Abstract
Calcineurin inhibitors (CNI) are known to be nephrotoxic although their effect on the renal medulla remains poorly defined. Their potential to alter vasa recta diameter as a read out of altered medullary blood flow (MBF) was investigated in this study with a view to determining their effect on MBF in vivo. CNI-mediated changes in vasa recta diameter were measured following luminal perfusion and bath superfusion of cyclosporine (CsA) and tacrolimus (FK506). Luminal perfusion of CsA (3 μM) and FK506 (0.1 μM) resulted in a pericyte-mediated constriction of vasa recta (25 ± 1.8%, n= 8 and 20.38 ± 2.1%, n=8 respectively), which was significantly greater than the pericyte-mediated constriction evoked following superfusion of tissue with CsA (3 μM) and FK506 (0.1 μM; 8.79 ± 1.03%, p< 0.001 n=8; and 8.03 ± 1.36%, p< 0.001, n= 8 respectively). Interestingly, luminal perfusion and superfusion of tissue with rapamycin (0.05 μM) failed to evoke a significant pericyte-mediated constriction of vasa recta (3.4 ± 0.87 % and 3.16 ± 1.01% respectively), which is in fitting with clinical observations that report reduced nephrotoxicity associated with this drug. Given that in vivo, the kidney is exposed to CNIs via the blood, it is likely that these agents evoke a more significant effect on the medullary microcirculation than has previously been appreciated. Further studies are now needed to better understand the cellular mechanisms underlying the CNI-mediated constriction of vasa recta that is likely to impact upon medullary blood flow following chronic exposure to these drugs.
Published Version
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