Effect of selective inhibition of thromboxane synthesis on renal function in diabetic nephropathy.
Studies of nondiabetic renal disease suggest that thromboxane may be an important mediator of abnormal renal function. The role of thromboxane in diabetic nephropathy is not fully understood. We measured in a double-blind, randomized, placebo-controlled crossover study the effect of a thromboxane synthase inhibitor (FCE 22178, 400 mg two or three times per day) on urinary excretion of thromboxane B2 and 6-keto-prostaglandin F1 alpha, glomerular filtration rate (measured as clearance of polyfructosan), effective renal plasma flow (clearance of para-aminohippuric acid), fractional clearances of albumin and immunoglobin G and the reabsorption rate of beta 2-microglobulin in 15 patients with type 1 (insulin-dependent) diabetic nephropathy. In seven additional patients, the effect of the thromboxane synthase inhibitor given as 400 mg twice per day was compared with that of the thromboxane synthase inhibitor given as 400 mg three times per day. FCE 22178 administration caused a significant inhibition in the excretion of urinary thromboxane B2 and 2,3-dinor-thromboxane B2 compared with placebo (12.3 +/- 2.1 vs 24.6 +/- 5.1 ng/gm creatinine, p = 0.006, and 78.5 +/- 20.3 vs 335.5 +/- 84.1 ng/gm creatinine, p = 0.004, respectively) without any compensatory increase of 6-keto- prostaglandin F1 alpha or 2,3-dinor-6-keto-prostaglandin F1 alpha that reflect prostacyclin I2 biosynthesis. Glomerular filtration rate, effective renal plasma flow, renal vascular resistance, and filtration fraction were not significantly different after placebo or thromboxane synthase inhibitor treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Kontessis
P S
PS
Unit for Metabolic Medicine, UMDS Guy's Hospital Campus, London Bridge, London, UK.
Jones
S L
SL
Barrow
S E
SE
Stratton
P D
PD
Alessandrini
P
P
De Cosmo
S
S
Ritter
J M
JM
Viberti
G C
GC
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004573:Electrolytes / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000652:urine; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D011507:Proteinuria / Q000652:urine*; D012079:Renal Circulation / Q000187:drug effects; D013929:Thromboxane B2 / Q000652:urine*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014508:Urea / Q000097:blood / Q000652:urine
D004573:Electrolytes; D007093:Imidazoles; D007074:Immunoglobulin G; D009281:Naphthalenes; D013929:Thromboxane B2; D014508:Urea; D003404:Creatinine; D013930:Thromboxane-A Synthase; C066217:rolafagrel