The natriuretic activity of the K+ channel blocker U-37883A displays an ADH-dependence

We reported previously that K+ channel blockers induce diuresis and natriuresis in conscious and anesthetized rats. Free-water clearance studies suggested that K+ channel blockers inhibit NaCl reabsorption in the thick ascending limb (TAL) by blocking K+ recycling through a low-conductance, usually open, apical ATP-sensitive K+ channel. In the present study, we measured the effect of U-37883A (15 mg/kg, i.v.) on Na+ reabsorption in rats preconditioned to alter ADH levels. In water-loaded animals with suppressed ADH levels, U-37883A was 50% less natriuretic than in saline-loaded rats. Infusion of ADH to water-loaded rats restored the natriuretic response to a level comparable to saline-loaded rats. Loss of natriuretic efficacy was not secondary to changes in GFR or renal perfusion pressure since GFRs did not vary before or after drug administration in any of the respective groups. Decreases in blood pressure were not significantly different in saline-loaded, water-loaded and water-loaded/ADH rats. The natriuretic response of U-37883A as varied by ADH levels may be the first observation, in vivo, to support the observation that the cotransporter in TAL can exist in two modes as previously observed in vitro by Hebert and colleagues.