R publications support many different etiologies for cyclosporine-induced hypertension, but none have been definitive. Several studies have demonstrated impaired endothelium-dependent vasodilation in arteries isolated from cyclosporine-treated animals,1,2 and in human peripheral arteries exposed to cyclosporine in vitro.3 Furthermore, studies suggest that long-term cyclosporine treatment suppresses synthesis of nitric oxide (NO), a potent endogenous vasodilator.4–6 Pretreatment with L-arginine, the amino acid precursor for NO, preserves endothelium-dependent vascular relaxation and prevents systemic hypertension in cyclosporine-treated animals.7,8 Therefore, we hypothesized that cyclosporine-induced hypertension is associated with an altered L-arginine/NO pathway in vivo. To evaluate this hypothesis, we studied the acute effects of intravenous L-arginine infusion on blood pressure (BP), heart rate, left ventricular (LV) function, and NO production in young heart transplant patients receiving cyclosporine. • • • The study population consisted of 9 young cardiac transplant patients and 5 healthy volunteers. All patients were receiving cyclosporine as part of their immunosuppressive regimen, in addition to an antihypertensive medication (either a calcium channel antagonist or an angiotensin-converting enzyme inhibitor). No control subject was taking any medications at the time of the study. Patient and parental permission were obtained for inclusion in the study. The research protocol was approved by The University of Michigan Medical School Institutional Review Board for Human Subject Research. Heart transplant patients were studied in the cardiac catheterization laboratory after routine cardiac catheterization and endomyocardial biopsy (Figure 1). All patients were awake and alert; only local anesthetic was used for the catheterization. Control subjects were also studied in the cardiac catheterization laboratory. All subjects fasted for $4 hours before the study, and all subjects remained in the supine position throughout the protocol. Baseline noninvasive BP (Dinamap) and heart rate were determined. Following baseline measurements, all subjects received a continuous intravenous infusion of 10% Larginine hydrochloride (total dose 500 mg/kg, maximum of 30 g).9,10 The pharmacokinetics of intravenous arginine have been debated in the literature. One recent study showed a biphasic elimination pattern after intravenous administration,11 whereas others have found the pharmacokinetics to be constant in the range of infusion rates used in our study.9 Depending on the study, the half-life of arginine for the dose used in this protocol ranged from 17.8 6 1.9 to 42 6 2 minutes. In our study, arginine infusion was given over 30 minutes to achieve a steady state, and then discontinued, followed by a 30-minute recovery period. NO is synthesized in biologic systems by the enzyme NO synthase, which acts on L-arginine and molecular oxygen to produce NO and citrulline in a stoichiometric fashion. NO is rapidly degraded and is difficult to quantitate directly. Therefore, as an indirect measure of NO production, we measured serum citrulline concentrations by high-performance liquid chromatography, at baseline, 30, and 60 minutes. To determine LV function, either LV shortening fraction (measured by M-mode echocardiography in the parasternal short-axis view), or LV ejection fraction (measured by Simpson’s method from 2-dimensional echocardiography in the apical 4-chamber view) was obtained in 6 of the 9 transplant patients at baseline and at 30 minutes. Echocardiograms were not available in the control patients. Baseline, 30-minute (“arginine infusion”), and 60minute (“recovery”) systolic BP, diastolic BP, mean arterial BP, and serum citrulline concentration are reported for transplant patients and control subjects (expressed as mean 6 SD). Differences between patients and controls were tested using a Student’s t test. Differences in the same patient compared at baseline, with arginine infusion, and recovery were tested using a paired Student’s t test. • • • Baseline characteristics as well as experimental data on all subjects are presented in Table 1. Mean age of the cardiac transplant patients was 20 years (range 13 to 26) and mean systolic blood pressure was 130 mm Hg (range 103 to 147). Mean age of the control subjects was 34 years (range 28 to 38) and mean systolic blood pressure was 129 mm Hg (range 122 to 143). There was no significant difference in baseline BP From the Departments of Pediatrics and Communicable Diseases, and Physiology, University of Michigan Medical Center, Ann Arbor, Michigan. This study was supported by grants from the American Heart Association, Michigan Affiliate (grant #07FW978), and the General Clinical Research Center of the University of Michigan (NIH grant #M01-RR00042). Dr. Gomez’s address is: University of Michigan Congenital Heart Center, University of Michigan, F1310 MCHC, Box 0204, 1500 E. Medical Center Drive, Ann Arbor, Michigan 481090204. E-mail: cago@umich.edu. Manuscript received May 30, 2000; revised manuscript received and accepted October 17, 2000.
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Jun 26, 2003
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