Differential effects of acute and sustained cyclosporine and tacrolimus on sympathetic nerve activity.

BACKGROUND: We studied the effect of acute and sustained cyclosporine and tacrolimus on muscle sympathetic nerve activity (MSNA) in groups of healthy male volunteers. METHODS AND RESULTS: Acute cyclosporine in normal dose (2.5 mg/kg) increased MSNA from 11 +/- 6 to 19 +/- 8 bursts/min (P < 0.05). Acute cyclosporine in high dose (10 mg/kg) increased MSNA from 13 +/- 6 to 25 +/- 4 bursts/min (P < 0.05) and increased heart rate and mean arterial pressure (heart rate from 64 +/- 8 to 74 +/- 6 b.p.m., MAP from 92 +/- 10 to 105 +/- 8 mmHg; both P < 0.05). Sustained cyclosporine (2.5 mg/kg b.i.d. for 2 weeks) suppressed MSNA from 14 +/- 6 to 8 +/- 7 bursts/min (P < 0.05). Blood pressure increased from 89 +/- 6 to 98 +/- 6 mmHg (P < 0.05). Body weight increased and plasma renin activity was suppressed. Acute tacrolimus in regular dose (0.05 mg/kg) and high dose (0.20 mg/kg) had no effect on MSNA and blood pressure. Sustained tacrolimus (0.05 mg/kg b.i.d. for 2 weeks) had no effect on blood pressure, body weight and plasma renin activity, but decreased MSNA from 14 +/- 6 to 8 +/- 5 bursts/min (P < 0.05). CONCLUSION: Sympathetic overactivity plays a role in the acute hypertensive action of cyclosporine. Cyclosporine given during 2 weeks increases blood pressure and suppresses MSNA, possibly by volume retention. Tacrolimus, in the presently applied dosages, does not cause hypertension or sympathetic overactivity. However, sustained tacrolimus also suppresses sympathetic activity, the reason of which is unclear.

Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects.

BACKGROUND: The side effects of cyclosporine, nephrotoxicity and hypertension, contribute to long-term renal graft failure and cardiovascular morbidity in graft recipients. It is not clear whether tacrolimus is as nephrotoxic and hypertensive as cyclosporine. Data on this subject are not consistent because of differences in dosage and duration of treatment and the presence of comorbidity in the studied patients. A comparison of both drugs with respect to renal hemodynamics and blood pressure has not been performed yet in healthy subjects. METHODS: We studied blood pressure, glomerular filtration rate, and effective renal plasma flow in eight healthy subjects at baseline and after 2 weeks administration of cyclosporine and tacrolimus, in randomized order. Trough levels of either drug were within the currently recommended therapeutical range of 100-200 ng/ml for cyclosporine and 5-15 ng/ml for tacrolimus. RESULTS: Tacrolimus did not influence renal hemodynamic parameters, in contrast to cyclosporine. During cyclosporine, glomerular filtration rate decreased from 98+/-9 ml/min/1.732 to 85+/-10 ml/min/1.732 (P<0.05), and ERPF decreased from 597+/-108 ml/min/1.732 to 438+/-84 ml/min/1.732 (P<0.01). Mean arterial blood pressure increased from 93+/-8 mmHg to 108+/-10 mmHg (P<0.05) during cyclosporine and remained unchanged during tacrolimus. CONCLUSIONS: We conclude that tacrolimus given during 2 weeks in the currently advised dosage has no unfavorable effects on renal hemodynamics and blood pressure in healthy individuals. The use of tacrolimus in organ transplant recipients may in the long-term lead to better renal function and less cardiovascular morbidity than the use of cyclosporine.