Thromboxane synthesis inhibition increases renal prostacyclin and prevents renal disease progression in rats with remnant kidney.
Previous studies have demonstrated that inhibition of thromboxane A2-dependent platelet aggregation by the thromboxane A2 synthase inhibitor, OKY 1581, ameliorated the progressive kidney disease of rats with subtotal renal ablation. OKY 1581 also decreased the excessive renal thromboxane A2 synthesis and lowered systemic blood pressure. In the same model, a low dose aspirin and a specific thromboxane A2 receptor antagonist failed to influence proteinuria, glomerulosclerosis, and hypertension, thus excluding a role for either platelet or renal thromboxane A2 in renal disease progression. The aims of this study were to establish (1) whether a thromboxane A2 synthase inhibitor different from OKY 1581 could retard the progression of glomerular disease in rats with remnant kidney and (2) whether this effect was associated with an increase in renal synthesis of the vasodilatory prostacyclin. Treatment of rats with renal mass ablation with FCE 22178 (100 mg/kg by gavage and 200 mg/kg in the drinking water) for 35 days starting 10 days after surgical ablation was associated with an improvement in renal function in comparison with rats receiving the vehicle alone. Proteinuria was significantly lower, and rats were partially protected from the development of glomerulosclerosis. Systolic blood pressure was significantly lower than in animals given the vehicle. Urinary thromboxane B2 excretion was significantly decreased, and urinary 6-keto-prostaglandin F1 alpha increased in respect to vehicle-treated rats. We conclude that FCE 22178 limits glomerular injury in rats with remnant kidney.
Zoja
C
C
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Perico
N
N
Corna
D
D
Benigni
A
A
Gabanelli
M
M
Morigi
M
M
Bertani
T
T
Remuzzi
G
G
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000818:Animals; D001760:Bleeding Time; D001794:Blood Pressure / Q000187:drug effects; D011464:Epoprostenol / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000473:pathology / Q000503:physiopathology* / Q000652:urine; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011507:Proteinuria / Q000209:etiology; D051381:Rats; D011919:Rats, Inbred Strains; D013929:Thromboxane B2 / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D007093:Imidazoles; D009281:Naphthalenes; D013931:Thromboxanes; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D013930:Thromboxane-A Synthase; C066217:rolafagrel