Riegger, Günter A.J.

Endothelin-1 (ET-1) is a peptide that has been implicated in congestive heart failure (CHF). Although increased concentrations of circulating ET-1 have been repeatedly demonstrated, the activation of local ET-1 in target tissues of CHF remains poorly defined. Our objective was to characterize ET-1 tissue concentrations and gene expression of prepro ET-1 in myocardial, renal, and pulmonary tissue in rapid ventricular pacing-induced canine CHF. Progressive rapid ventricular pacing (38 days) resulted in impaired cardiovascular hemodynamics, increased atrial and left ventricular mass, decreased renal sodium excretion, and increased ET-1 plasma concentrations (all P < 0.05). Tissue analysis revealed significant increases in local ET-1 during CHF in left ventricular, renal, and pulmonary tissue, whereas a moderate increase in left atrial ET-1 did not reach statistical significance. In contrast, prepro-ET-1 gene expression was increased more than threefold in pulmonary tissue and more than twofold in left atrial myocardium with no increase in left ventricular or renal gene expression. The present studies demonstrate a differential pattern of ET-1 activation in cardiorenal and pulmonary tissue with a strong accumulation of ET-1 in kidney and lung during CHF. Although the observed increase in left ventricular and renal ET-1 in association with unaltered gene expression is consistent with increased uptake, pulmonary and atrial tissue may contribute to increased circulating and local ET-1 in CHF.

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&lt;0.05 each) and a marked increase in left ventricular systolic wall stress (+68%, P&lt;0.01), left ventricular ANP gene expression was unchanged as compared to control. In contrast, strong left ventricular ANP gene expression (+449%, P&lt;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&lt;0.05) and left ventricular mass index (+13%, P&lt;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&lt;0.01) and overt CHF (+76% and +336% vs. control, P&lt;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.