Hiromi Shimizu*, Toshio Kumai and Shinichi Kobayashi
Department of Pharmacology, St. Marianna University School of Medicine,
2-16-1, Sugao, Miyamae-ku, Kawasaki-shi, Kanagawa 216-8511, Japan
*Corresponding author. FAX: +81-44-975-0509
E-mail: yakuri@marianna-u.ac.jp
Abstract: 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 the cyclosporine-treated group in comparison to that in the control group.
Norepinephrine and epinephrine levels in the adrenal medulla and plasma
of cyclosporine-treated rats were also significantly higher than levels
in the control rats. Moreover, tyrosine hydroxylase (TH) activity and TH
mRNA expression in the adrenal medulla of cyclosporine-treated rats were
significantly elevated. Administration of the TH inhibitor a-methyl-p-tyrosine
(200 mg/kg, b.i.d., s.c.) for 3 days significantly suppressed cyclosporine-induced
increases in systolic blood pressure. Phosphorylation of cyclic AMP responsive
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 expression of
cyclosporine-treated rats was less than that of the control rats. These
results suggest that cyclosporine increased blood pressure via activation
of the catecholamine synthetic pathway due to the activation of transcription
factor CREB.
Keywords: Cyclosporine, Hypertension, Tyrosine hydroxylase, Catecholamine,
Transcription factor
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