SYMPATHETIC NEURAL MECHANISMS OF CYCLOSPORINE-INDUCED HYPERTENSION

The immunosuppressant drug cyclosporine A (CsA) has emerged as an impo rtant new cause of hypertension in both organ transplant recipients an d patients with autoimmune diseases. Despite the clinical importance o f this hypertension, the underlying mechanisms have been enigmatic. Th is article presents a conceptual framework for understanding the patho physiologic basis of CsA-induced hypertension and focuses on the hypot hesis that a common molecular mechanism is involved in mediating the i mmunosuppressive and the hypertensive effects of CsA. This mechanism i nvolves the binding of CsA to a newly discovered class of cytoplasmic receptors (termed ''immunophilins'') not only in T lymphocytes but als o in the kidney, vascular smooth muscle, and central nervous system, w hich are the main target tissues mediating CsA-induced hypertension. B inding 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 ro le in mediating both CsA-induced immunosuppression and hypertension, t he latter being produced at least in part by sympathetic neural activa tion. The elucidation of novel CsA-sensitive cellular signaling pathwa ys has lead to the search for the ideal immunosuppressant drug, one wh ich retains CsA's immunosuppressive efficacy but without its toxicity.