Citations

Abstract Objectives This study defined the modulating actions of sulfonylurea on acute release of atrial natriuretic peptide (ANP) in experimental acute heart failure. Background Sulfonylurea drugs, blockers of cardioprotective ATP-sensitive K+ (KATP) channels, may increase the risk of early cardiovascular mortality. In cardiovascular diseases such as acute heart failure, early release of ANP is essential for cardiorenal homeostasis. Although KATP channels regulate secretion of hormones, such as insulin, it is unknown whether 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 KATP 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 time required for peak plasma ANP secretion to 48±5 min. This resulted in reduced natriuresis from 84±17 μEq/min in the absence of glyburide, to 34±9 μEq/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 KATP channel subunit, Kir6.2, displayed strong immunoreactivity and co-localization. Conclusions Glyburide delays release of ANP in acute heart failure resulting in impaired natriuresis. This cannot be ascribed to an antinatriuretic effect on the kidney, but rather may be due to interference with KATP channel-dependent ANP secretion from the atrium. Such adverse outcome of sulfonylurea drug use could reduce the compensatory capacity to preserve cardiorenal homeostasis in acute heart failure.

Abstract We have recently described a modified model of progressive rapid ventricular pacing-induced heart failure which evolves over a period of 38 days. To further characterize left ventricular remodeling during the progression of heart failure, we assessed left ventricular geometry, wall stress, and atrial natriuretic peptide (ANP) gene expression and protein content during control conditions, asymptomatic left ventricular dysfunction, and overt congestive heart failure (CHF). Although asymptomatic left ventricular dysfunction was characterized by a significant increase in systolic and diastolic left ventricular dimension (+30% and +6%, respectively, P<0.05 each) and a marked increase in left ventricular systolic wall stress (+68%, P<0.01), left ventricular ANP gene expression was unchanged as compared to control. In contrast, strong left ventricular ANP gene expression (+449%, P<0.05) was observed during overt CHF in the absence of further significant increases in left ventricular systolic wall stress. The onset of strong left ventricular ANP gene expression was associated with increased ANP content (+88%, P<0.05) and left ventricular mass index (+13%, P<0.05). In contrast, left atrial ANP gene expression and left ventricular diastolic wall stress increased progressively during asymptomatic left ventricular dysfunction (+39%, P=n.s. and +131%, P<0.01) and overt CHF (+76% and +336% vs. control, P<0.01 each). Progressive rapid ventricular pacing is associated with the induction of left ventricular ANP gene expression and protein synthesis exclusively during overt CHF. The current studies provide new insight into the temporal pattern of ANP-activation and the disparity between left ventricular systolic wall stress and ANP-activation in a large animal model of progressive CHF.