PROTECTION AGAINST HYPOXIC INJURY OF RAT PROXIMAL TUBULES BY FELODIPINE VIA A CALCIUM-INDEPENDENT MECHANISM

Most evidence for a key role of calcium entry in hypoxia-induced renal damage stems from studies with calcium channel blockers. In proximal tubules. a primary site of renal ischaemic injury only phenyl-alkylami nes, especially verapamil, have been studied. In the present study the effect of the dihydropyridine felodipine on hypoxic injury in isolate d rat proximal tubules was investigated. To discriminate between the b lock of calcium entry and other effects, the enantiomers and a non-cal cium blocking derivative of felodipine (H186/86) were included. Cell m embrane injury was assessed by measuring the release of lactate dehydr ogenase (LDH). At high concentrations (100 mu M) felodipine, H186/86 a nd the two enantiomers all protected rat proximal tubules against hypo xia-induced injury to the same extent. Absence of extracellular calciu m did not offer protection, but rather enhanced hypoxic injury. All di hydropyridines used increased the intracellular potassium concentratio n during normoxia. Felodipine attenuated the hypoxia-induced loss of c ellular potassium. We have tried to mimic the effects of felodipine by using potassium channel blockers. The potassium channel blockers quin idine and glibenclamide afforded some protection against hypoxic injur y, although their effects on cellular potassium were equivocal. We con clude that the dihydropyridine calcium channel blocker felodipine prot ects rat proximal tubules against hypoxic injury via a calcium-indepen dent mechanism. We propose that high levels of intracellular potassium and attenuation of potassium loss during hypoxia are important in thi s protection.