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J Thorac Cardiovasc Surg 1999;117:391-392
© 1999 Mosby, Inc.

BRIEF COMMUNICATIONS

SHORT-TERM EFFECT OF CYCLOSPORINE ON CIRCULATING ADRENOMEDULLIN AFTER HEART TRANSPLANTATION

Bernard Geny, MD, PhD, Hélène Hardy, Eliane Lampert, MD, Anne Charloux, MD, Arnaud Charpentier, MD, Jean Lonsdorfer, MD, Pascal Haberey, MD, François Piquard, PhD, Strasbourg, France

From Laboratoire des Régulations Physiologiques et des Rythmes Biologiques chez l'Homme et Service de Chirurgie Cardio-Vasculaire, Faculté de Médecine, Strasbourg, France.

Received for publication Oct 8, 1998. Accepted for publication Oct 14, 1998. Address for reprints: Bernard Geny, MD, PhD, Institut de Physiologie, Faculté de Médecine, 67085 Strasbourg Cedex, France.

Adrenomedullin (ADM) is a newly discovered potent endogenous vasorelaxing and natriuretic peptide produced by vascular smooth muscle and endothelial cells.Go 1 Secreted by the failing human heart in proportion to the severity of the disease, ADM has been proposed to oppose the local and circulating vasoconstrictive and sodium-retaining factors during heart disease.Go 2

Cardiac transplantation, an important surgical treatment for end-stage heart failure, partially normalizes the neurohumoral activation, but heart transplant recipients generally have hypertension and body fluid volume expansion. This may explain why both cardiac hormones, atrial and brain natriuretic peptides, remain elevated after heart transplantation.Go 3 Consistently, ADM has recently been reported to be elevated in heart transplant recipients in relation to cyclosporine (CsA) therapy (INN: ciclosporin), suggesting that ADM might be a compensatory mechanism to offset further CsA-induced development of cardiac or renal dysfunction.Go 4 However, whether CsA acutely increases the third cardiac hormone, ADM, in heart transplant recipients remains unknown.

Methods and results
Six heart transplant recipients gave informed consent and participated in the study, which was approved by the institutional review board for human studies. Resting values of plasma ADM, CsA, and creatinine, together with systemic blood pressure, were determined with the patient in the supine position, and the time courses of both plasma ADM and CsA were obtained simultaneously during the 7 hours after oral CsA administration (125 mg twice a day). Plasma ADM concentration was determined by radioimmunoassay with kits from Peninsula Laboratories (Belmont, Calif), after extraction by Sep-Pak C18 cartridges (Waters Corporation, Milford, Mass.). Total blood cyclosporinemia was determined by immunoenzymatic assay using kits from Behring Diagnostics Inc (Cupertino, Calif).

Heart transplant recipients were 47 ± 4 (mean ± SEM) years old, weighed 70 ± 3 kg, and the delay since transplantation was 44 ± 9 months. Systolic and diastolic blood pressures were 157 ± 9 and 98 ± 4 mm Hg, respectively, and serum creatinine concentration was 108 ± 7 µmol/L. Circulating ADM was higher than control values (110 ± 17 vs 20 ± 3 pmol/L in heart transplant recipients and control subjects, respectively; analysis of variance, P < .0001) and tended to correlate positively with CsA through levels (r = 0.79, P = .059). No relationship was observed between ADM and serum creatinine or blood pressure. Fig. 1 shows the simultaneous time course of plasma ADM and CsA. CsA concentrations increased significantly, peaked 90 minutes after drug administration (from 132 ± 17 to 783 ± 155 µg/L, P = .002), and returned near baseline value 7 hours later. However, interestingly, plasma ADM concentration failed to change significantly after CsA administration.



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  		Fig 1. Time course of plasma cyclosporinemia and ADM concentrations (means ± SEM) before (time 0) and after an acute administration of CsA. Differences between means were obtained by 1-way analysis of variance with repeated measures on time. When probability was lower than .05, pairwise comparisons with values at "time 0" were assessed by Tukey's test: *P < .01.

 
Discussion
Confirming the elevation of circulating ADM after heart transplantation in relation to CsA therapy, this study demonstrates for the first time the lack of short-term CsA-induced ADM increase in heart transplant recipients.

Although a decreased ADM renal clearance may participate in ADM elevation, the very mild degree of renal impairment generally observed after heart transplantation is unlikely to participate significantly in ADM increase in heart transplant recipients.Go Go 2,4 Accordingly, no correlation was observed between circulating ADM and serum creatinine in our patients.

Thus an increased secretion and release may explain ADM elevation after heart transplantation. Particularly, and consistently with a positive relationship between CsA trough levels and circulating ADM, it has been proposed that CsA may enhance ADM release from vascular endothelial and smooth muscle cells in heart transplant recipients.Go 4 To investigate whether this is a short-term effect of CsA, we monitored both cyclosporinemia and ADM during the 7 hours after oral CsA administration. This follow-up period appears long enough because peak CsA level and maximal acute nephrotoxic effect of CsA occur about 2 and 6 hours, respectively, after CsA administration. The results show that, although CsA concentrations were greatly modified, no simultaneous change in circulating ADM level was observed.

These data support the hypothesis that clinically relevant CsA therapy does not acutely increase ADM in heart transplant recipients. Furthermore, inasmuch as ADM increases local blood flow in heart and kidneys and may be involved in the defense mechanisms against further vascular resistance increase in heart transplant recipients,Go Go 4,5 it is possible that the low-dose CsA commonly used in stable heart transplant recipients may not significantly reduce renal or other local circulations. Further studies will be useful to determine whether increased ADM counteracts the long-term deleterious effects of CsA after cardiac transplantation.

References

  1. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993;192:553-60. [Medline]
  2. Jougasaki M, Rodeheffer RJ, Redfield MR, Yamamoto K, Wei CM, McKinley LJ, et al. Cardiac secretion of adrenomedullin in human heart failure. J Clin Invest 1996;97:2370-6. [Medline]
  3. E1 Gamel A, Campbell C, Yonan N, Keevil B, Warbuton R, Woodcock A, et al. Atrial natriuretic peptide release after cardiac transplantation. J Thorac Cardiovasc Surg 1996;112:1128-9. [Free Full Text]
  4. Geny B, Brandenberger G, Lonsdorfer J, Chakfé N, Haberey P, Piquard F. Circulating adrenomedullin is increased after heart transplantation. Cardiovasc Res 1999. In press.
  5. He H, Bessho H, Fujisawa Y, Horiuchi K, Tomohiro A, Kita T, et al. Effects of synthetic rat adrenomedullin on regional hemodynamics in rats. Eur J Pharmacol 1995;273:209-14. [Medline]



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