Diuretic and non-diuretic actions of furosemide: effects of probenecid.
Furosemide causes not only natriuresis, but a rapid (5-10 min) increase in plasma renin activity. The latter has been attributed both to the release of eicosanoids from renal blood vessels and to changes in sodium delivery to the macula densa. Drugs like indomethacin abolish the renin increment and could potentially affect both mechanisms: they inhibit cyclooxygenase but could also compete with furosemide for transport into the tubular lumen, reducing furosemide concentration at its site of action. We studied the effects of probenecid, a weak acid without cyclooxygenase activity, on the responses to furosemide in 20 healthy young men. Each received placebo and low (1000 mg/d) or high (2000 mg/d) doses of probenecid for one week in double-blind, randomized trials, crossover fashion. One hour after the last dose, all participants were given furosemide 0.5 mg/kg intravenously. Probenecid reduced serum uric acid in a dose-dependent manner but did not change platelet thromboxane B2 production. Similarly, there was no change in urine excretion rates of thromboxane B2 or 6ketoprostaglandin F1 alpha, or in baseline or stimulated plasma renin activity. The total natriuresis in 4 h was also unchanged. By contrast, the sodium excretion rate in the first 30 min was reduced after both probenecid regimens while that of later periods was increased. These findings are consistent with the proposed effect of probenecid as reducing furosemide secretion in the proximal tubule, which reduces its concentration at the lumenal surface of the thick ascending limb of Henle's loop, but also prevents its excretion from the body.(ABSTRACT TRUNCATED AT 250 WORDS)
Walshaw
P E
PE
Department of Pharmacology, University of Saskatchewan, Saskatoon.
McCauley
F A
FA
Wilson
T W
TW
D000328:Adult; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D015777:Eicosanoids / Q000652:urine; D005665:Furosemide / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011339:Probenecid / Q000494:pharmacology*; D012083:Renin / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood; D014527:Uric Acid / Q000652:urine
D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D014527:Uric Acid; D013929:Thromboxane B2; D005665:Furosemide; D012083:Renin; D011339:Probenecid