K+ channel blockers: natriuretic potency correlates to vascular ATP-sensitive K+ channel blockade

Using analogs of known vascular ATP-sensitive K+ channel (KATP) blockers, we identified compounds with a wide range of potencies (over 500-fold) in their capacity to block the hypotensive response of 0.2 mg/kg pinacidil in rats. The most potent of these, U-97025E, belongs to a newly disclosed class of compounds, the cyanoguanidines. U-97025E at 0.04 mg/kg blocked 50% of the depressor response induced by 0.2 mg/kg pinacidil. The maximal natriuresis induced by U-97025E (0.4 mg/kg i.v.) increased Na+ excretion by approximately 60%. This natriuresis is of the same magnitude as that induced by thiazide without any effect on K+ excretion. We found a high degree of correlation between natriuretic potency and the capacity to block the blood pressure lowering effects of pinacidil, both among closely related analogs and dissimilar compounds. These findings imply an obligatory rather than incidental relationship between vascular KATP blockade and natriuresis. The exact molecular link of the vascular and renal effects remains to be determined.