrations using the sequence analysis technique. The sympathetic nerve activity was estimated by calculating the low frequency oscillation of heart rate and blood pressure following Fast Fourier Transformation (FFT). Besides cyclosporine, azathioprine and prednisolone no other drugs were used. The increase in cyclosporine whole blood levels (from 101±13.4 ng/ml to 469±52 ng/ml) did not change mean arterial blood pressure significantly (83.7±2.5 vs. 82.2±2.0 mmHg). Baroreflex sensitivity in +PI/+RR (+pulsinterval/+blood pressure) sequences, however, increased from 11.2±0.4 to 13.0±0.5 ms/mmHg, whereas it was reduced in −PI/−RR (−pulsinterval/−blood pressure) sequences (14.4±0.3 to 12.5±1.1 ms/mmHg). The increase in cyclosporine whole blood concentrations was associated with an increase in low frequency oscillation of heart rate (430±12 to 461±13) and blood pressure (452±9 to 469±12), indicating an enhanced sympathetic tone. Our results provide evidence that cyclosporine A by itself alters baroreceptor function. An imbalance between the sympathetic and parasympathetic nervous system due to an enhanced sympathetic tone may explain the reduction in −PI/−RR and the increase in +PI/+RR sequence baroreflex sensitivity.

Introduction

Kidney transplant recipients show an enhanced risk of cardiovascular diseases which might be due to deteriorations in central nervous blood pressure regulation [1]. Besides other factors, immunosuppressive drugs also probably have to be considered as a factor influencing baroreceptor function. At the present time, cyclosporine A is still the most important orally active immunosuppressant drug used in human kidney transplantation. It prolongs survival after transplantation. The therapeutical use of cyclosporine A, however, is limited due to its adverse effects. One of the most undesirable side effects is nephrotoxicity [2]. Furthermore, systemic arterial hypertension has also been reported in patients treated with cyclosporine A after kidney transplantation 3, 4. Interestingly, cyclosporine A increases the activity of the sympathetic nervous system in animals 5, 6and humans [7]. In animals, a resetting of the arterial baroreflex has been reported [6].

Recent work from the same laboratory showed a similar baroreflex sensitivity in kidney transplant recipients with low cyclosporine whole blood levels and healthy volunteers [8]. Surprisingly, the low frequency oscillation obtained after Fast Fourier Transformation (FFT) of heart rate and blood pressure was reduced. Similar results have already been reported in resting kidney transplant recipients [9]. The purpose of the present study was, therefore, to compare baroreceptor sensitivity in kidney transplant recipients with low and high cyclosporine whole blood levels to get information on a possible influence of this immunosuppressive drug on baroreceptor function and sympathetic tone.

Section snippets

Subjects and methods

Fourteen male and six female renal transplant recipients which had been given a donor kidney 19±19 months ago and therefore underwent immunosuppression by cyclosporine A (Sandimmun) were included in this study. None of the patients had a history of hypertension, heart disease or any abnormal findings on history, physical examination, or electrocardiography. Except for cyclosporine (125±15 mg during the first measurement), the patients did not receive any drugs until the end of the second

Study protocol

After a 20-min rest period, the registrations were performed from 7:45 to 8:15 a.m. (low cyclosporine whole blood levels). Cyclosporine A application took place exactly at 8:00 a.m. After another 20-min rest period, the second measurement was registered from 09:45 to 10:15 a.m. (our experiences show that then the cyclosporine concentration peak is reached) with no exception. The continuous registrations were performed simultaneously with the beat-to-beat-measurements. Physiological calibration

Data analysis

Blood pressure, heart rate, sequence analysis, regressions, spectral analysis data and cyclosporine A data were subjected to Student's t-test. Data are given as mean±S.E.M. (standard error of the mean). A p<0.05 was considered to be statistically significant.

Blood pressure

In Table 2 blood pressure and heart rate data at low and high cyclosporine whole blood levels are summarised. The increase in cyclosporine A whole blood levels from 101±13 to 469±52 ng/ml had no significant influence on mean arterial blood pressure. Heart rate, however, showed a statistically significant increase 2 h following cyclosporine A intake.

In Fig. 1 baroreceptor sensitivity data under low and high cyclosporine whole blood levels are depicted. The increase in cyclosporine concentrations

Discussion

The present study of 20 normotensive kidney transplant recipients investigated baroreceptor function under basal conditions and 2 h after cyclosporine A intake to get information on a possible participation of this immunosuppressive drug in the development of baroreceptor dysfunction in kidney transplant recipients. In contrast to other investigations published previously, the sequence analysis technique [11]and FFT was used. The potential importance of these techniques is in particular related

Acknowledgements

This work was supported by a grant (01EC9801/4) of the German Federal Ministry of Science and Technology.

