Suppression of urinary albumin excretion in diabetic rats by 4'(imidazol-1-yl) acetophenone, a selective inhibitor of thromboxane synthesis.
Thromboxane contributes to the regulation of glomerular hemodynamics in experimental models of diabetes and has been implicated as mediator in some models of glomerular injury. In the present study we examined urinary albumin, protein, and thromboxane B2 (TXB2) excretion during the 170 days after induction of diabetes by injection of streptozotocin in insulin-treated moderately hyperglycemic (200 to 400 mg/dl glucose) rats (SDRs). The effects of a thromboxane synthesis inhibitor, 4'-(imidazol-1-yl)acetophenone (TXI) (100 mg/kg/day) on these parameters were also assessed. Urinary TXB2 and albumin excretion in SDRs was not different from that in normal rats between 7 and 90 days but were three times higher than normal in SDRs at 125 and 170 days after induction of diabetes. In SDRs, urinary protein excretion was higher than in controls at 170 days but not at earlier time points. Inulin clearance (CIn) of SDRs was significantly higher than control values at 7 and 90 days and was not influenced by TXI during this period. At 170 days CIn was not significantly different in SDRs and normal rats. By contrast, albumin clearance (CAIb) and fractional CAIb were elevated in SDRs when compared with those values in normal rats. Treatment of SDRs with TXI for 170 days completely prevented the rise in urinary TXB2, albumin, and protein excretion, as well as the rise in fractional CAIb, but did not alter prostaglandin E2 (PGE2) excretion. TXI also increased CIn in SDRs to levels that were significantly higher than normal at 170 days. TXI had no significant effect on urinary PGE2, TXB2, albumin, or protein excretion or on CIn in normal rats and did not influence blood pressure or blood glucose in normal rats or SDRs. The results suggest a role for thromboxane in the mediation of albuminuria in the SDR.
Department of Medicine, University of Pittsburgh, PA.
P A
PA
Craven
F R
FR
DeRubertis
D000419:Albuminuria; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology / Q000652:urine*; D015232:Dinoprostone / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D011507:Proteinuria; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012709:Serum Albumin / Q000378:metabolism; D013929:Thromboxane B2 / Q000652:urine*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D001786:Blood Glucose; D007093:Imidazoles; D012709:Serum Albumin; D013931:Thromboxanes; C034480:Ro 22-3581; D013929:Thromboxane B2; D015232:Dinoprostone