THE ACUTE EFFECTS OF INTRAVENOUS FRUSEMIDE ON THE RENAL KALLIKREIN-KININ SYSTEM IN MAN - RELATIONSHIP TO DOSE

Frusemide (F) is a potent natriuretic and diuretic that acts mainly on the luminal side of the ascending loop of Henle (Schlatter et al. (19 83) Pflug. Arch. 396: 210-217). F increases the urinary excretion of p rostaglandin (PG) E (Mackay et al. (1984) Contr. Nephrol. 41: 160-162) and its diuretic and natriuretic effects are blunted by indomethacin, suggesting that PGs are involved in the cellular action of this drug (Chennavasin et al. (1980) J. Pharmacol. Exp. Ther. 215: 77-81; Waller et al. (1987) Arch. Pharmacodyn, Ther. 290: 145-150), Several investi gators have shown a rapid but short-lived rise in urinary kallikrein ( UK) excretion after F administration in man, which could represent a ' wash-out' phenomenon rather than indicating a direct involvement of th e kallikrein-kinin system (KKS) in mediating the action of F (Zschiedr ich et al. (1979) Clin. Sci. 57: 247-250; Waller et al. (1987); Waller et al. (1990) Clin. Sci, 79: 117-121). However, using a mouse model, 5 days treatment with F has been shown to stimulate renal cortical tub ular messenger RNA for tissue kallikrein (Penchow and Coghlan (1994) J . Hypertension 12 (Suppl. 3): 887). Urinary excretion of the component s of the KKS is believed to reflect the intra-renal activity of the sy stem (Bhoola et al. (1992) Am. Sec. Pharmacol. Exp. Ther. 44: 1-80) Th erefore, if the KKS is directly involved in the natriuretic action of F, a dose-related release of the active components of the system would be expected. This study was designed to examine the effect of three i ntravenous (i.v.) doses of F on the urinary excretion of components of the renal KKS and the relationships of these components with the excr etion of water, electrolytes and F.