Sulphonylurea drugs reduce hypoxic damage in the isolated perfused rat kidney.
Sulphonylurea drugs have been shown to protect against hypoxic damage in isolated proximal tubules of the kidney. In the present study we investigated whether these drugs can protect against hypoxic damage in a whole kidney preparation. Tolbutamide (200 microM) and glibenclamide (10 microM) were applied to the isolated perfused rat kidney prior to changing the gassing from oxygen to nitrogen for 30 min. Hypoxic perfusions resulted in an increased fractional excretion of glucose (FE % glucose 14.3+/-1.5 for hypoxic perfusions vs 4.9+/-1.6 for normoxic perfusions, mean +/- s.e. mean, P<0.05), which could be completely restored by 200 microM tolbutamide (5.7+/-0.4 for tolbutamide vs 14.3+/-1.5 for untreated hypoxic kidneys, P<0.01). Furthermore, tolbutamide reduced the total amount of LDH excreted in the urine (220+/-100 mU for tolbutamide vs. 1220+/-160 mU for untreated hypoxic kidneys, P<0.01). Comparable results were obtained with glibenclamide (10 microM). In agreement with the effect on functional parameters, ultrastructural analysis of proximal tubules showed increased brush border preservation in tolbutamide treated kidneys compared to untreated hypoxic kidneys. We conclude that glibenclamide and tolbutamide are both able to reduce hypoxic damage to proximal tubules in the isolated perfused rat kidney when applied in the appropriate concentrations.
Department of Pharmacology and Toxicology 233, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
R
R
Engbersen
M M
MM
Moons
A C
AC
Wouterse
H B
HB
Dijkman
C
C
Kramers
P
P
Smits
F G
FG
Russel
D018528:ATP-Binding Cassette Transporters; D000704:Analysis of Variance; D000818:Animals; D005905:Glyburide / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism / Q000517:prevention & control*; D054086:KATP Channels; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D010477:Perfusion; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014044:Tolbutamide / Q000627:therapeutic use*
D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D054086:KATP Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D020011:Protective Agents; C092520:uK-ATP-1 potassium channel; D014044:Tolbutamide; D005905:Glyburide