The modulating actions of sulfonylurea on atrial natriuretic peptide release in experimental acute heart failure

Objectives: This study defined the modulating actions of sulfonylurea on ac ute release of atrial natriuretic peptide (ANP) in experimental acute heart failure. Background: Sulfonylurea drugs, blockers of cardioprotective ATP- sensitive K+ (K-ATP) channels, may increase the risk of early cardiovascula r mortality. In cardiovascular diseases such as acute heart failure, early release of ANP is essential for cardiorenal homeostasis. Although K-ATP cha nnels regulate secretion of hormones, such as insulin, it is unknown whethe r sulfonylureas interfere with ANP release in acute heart failure. Methods: The effects of acute administration of glyburide (0.3 mg/kg), a prototype sulfonylurea, on ANP release and sodium excretion were measured in vivo in a canine model of pacing-induced acute heart failure characterized by acute atrial stretch. Immunoreactivity, in atrial tissue, for ANP and the K-ATP channel subunit, Kir6.2, was determined using specific antibodies. Results: With increased left atrial pressure in heart failure, plasma levels of ANP increased rapidly and peaked within 25 +/- 3 min. Glyburide delayed the ti me required for peak plasma ANP secretion to 48 +/- 5 min. This resulted in reduced natriuresis from 84 +/- 17 mu Eq/min in the absence of glyburide, to 34 +/- 9 mu Eq/min in the presence of glyburide. However, glyburide did not alter the renal natriuretic responsiveness to exogenously administered ANP in normal dogs. In atrial tissue, both ANP and the K-ATP channel subuni t, Kir6.2, displayed strong immunoreactivity and co-localization. Conclusio ns: Glyburide delays release of ANP in acute heart failure resulting in imp aired natriuresis. This cannot be ascribed to an antinatriuretic effect on the kidney, but rather may be due to interference with K-ATP channel-depend ent ANP secretion from the atrium. Such adverse outcome of sulfonylurea dru g use could reduce the compensatory capacity to preserve cardiorenal homeos tasis in acute heart failure. (C) 2000 European Society of Cardiology. All rights reserved.