References (35)

  • U Scherrer et al.

    Cyclosporine-induced sympathetic activation and hypertension after heart transplantation

    New Engl. J. Med.

    (1990)
  • H Hohage et al.

    Baroreceptor function in kidney transplant recipients

    Clin. Nephrol.

    (1998)
  • S Strano et al.

    Power spectrum analysis of heart rate variability following kidney transplantation

    Transplant. Proc.

    (1993)
  • L Cloared-Blanchard et al.

    Spectral analysis of short-term blood pressure and heart rate variability in uremic patients

    Kidney Int.

    (1992)
  • S Omboni et al.

    Spectral and sequence analysis of finger blood pressure variability; comparison with analysis of intra-arterial recordings

    Hypertension

    (1993)
  • H.F Grobecker et al.

    Cyclosporine A-induced hypertension in SHR and WKY. Role of the sympatho–adrenal system

    Clin. Exp. Pharmacol. Physiol.

    (1995)
  • R.B Schwartz et al.

    Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy. CT and MR findings in 16 cases

    AJR. Am. J. Roentgenol.

    (1995)
  • Cited by (19)

    • Cardiovascular and renal interactions between cyclosporine and NSAIDs: Underlying mechanisms and clinical relevance

      2018, Pharmacological Research
      Citation Excerpt :

      Enhanced sympathoexcitatory discharge was reported for both drug groups as discussed in the previous section. Additionally, numerous studies describe a CSA-mediated attenuation of the chronotropic reflex via impairment of the autonomic modulation of the baroreceptor neural pathways [19,20,104–107] that is thought to be a result of an enhanced oxidative stress in central neuronal pools [44,108]. Similarly, animal studies showed that non-selective COX inhibitors impaired baroreceptor responsiveness when applied locally to the carotid sinus [108,109].

    • Cyclosporine counteracts endotoxemia-evoked reductions in blood pressure and cardiac autonomic dysfunction via central sGC/MAPKs signaling in rats

      2017, European Journal of Pharmacology
      Citation Excerpt :

      The inflammatory state induced by endotoxemia negatively correlates and predisposes to the reduced HRV and impaired cardiac autonomic function (Mazloom et al., 2013; Tateishi et al., 2007). The CSA facilitation of cardiac autonomic control appears to be specific to the endotoxic state because evidence from clinical (Gerhardt et al., 1999) and experimental reports (El-Mas et al., 2002) highlights a depressant effect for CSA on reflex cardiac autonomic function. In these latter studies, CSA impaired the arterial baroreflex function through the inhibition of central parasympathetic discharges.

    • Blockade of endothelin ET<inf>A</inf>, but not thromboxane, receptors offsets the cyclosporine-evoked hypertension and interrelated baroreflex and vascular dysfunctions

      2014, European Journal of Pharmacology
      Citation Excerpt :

      Regression analyses of the current data established a significant correlation between the hypertensive and baroreflex depressant effects of CSA, highlighting the potential of a causal relationship between the two hemodynamic effects of CSA. Similar blood pressure elevation and baroreflex dysfunction in response to CSA have been previously reported (Gerhardt et al., 1999; El-Mas et al., 2012). The concept that baroreflex impairment predisposes to hypertension has been established in clinical (Goldstein, 1983) and experimental studies (Fardin et al., 2012).

    • Redox imbalances incite the hypertensive, baroreflex, and autonomic effects of cyclosporine in rats

      2012, European Journal of Pharmacology
      Citation Excerpt :

      These findings convincingly argue for the importance of preserving the antioxidant propensity in guarding against the deleterious hypertensive, baroreflex and autonomic actions of CSA. Our findings that CSA elevated blood pressure and impaired baroreflexes are consistent with reported studies (Gerhardt et al., 1999; Shaltout and Abdel-Rahman, 2003), and raise the possibility that these two effects of CSA might be causally related. The concept that baroreflex impairment predisposes to hypertension has been established in clinical (Goldstein, 1983) and experimental studies (Fardin et al., 2012).

    • Determinants of baroreflex function in juvenile end-stage renal disease

      2006, Kidney International
      Citation Excerpt :

      Since HD and RT were on different medications, we must consider this as a confound. Cyclosporine A was found to depress baroreflex function both in animals and in humans.32, 33 Antihypertensive drugs can also modify our variables investigated.

    View all citing articles on Scopus
    View full text