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.