Cyclosporine A--calcium channels interaction: a possible mechanism for nephrotoxicity

Rabbit PTC concentrated CsA rapidly and reached saturation by two to three minutes. CsA uptake was temperature dependent but was not altered by replacement of uptake medium Na with K or mannitol, changes in extracellular pH, and the presence of metabolic inhibitors or organic anions and cations. The organic Ca channel blockers verapamil and diltiazem and the inorganic Ca channel blocker cadmium caused significant inhibition in both Ca and CsA uptake by PTC. Other Ca transport modulators, ruthenium red and trifluoroperazine, decreased PTC Ca uptake, and A23187 increased PTC Ca uptake, but they were all without effect on CsA uptake. We propose that the CsA uptake pathway through PTC is situated at or close to Ca channels so that changes induced by Ca channel blockers also affect transit of CsA through the CsA "passageway." The close spatial relationship between CsA and Ca channels also raises the possibility that CsA uptake may intiate Ca channel-related activities, thereby leading to a cascade of Ca-dependent processes and causing nephrotoxicity. A hypothesis is depicted in Fig 1.