Citations

Abstract Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that induces cardiac myocyte hypertrophy through the signal transducing molecule, glycoprotein 130. To date, localization of LIF in the heart and regulation of cardiac LIF expression in congestive heart failure (CHF) remain undefined. The present study investigates the potential activation of LIF expression in the failing canine heart that was produced by progressive rapid ventricular pacing. Immunohistochemistry for LIF revealed that LIF immunoreactivity was present in the atrial and ventricular myocytes of the normal heart and was markedly increased in the failing heart as compared to the normal heart. Northern blot analysis demonstrated that cardiac LIF mRNA was increased in both atrium and ventricle in CHF as compared to the normal heart (P<0.01). Linear regression analysis revealed a positive correlation between atrial LIF mRNA and atrial pressure (r=0.87, P<0.001 in right atrium and r=0.86, P<0.001 in left atrium). Positive correlations between left ventricular LIF mRNA and left ventricular dimensions (r=0.91, P<0.0001 in end-systolic diameter; r=0.86, P<0.001 in end-diastolic diameter), and an inverse correlation between left ventricular LIF mRNA and left ventricular ejection fraction (EF) were observed (r=−0.93, P<0.0001). There was a positive correlation between left ventricular LIF mRNA and left ventricular mass index (LVMI) (r=0.85, P<0.001). The present study demonstrates that cardiac LIF immunoreactivity and its gene expression are increased in a canine model of experimental CHF and suggests a potential role for LIF in the pathophysiology of CHF.

Background— BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG). Methods and Results— CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 μg · kg −1 · min −1 ; n=8) or NTG (1 and 5 μg · kg −1 · min −1 ; n=6). Administration of 10 μg · kg −1 · min −1 BAY 41-2272 reduced mean arterial pressure (113±8 to 94±6 mm Hg; P <0.05), pulmonary artery pressure (29±2 to 25±2 mm Hg; P <0.05), and pulmonary capillary wedge pressure (25±2 to 20±2 mm Hg; P <0.05). Cardiac output (2.1±0.2 to 2.3±0.2 L/min; P <0.05) and renal blood flow (131±17 to 162±18 mL/min; P <0.05) increased. Glomerular filtration rate was maintained. There were no changes in plasma renin activity, angiotensin II, or aldosterone. NTG mediated similar hemodynamic changes and additionally decreased right atrial pressure and pulmonary vascular resistance. Conclusion— The new sGC stimulator BAY 41-2272 potently unloaded the heart, increased cardiac output, and preserved glomerular filtration rate without activation of the renin-angiotensin-aldosterone system in experimental CHF. These beneficial properties make direct sGC stimulation with BAY 41-2272 a promising new strategy for the treatment of cardiovascular diseases such as CHF.

Cardiac fibroblasts (CFs) produce extracellular matrix proteins and participate in the remodeling of the heart. It is unknown if brain natriuretic peptide (BNP) is synthesized by CFs and if BNP participates in the regulation of extracellular matrix turnover. In this study, we examined the production of BNP in adult canine CFs and the role of BNP and its signaling system on collagen synthesis and on the activation of matrix metalloproteinases (MMPs). BNP mRNA was detected in CFs, and a specific radioimmunoassay demonstrated that BNP 1-32 was secreted into the media at a rate of 11.2±1.0 pg/10 5 cells per 48 hours (mean±SEM). The amount of BNP secretion was significantly ( P <0.01) augmented by 10 −7 mol/L tumor necrosis factor-α in a time-dependent manner. BNP significantly ( P <0.01) inhibited de novo collagen synthesis as assessed by [ 3 H]proline incorporation, whereas zymographic MMP-2 (gelatinase) abundance was significantly ( P <0.05) stimulated by BNP between 10 −7 and 10 −6 mol/L. In addition, protein expression of MMP-1, -2, and -3 and membranous type-1 MMP was significantly increased by 10 −6 mol/L BNP. The cGMP analogue 8-bromo-cGMP (10 −4 mol/L) mimicked the BNP effect, whereas inhibition of protein kinase G by KT5823 (10 −6 mol/L) significantly ( P <0.05) attenuated BNP-induced zymographic MMP-2 abundance. In summary, this study reports that BNP is present in cultured CFs and that BNP decreases collagen synthesis and increases MMPs via cGMP–protein kinase G signaling. These in vitro findings support a role for BNP as a regulator of myocardial structure via control of cardiac fibroblast function.

Abstract Background Digitalis has a long history in the treatment of heart failure but its effects on cardiac hemodynamics and neurohormonal modulation are not well characterized. Aims The purpose of this study was to evaluate the relationship between atrial natriuretic peptide (ANP) and the hemodynamic responses to acute digitalis administration in patients with normal and impaired left ventricular function (LVD). Methods and Results Thirty patients were enrolled in the study, 20 with LVD (LVEF-22±8%) and 10 control subjects (LVEF-77±10%). Hemodynamics and plasma ANP concentrations were measured supine and with leg elevation before and after digitalis. In patients with normal ventricular function, the hemodynamic stress of leg elevation in the pre-digitalis state resulted in significant (P&lt;0.05) increases in PAWP and MPAP. Digitalis administration in the supine position produced reductions in heart rate, PAWP, MPAP and CI; SVR was increased. In LVD patients leg elevation further increased PAWP, RAP and MPAP. Digitalis in the supine position, however, reduced RAP, MPAP and PAWP and increased CI. These improved hemodynamics were preserved during the stress of leg elevation. Leg elevation following digitalis resulted in increased ANP concentrations despite decreased cardiac filling pressures. Conclusions Acute digitalis administration results in hemodynamic improvement in LVD patients which may in part result from digitalis stimulated release of myocardial ANP under conditions of hemodynamic stress.

Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, and endothelin-1 (ET-1) are potent hypertrophic factors in cardiomyocytes. Although CT-1 and ET-1 gene expression in the heart is upregulated in experimental heart failure, their role in the activation of the cardiac fibroblast is unknown. This study was designed to identify the presence and action of CT-1 and its receptor complex, glycoprotein130 (gp130) and leukemia inhibitory factor (LIF) receptor, on cardiac fibroblast growth in cultured adult canine cardiac fibroblasts. In addition, we investigated the interaction between CT-1/gp130/LIF receptor and ET-1/endothelin type A (ET A ) receptor axis. Immunohistochemistry was performed using the indirect immunoperoxidase method, while we assessed the cell cycle of cardiac fibroblasts by flow cytometry, DNA synthesis by [ 3 H]thymidine incorporation, and collagen synthesis by [ 3 H]proline incorporation, respectively. CT-1 and gp130/LIF receptor were widely present in the cytoplasm of the cardiac fibroblasts. Exogenous CT-1 markedly stimulated [ 3 H]thymidine and [ 3 H]proline incorporations ( P <0.01), with accumulation of cells in the S phase. Blockade of gp130 or LIF receptor inhibited basal growth as well as CT-1– or ET-1–stimulated cardiac fibroblast growth. The specific ET A receptor antagonist, BQ123, significantly inhibited CT-1–stimulated DNA synthesis. This study demonstrates that CT-1 and its receptors are present in cardiac fibroblasts. In addition, growth of these cells stimulated by endogenous and exogenous CT-1 requires gp130/LIF receptor as well as ET A receptor activation. We conclude that gp130/LIF receptor and ET A receptor activation are essential for cardiac fibroblast growth by CT-1 and that there is synergism with ET-1/ET A receptor axis.

Background — A hallmark of congestive heart failure (CHF) is the elevation of the cardiac natriuretic peptides (NPs), which have natriuretic, renin-inhibiting, vasodilating, and lusitropic properties. We have reported that chronic subcutaneous (SQ) administration of brain natriuretic peptide (BNP) in experimental CHF improves cardiorenal function. Vasopeptidase inhibitors (VPIs) are single molecules that simultaneously inhibit both neutral endopeptidase 24.1 (NEP) and ACE. We hypothesized that acute VPI administration would potentiate the cardiorenal actions of SQ BNP in experimental CHF. Methods and Results — We determined the cardiorenal and humoral responses to acute VPI alone with omapatrilat (OMA) (1 μmol/kg IV bolus) (n=6), acute low-dose SQ BNP (5 μg/kg) alone (n=5), acute VPI plus low-dose SQ BNP (n=5), and acute high-dose SQ BNP (25 μg/kg) alone in 4 groups of anesthetized dogs with experimental CHF produced by ventricular pacing for 10 days. Plasma BNP was greater with VPI+low-dose SQ BNP compared with VPI alone or low-dose SQ BNP alone and was similar to high-dose SQ BNP alone. Urinary BNP excretion was greatest with VPI+SQ BNP. Urinary sodium excretion was also highest with VPI+SQ BNP, with the greatest increase in glomerular filtration rate. VPI+SQ BNP resulted in a greater increase in cardiac output and reduction in cardiac filling pressures as compared with low-dose SQ BNP, high-dose SQ BNP, or VPI alone. Conclusions — This study reports that acute VPI potentiates the cardiorenal actions of SQ BNP in experimental CHF. This study advances the concept that protein therapy with BNP together with vasopeptide inhibition represents a novel therapeutic strategy in CHF to maximize the beneficial properties of the natriuretic peptide system.

Background — Omapatrilat (OMA), a vasopeptidase inhibitor, simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase, which degrades vasodilatory factors (eg, ADM) and natriuretic peptides. Based on the beneficial cardiorenal and humoral properties of the natriuretic peptides, we hypothesized that an acute vasopeptidase inhibitor with or without diuretic would result in more favorable cardiorenal and hormonal actions than ACE inhibition plus diuretic (ACEI+D) in congestive heart failure. Methods and Results — We compared the actions of OMA alone and with diuretic (OMA+D) to ACEI+D in a model of pacing-induced congestive heart failure. OMA+D decreased pulmonary arterial and pulmonary capillary wedge pressures to a greater level than OMA alone or ACEI+D. Glomerular filtration rate was lower with ACEI+D than with either OMA group. Plasma renin activity and aldosterone immediately increased with ACEI+D, whereas OMA+D resulted in higher plasma renin activity and a delayed increase in aldosterone. OMA alone did not increase plasma renin activity and aldosterone, but resulted in a sustained increase in plasma adrenomedullin, with higher urinary atrial natriuretic peptide, adrenomedullin, and cGMP excretions than with ACEI+D. Conclusions — Acute administration of OMA with or without diuretic results in more favorable cardiorenal and humoral responses in experimental congestive heart failure than does ACEI+D. There is no acute activation of renin and aldosterone with OMA alone such as occurs with ACEI+D and OMA+D. Thus, OMA with or without a diuretic possesses beneficial cardiorenal and humoral actions comparable to those observed with ACEI+D that can be explained by potentiation of natriuretic peptides.

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.