Protection against hypoxic injury of rat proximal tubules by felodipine via a calcium-independent mechanism

Abstract

Most evidence for a key role of calcium entry Key words Ischaemia • Calcium channel blocker * in hypoxia-induced renal damage stems from studies potassium channels with calcium channel blockers. In proximal tubules, a primary site of renal ischaemic injury, only phenylalkylamines, especially verapamil, have been studied. In the present study the effect of the dihydropyridine felodipine on hypoxic injury in isolated rat proximal tubules was investigated. To discriminate between the block of calcium entry and other effects, the enantiomers and a non-calcium blocking derivative of felodipine (H I86/86) were included. Cell membrane injury was assessed by measuring the release of lactate dehydrogenase (LDH). At high concentrations (100 jiM) felodipine, H I86/86 and the two enantiomers all protected rat proximal tubules against hypoxiainduced injury to the same extent. Absence of extra cellular calcium did not offer protection, but rather enhanced hypoxic injury. All dihydropyridines used increased the intracellular potassium concentration during normoxia. Felodipine attenuated the hypoxiainduced loss of cellular potassium. We have tried to mimic the effects of felodipine by using potassium chan nel blockers. The potassium channel blockers quinidine and glibenclamide afforded some protection against hypoxic injury, although their effects on cellular potas sium were equivocal. We conclude that the dihydropy ridine calcium channel blocker felodipine protects rat proximal tubules against hypoxic injury via a cal cium-independent mechanism. We propose that high levels of intracellular potassium and attenuation of potassium loss during hypoxia are important in this protection.

Multiparametric monitoring of ischemia-reperfusion in rat kidney: effect of ischemic preconditioning

“…In the ischemic kidney, it has been postulated that the activation of potassium channels contributes to hypoxic injury in proximal tubules (5). Furthermore, contrary to what has been suggested for myocardial tissue, attenuation of potassium loss during hypoxia by channel blockage protects against hypoxia-induced injury (5,6). Surprisingly, we found higher tissue impedance values in the late ischemic phase of preconditioned kidneys.…”

“…In regard to extracellular [Kϩ], early increases have been detected after the onset of renal ischemia as the result of loss of intracellular potassium ions (5). In addition, attenuation of intracellular potassium loss by means of Kϩ channel blockage has been shown to reduce hypoxic renal injury (5,6). Finally, an increase in tissue bioimpedance has been considered a reliable indicator of anoxic cellular edema by the detection of the narrowing of extracellular space and closure of gap junctions (7).…”

Cyclosporin-A-induced effects on the free Ca 2+ concentration in LLC-PK 1 -cells and their mechanisms

“…CyA, which raises blood pressure more markedly, caused a higher [Ca 2+ ] i increase than Tac. There is ample evidence of the presence of L-type Ca 2+ channels in proximal tubular cells [19,21,28] and in particular in LLC-PK 1 cells [14]. This concentration is relevant from a clinical point of view because it corresponds to trough blood levels (12 h after application) which are target concentrations of both immunosuppressants after organ transplantation [27].…”