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-alkylamines, 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 (H186/86) were included. Cell membrane injury was assessed by measuring the release of lactate dehydrogenase (LDH). At high concentrations (100 microM) felodipine, H186/86 and the two enantiomers all protected rat proximal tubules against hypoxia-induced injury to the same extent. Absence of extracellular calcium did not offer protection, but rather enhanced hypoxic injury. All dihydropyridines used increased the intracellular potassium concentration during normoxia. Felodipine attenuated the hypoxia-induced loss of cellular potassium. We have tried to mimic the effects of felodipine by using potassium channel blockers. The potassium channel blockers quinidine and glibenclamide afforded some protection against hypoxic injury, although their effects on cellular potassium were equivocal. We conclude that the dihydropyridine calcium channel blocker felodipine protects rat proximal tubules against hypoxic injury via a calcium-independent mechanism. We propose that high levels of intracellular potassium and attenuation of potassium loss during hypoxia are important in this protection.
Peters
S M
SM
Department of Nephrology, University Hospital Nijmegen, Nijmegen, The Netherlands.
Tijsen
M J
MJ
Bindels
R J
RJ
van Os
C H
CH
Wetzels
J F
JF
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015687:Cell Hypoxia; D015736:Felodipine / Q000031:analogs & derivatives / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D007770:L-Lactate Dehydrogenase; D015736:Felodipine; D011188:Potassium; D005905:Glyburide; D002118:Calcium