Cyclosporine and FK506 differentially regulate the sarcolemmal Na+-K+ pump

Cyclosporine A (CsA) and FK506, important immunosuppressants, have been sho wn to inhibit the enzymatic equivalent of the Na+-K+ pump (Na+,K+-ATPase) i n renal tissue. A similar effect in the heart may contribute to the adverse effects of these agents that include calcification, contractile dysfunctio n, and altered calcium handling. However, inhibition of the pump has not be en demonstrated in cardiac myocytes. We isolated single ventricular myocyte s from control rabbits and from rabbits administered CsA or FK506 for 1 wee k. Na+-K+ pump current (I-p) was measured using the whole-cell patch-clamp technique. When patch pipettes contained Na+ in a concentration ([Na](pip)) near physiological intracellular levels mean I-p of cardiac myocytes from rabbits with serum CsA levels within the therapeutic range was significantl y lower than mean I-p of cardiac myocytes from controls. Treatment had no e ffect on I-p measured using a [Na] pip expected to nearly saturate intracel lular binding sites. The CsA-induced inhibition of I-p was dependent on the K+ concentration in pipette solutions. Mean Ip in myocytes from rabbits wi th serum levels of FK506 within the therapeutic range was similar to mean I -p in myocytes from controls, whereas FK506 in a dose inducing serum levels severalfold above the therapeutic range caused significant pump inhibition . Using ion-sensitive microelectrodes we showed the intracellular Na+ activ ity in papillary muscles isolated from rabbits treated with CsA was signifi cantly higher than in papillary muscles from control rabbits, indicating th at CsA causes pump inhibition in intact myocytes with a physiological intra cellular milieu.