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 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 alphamethyl-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.
Shimizu
H
H
Department of Pharmacology, St. Marianna University School of Medicine, Kanagawa, Japan. yakuri@marianna-u.ac.jp
Kumai
T
T
Kobayashi
S
S
D000313:Adrenal Medulla / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D015152:Blotting, Northern; D019703:Calcineurin / Q000378:metabolism; D002395:Catecholamines / Q000097:blood / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008297:Male; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D015854:Up-Regulation; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D002395:Catecholamines; D017362:Cyclic AMP Response Element-Binding Protein; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D019805:alpha-Methyltyrosine; D016572:Cyclosporine; D014446:Tyrosine 3-Monooxygenase; D019703:Calcineurin