Effects of diltiazem on plasma uric acid level and renal uric acid excretion in rats.

Abstract

Abstract-The effects of diltiazem on plasma uric acid level (PUA) and renal uric acid excretion were investigated in oxonate-loaded rats. Diltiazem (0.5 mg/kg, i.v.) decreased PUA without producing uricosuria, and it decreased fractional ex cretion of uric acid and renal blood flow. The present results suggest that diltiazem produces hypouricemia not accompanied by uricosuria, probably by affecting uric acid metabolism, and it may also cause an alteration in the renal handling of uric acid partly due to changes in renal hemodynamics. However, there is little information on the effects of calcium channel blockers on PUA and urinary uric acid excretion. In studies on nifedipine, the calcium channel blocker was found to be uricosuric (1) and both uricosuric and hypouricemic (2) in patients with essential hypertension.However, there have been no reports characterizing other kinds of calcium channel blockers.In an attempt to demonstrate the effects of diltiazem on PUA and renal uric acid excretion, we performed clearance studies using rats loaded with oxonate, a uricase inhibitor. Our preliminary study showed that diltiazem at 0.1 mg/kg was neither uricosuric nor hypo uricemic; and at 0.3 mg/kg, the drug was uricosuric, like nifedipine (1, 2). However, at 0.5 mg/kg, diltiazem caused hypouricemia without uricosuria. The present study, there fore, was designed to further clarify the action of diltiazem at 0.5 mg/kg on PUA and renal uric acid excretion.Male Wistar rats, weighing 230-280 g, were anesthetized by s.c. administration of urethane (1.2 g/kg). The left femoral vein and urinary bladder were catheterized for infusion of loading solution and collection of urine, respectively. The loading solution, containing 0.1% oxonate, 4% mannitol, 1.5% inulin, 0.85% NaCl and 0.03% NaHCO3, was infused at a rate of 3.2 ml/hr. After a 60 min equili brium period, 10 min urine was collected continuously. Diltiazem (0.5 mg/kg) or saline (0.5 ml/kg) as a control was administered intravenously at the mid-point of the 10 min urine collection period (0 time). Blood (0.37 ml) was taken from the jugular vein of each rat using a heparinized syringe at the mid point of each urine collection period, 10 min before, and 10, 30 and 60 min after drug administration, following the same experi mental protocol as reported previously (3). A plasma sample was obtained after centri fugation. Uric acid concentrations in the plasma and urine were measured by the phos photungustate colorimetric assay using a Uric Acid-Test Wako kit (Wako). Inulin concentrations in the plasma and urine were measured by the fluorometric method of Vurek and Pegram (4). Glomerular filtration rate (GFR) was calculated as inulin clearance, and fractional excretion of uric acid (FE, ,,) was calculated as uric acid clearance/inulin clearance ratio. Renal blood flow was measured by a laser Doppler flowmeter