Determination of efficacy of linotroban by inducing a reduction of renal inulin/para-aminohippuric acid clearances with the thromboxane A(2) mimetic U-46619 in the conscious female rat

Linotroban (CAS 141443-73-4), a potent and selective thromboxane (TXA(2)) r eceptor antagonist, is known as a novel antithrombotic agent. It is suggest ed that pharmacological inhibition of TXA(2) synthesis or action merits con tinued evaluation in the treatment of a variety of renal diseases. The aim of this study was the determination of efficacy of this new TXA(2) receptor antagonist by assessing its effect on the reduction in inulin and para-aminohippuric acid (PAH) clearances induced by the TX/prostaglandin en doperoxide mimetic U-46619 in the conscious female rats. The following doses (3, 10, 30 mg/kg/24 h) of linotroban mixed with 720 mu- g TX-mimetic U-46619/kg/24 h were administered via osmotic pumps at a deliv ery rate of 10 mu l/h, implanted s.c. during 72 h. Rats of the U-46619 group were administered 720 mu g U-46619/kg/24h alone a s described above, controls received 3.5 % NaHCO3, respectively. Inulin/PAH clearances were determined at the end of the 4-h clearance perio d (68 h-72 h). Summarizing the data glomerular filtration rate (GFR) and PA H clearances were reduced significantly by U-46619. When linotroban (3, 10 or 30mg/kg/24 h) was added to U-46619 the GFR and PAH clearance were revers ed to values that showed no significant differences to the controls.