Eukaliuric diuresis and natriuresis in response to the K ATP channel blocker U37883A: Micropuncture studies on the tubular site of action

Systemic application of U37883A, a blocker of ATP sensitive potassium (K ATP ) channels, elicits diuresis and natriuresis without significantly altering urinary potassium excretion. To elucidate tubular sites of action upstream to the distal nephron, micropuncture experiments were performed in nephrons with superficial glomeruli of anaesthetized Munich‐Wistar‐Frömter rats during systemic application of U37883A (1, 5 or 15 mg kg −1 i.v.). The observed eukaliuric diuresis and natriuresis in response to U37883A at 15 mg kg −1 was accompanied by an increase in early distal tubular flow rate (V ED ) from 10–18 nl min −1 reflecting a reduction in fractional reabsorption of fluid up to this site (FR‐fluid) of 13%. The latter proposed an effect on water‐permeable segments such as the proximal tubule which could fully account for the observed reduction in fractional reabsorption of Na + up to the early distal tubule (FR‐Na + ) of 8% and the increase in early distal tubular Na + concentration ([Na + ] ED ) from 35–51 m M whereas [K + ] ED was left unaltered. In comparison, furosemide (3 mg kg −1 i.v.), which acts in the water‐impermeable thick ascending limb, elicited diuresis, natriuresis and kaliuresis which were associated with a fall in FR‐Na + of 10% with no change in FR‐fluid, and a rise in [Na + ] ED from 42–117 m M and [K + ] ED from 1.2–5.7 m M with no change in V ED . Direct late proximal tubular fluid collections confirmed a significant inhibition of fluid reabsorption in proximal convoluted tubule in response to systemic application of U37883A. These findings suggest that the diuretic and natriuretic effect upstream to the distal tubule in response to systemic application of U37883A involves actions on water‐permeable segments such as the proximal convoluted tubule.British Journal of Pharmacology (1999) 127 , 1811–1818; doi: 10.1038/sj.bjp.0702742