CYCLOSPORINE-INDUCED HYPERTENSION AND DECLINE IN RENAL-FUNCTION IN HEALTHY-VOLUNTEERS

Objective To investigate the effect of cyclosporine A (CsA; Sandimmun Neoral) on systemic and renal hemodynamics, tubular function, and sodi um excretion in healthy volunteers. Furthermore, we studied whether Cs A enhances the systemic and renal hemodynamic sensitivity to norepinep hrine, Methods Eighteen healthy volunteers were administered 10 mg/kg CsA or placebo capsules in a double-blind fashion. The mean arterial b lood pressure (MAP), renal vascular resistance (RVR), glomerular filtr ation rate (GFR), and renal clearances of lithium (C-Li) and sodium (C -Na) were measured for 8 h after ingestion of the capsules. Norepineph rine (2 mu g/kg per h) was infused intravenously for 1.5 h into nine s ubjects. Results CsA increased the MAP by 17 +/- 2 mmHg. The GFR decre ased by 18 +/- 2% (P < 0.001) and the RVR increased by 37 +/- 4% (P < 0.001) after ingestion of CsA. The CsA-induced increase in MAP precede d the CsA-induced fall in GFR. The rise in MAP was followed by an earl y 35 +/- 8% increase in C-Na (P < 0.001). At the end of the 8 h study period, C-Na decreased by 25 +/- 7% (P < 0.001). Using C-Li, it was fo und that the initial natriuresis had been caused by a relative decreas e both in proximal and in distal tubular reabsorption of sodium, where as the late sodium retention was secondary to the CsA-induced fall in GFR. Infusion of norepinephrine increased the MAP, RVR, and filtration fraction, and decreased the renal plasma flow, without CsA having any additional effect.Conclusion It was demonstrated that a single oral d ose of CsA caused a rise in blood pressure and transient natriuresis, followed by a fall in GFR and antinatriuresis. Thus, the present study confirms and extends earlier observations that renal dysfunction and sodium retention are not the initiating events in CsA-induced hyperten sion. The study also affords evidence suggesting that such rises in bl ood pressure are not mediated by an increased sensitivity to norepinep hrine.