Cyclosporine A-induced hypertension in SHR and WKY: role of the sympatho-adrenal system.
1. Cyclosporine A induced a highly significant additional increase in blood pressure in spontaneously hypertensive rats (SHR) and elevated clearly the blood pressure in the genetically related normotensive controls, Wistar-Kyoto (WKY) rats, after both single (i.v.) and long-term administration (oral). 2. Acceleration of rise in blood pressure by cyclosporine is caused by sympatho-adrenal activation. Evidence for this mechanism of action came from the following pharmacological interventions: After chemical sympathectomy with 6-hydroxydopamine increase in blood pressure by cyclosporine was significantly reduced. Depletion of catecholamine stores by reserpine also diminished significantly the cyclosporine induced hypertension. Selective alpha1-adrenergic receptor blockade by prazosin blunted acute hypertension induced by cyclosporine. 3. Norepinephrine concentrations in the spleen of both WKY and SHR were reduced by long-term administration of cyclosporine. In the kidneys of WKY rats the level of norepinephrine was decreased but increased in the kidneys of SHR after long-term administration of cyclosporine. 4. Also the immunosuppressive agent FK506 with a macrolide-like structure induced acute hypertension in normotensive rats. The hypertensive effect was blunted by the vasoselective calcium channel blocker felodipine. 5. It is concluded that immunosuppressive agents like cyclosporine or FK506 activate the sympatho-adrenal system in normotensive and genetically hypertensive rats, thereby inducing hypertension. The mechanism of action may contribute to the hypertension seen in patients treated with cyclosporine after transplantation of heart, kidney or liver.
Grobecker
H F
HF
Department of Pharmacology, University of Regensburg, Germany.
Riebel
K
K
Wellenhofer
T
T
D000311:Adrenal Glands / Q000187:drug effects / Q000503:physiopathology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus; D009638:Norepinephrine