Sympathetic neural mechanisms of cyclosporine-induced hypertension.
The immunosuppressant drug cyclosporine A (CsA) has emerged as an important new cause of hypertension in both organ transplant recipients and patients with autoimmune diseases. Despite the clinical importance of this hypertension, the underlying mechanisms have been enigmatic. This article presents a conceptual framework for understanding the pathophysiologic basis of CsA-induced hypertension and focuses on the hypothesis that a common molecular mechanism is involved in mediating the immunosuppressive and the hypertensive effects of CsA. This mechanism involves the binding of CsA to a newly discovered class of cytoplasmic receptors (termed "immunophilins") not only in T lymphocytes but also in the kidney, vascular smooth muscle, and central nervous system, which are the main target tissues mediating CsA-induced hypertension. Binding of CsA to its receptor leads to inhibition of calcineurin, the Ca2+/calmodulin-dependent protein phosphatase. Evidence is reviewed to support the hypothesis that calcineurin inhibition plays a pivotal role in mediating both CsA-induced immunosuppression and hypertension, the latter being produced at least in part by sympathetic neural activation. The elucidation of novel CsA-sensitive cellular signaling pathways has lead to the search for the ideal immunosuppressant drug, one which retains CsA's immunosuppressive efficacy but without its toxicity.
Sander
M
M
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8573, USA.
Lyson
T
T
Thomas
G D
GD
Victor
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RG
D000591:Amino Acid Isomerases / Q000378:metabolism; D000818:Animals; D019703:Calcineurin; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000378:metabolism; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000503:physiopathology*
D002121:Calcium Channel Blockers; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase