Objectives--FK506 Binding Protein 12 and its related isoform 12.6 (FKBP12/12.6) stabilize a closed state of intracellular Ca²⁺ release channels (ryanodine receptors [RyRs]), and in myocytes removal of FKBP12/12.6 from RyRs alters intracellular Ca²⁺ levels. The immunosuppressive drugs rapamycin and FK506 bind and displace FKBP12/12.6 from RyRs, and can also cause endothelial dysfunction and hypertension. We tested whether rapamycin and FK506 cause an intracellular Ca²⁺ leak in endothelial cells and whether this affects endothelial function and blood pressure regulation.

Methods and Results--Rapamycin or FK506 concentration-dependently caused a Ca²⁺ leak in isolated endothelial cells, decreased aortic NO production and endothelium-dependent dilation, and increased systolic blood pressure in control mice. Rapamycin or FK506 at 10 µmol/L abolished aortic NO production and endothelium-dependent dilation. Similar results were obtained in isolated endothelial cells and aortas from FKBP12.6^-/- mice after displacement of FKBP12 with 1 µmol/L rapamycin or FK506. In hypertensive FKBP12.6^-/- mice, systolic blood pressures were further elevated after treatment with either rapamycin or FK506. Blockade of the Ca²⁺ leak with ryanodine normalized NO production and endothelium-dependent dilation.

Conclusions--Complete removal of FKBP12 and 12.6 from endothelial RyRs induces an intracellular Ca²⁺ leak which may contribute to the pathogenesis of endothelial dysfunction and hypertension caused by rapamycin or FK506.