Effect of pH and amiloride on the intrarenal formation of kinins

Abstract

Changes in urinary kallikrein excretion are assumed to reflect changes in intrarenal formation of kinins. Yet factors that alter the enzymatic activity of renal kallikrein and kininases may alter the concentration of kinins in the nephron independent of amount of kallikrein excreted. In anesthetized rats, we measured excretion of urinary kallikrein (kininogenase activity) and kinin excretion during altered urinary pH and after amiloride, which reportedly inhibits urinary kallikrein. In rats fed a low sodium diet, urine was acidified by intravenous 0.28 M sodium sulfate. This decreased urinary pH from 6.1 +/- 0.09 to 5.3 +/- 0.17 and urinary kinin excretion from 28.0 +/- 9.0 to 10.5 +/- 5.0 pg/min. Urinary kallikrein excretion doubled from 43.0 +/- 5.0 to 82.5 +/- 13.5 ng/min. The optimum pH of kallikrein is congruent to 8.5, so the decreased excretion of urinary kinins is probably secondary to decreased kininogenase activity at lower urinary pH. Amiloride decreased urinary kinins from 35.5 +/- 7.3 to 18.2 +/- 2.5 pg/min and kallikrein from 18.7 +/- 4.9 to 9.3 +/- 1.8 ng/min, while urinary pH increased from 6.7 +/- 0.07 to 7.3 +/- 0.07. The depressed excretion of kallikrein and kinins with amiloride may not have been due to inhibition of kallikrein, since amiloride (1 mM) did not inhibit the kininogenase activity of rat urinary kallikrein (congruent to 1.2 nM) on dog or rat kininogen in vitro. We conclude that changes in urinary kallikrein may not reflect changes in intrarenal formation of kinins. These data also indicate that kallikrein excretion increases and kinin formation decreases when urine is acidified in the distal nephron and that there may be a link between the kallikrein-kinin system and the renal mechanisms affected by amiloride.