Effect of furegrelate on renal plasma flow after angiotensin II infusion

Abstract

We had previously shown that selective thromboxane synthetase inhibition with furegrelate increases urinary excretion of 6-ketoPGF_1α, the hydrolysis product of prostacyclin after stimulation of renal prostaglandin synthesis with furosemide. The present study assessed the functional significance of this "redirection" of prostaglandin formation using a more physiologic stimulus, angiotensin II. Sprague–Dawley rats (n = 27) were fitted with a transabdominal bladder cannula. Five days later they were given angiotensin II (10 mg∙kg⁻¹∙min⁻¹) by intravenous infusion. After 30 min, an infusion of furegrelate, 2 mg/kg, then 2 mg∙kg⁻¹∙h⁻¹, (n = 9); indomethacin, 2 mg/kg, then 2 mg∙kg⁻¹∙h⁻¹ (n = 9); or vehicle, 250 μL, then 0.018 mL/min (n = 9) was begun for 60 min. Clearance of [¹⁴C]para-aminohippuric acid was taken as a measure of renal plasma flow. Angiotensin II raised the mean arterial pressure in all groups. Administration of furegrelate or indomethacin did not change mean arterial pressure or heart rate. Angiotensin II reduced [¹⁴C]p-aminohippuric acid clearance by about 32% (1.42 ± 0.18 to 0.97 ± 0.07 mL∙min⁻¹∙100 g⁻¹, p < 0.05). Furegrelate attenuated this renal vasoconstriction (0.97 ± 0.07 to 1.38 ± 0.17 mL∙min⁻¹∙100 g⁻¹, p < 0.05), while indomethacin increased it by a further 32% (1.78 ± 0.12 to 1.20 ± 0.12 mL∙min⁻¹∙100 g⁻¹, p < 0.05). Vehicle alone had no effect. Furegrelate reduced serum thromboxane B₂ by 90% (6.52 ± 0.030 to 0.7 ± 0.21 ng/100 μL, p < 0.05), while indomethacin reduced it by 73% (5.9 ± 0.99 to 1.4 ± 0.20 ng/100 μL, p < 0.05). We conclude that furegrelate attenuates the renal vasoconstriction of angiotensin II, presumably by enhancing the formation of vasodilator prostaglandins.Key words: angiotensin II, furegrelate, indomethacin, para-aminohippuric acid clearance.