The acute effects of intravenous frusemide on the renal kallikrein kinin system in man: relationship to dose

Abstract Frusemide (F) is a potent natriuretic and diuretic that acts mainly on the luminal side of the ascending loop of Henle (Schlatter et al. (1983) Pflug. Arch. 396: 210–217). F increases the urinary excretion of prostaglandin (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 investigators 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 the kallikrein-kinin system (KKS) in mediating the action of F (Zschiedrich 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 tubular messenger RNA for tissue kallikrein (Penchow and Coghlan (1994) J. Hypertension 12 (Suppl. 3): 887). Urinary excretion of the components of the KKS is believed to reflect the intra-renal activity of the system (Bhoola et al. (1992) Am. Soc. Pharmacol. Exp. Ther. 44: 1–80) Therefore, 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 intravenous (i.v.) doses of F on the urinary excretion of components of the renal KKS and the relationships of these components with the excretion of water, electrolytes and F.