Increased sensitivity to endothelin-1 in isolated Krebs'-perfused kidneys of streptozotocin-diabetic rats.
1. Vascular responses to endothelin-1 (ET-1) and noradrenaline (NA) were measured in isolated Krebs'-perfused kidneys of 2 week old streptozotocin-diabetic and non-diabetic rats. 2. Bolus injections of either ET-1 or NA caused dose-dependent increases in perfusion pressure. Responses to ET-1 (10-60 ng/g kidney), but not to NA (0.001-10 micrograms/g kidney), were significantly potentiated in kidneys of diabetic rats compared with non-diabetics. 3. Indomethacin significantly attenuated responses to NA (0.3-10 micrograms/g kidney) in kidneys of both diabetic and non-diabetic rats. 4. Neither indomethacin (1 mumol/L) nor the cyclo-oxygenase/lipoxygenase inhibitor BW755C (1 mumol/L) had any significant effect on the log dose-response curve to ET-1 in either group of kidneys. 5. Perfusion with N-nitro-L-arginine (NOLA; 10 mumol/L) had no effect on basal perfusion pressures, but potentiated responses to ET-1 in both groups of kidneys. However, the difference in responses to ET-1 between kidneys from diabetic and non-diabetic rats remained significant in the presence of NOLA. 6. ET-1 responses were inhibited in Ca(2+)-free Krebs' solution (plus 1 mmol/L EGTA). 7. The results of the present study indicate an increased sensitivity to ET-1 in isolated Krebs'-perfused kidneys of diabetic rats. Responses to ET-1 were unaffected by cyclo-oxygenase and/or lipoxygenase inhibitors, but were potentiated by an endothelium-derived relaxing factor (EDRF) synthesis inhibitor.
Tammesild
P J
PJ
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Hodgson
W C
WC
King
R G
RG
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D016232:Endothelins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology; D019335:Nitroarginine; D009638:Norepinephrine / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D019335:Nitroarginine; D009569:Nitric Oxide; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D001120:Arginine; D009638:Norepinephrine