Involvement of tyrosine hydroxylase upregulation in cyclosporine-induced hypertension

To identify the mechanism of cyclosporine-induced hypertension, we studied the effect of cyclosporine on the catecholamine synthetic pathway in rats. We administered cyclosporine (10 mg/kg per day, s.c.) for 3 days to 10-week -old male Wistar rats. Systolic blood pressure increased significantly in t he cyclosporine-treated group in comparison to that in the control group. N orepinephrine and epinephrine levels in the adrenal medulla and plasma of c yclosporine-treated rats were also significantly higher than levels in the control rats. Moreover, tyrosine hydroxylase (TH) activity and TH mRNA expr ession in the adrenal medulla of cyclosporine-treated rats were significant ly elevated. Administration of the TH inhibitor alpha -methyl-p-tyrosine (2 00 mg/kg, b.i.d., s.c.) for 3 days significantly suppressed cyclosporine-in duced increases in systolic blood pressure. Phosphorylation of cyclic AMP r esponsive element-binding protein (CREB) and its binding activity to DNA in the nuclear fraction from the adrenal medulla of cyclosporine-treated rats were much higher than that of the control rats. Calcineurin protein expres sion of cyclosporine-treated rats was less than that of the control rats. T hese results suggest that cyclosporine increased blood pressure via activat ion of the catecholamine synthetic pathway due to the activation of transcr iption factor CREB.