Citations

Atrial natriuretic peptide is an important peptide hormone of cardiac origin that functions to regulate cardiac preload via the regulation of sodium excretion. This natriuretic action occurs through activation of the particulate guanylyl cyclase-linked natriuretic peptide-A receptor. HS-142-1 is a newly discovered antagonist of the natriuretic peptide-A receptor that permits insight into the functional role of atrial natriuretic peptide in cardiorenal homeostasis. The first objective of this study was to define for the first time the intrarenal action of HS-142-1 on exogenous atrial natriuretic peptide-mediated natriuresis in anesthetized normal dogs. In group 1 (n = 6), which received intravenous atrial natriuretic peptide at 100 ng/kg per minute, intrarenal HS-142-1 (0.5 mg/kg bolus) attenuated atrial natriuretic peptide-induced increases in glomerular filtration rate, urine flow, sodium excretion, and renal cyclic GMP generation and decreases in distal tubular sodium reabsorption. The second objective was to determine whether endogenous atrial natriuretic peptide participates in the regulation of basal sodium excretion. In group 2 (n = 6), intrarenal HS-142-1 alone decreased both absolute and fractional sodium excretion and renal cyclic GMP generation and increased distal tubular sodium reabsorption. These studies demonstrate that HS-142-1 markedly attenuates exogenous atrial natriuretic peptide-mediated natriuresis via enhancement of distal tubular reabsorption and blunting of increases in glomerular filtration rate. Second, the current studies support a functional role for endogenous atrial natriuretic peptide in the regulation of basal sodium excretion.

BACKGROUND Hypercholesterolemia is characterized by a coronary vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. This abnormality may be due to reduced synthesis of endothelium-derived relaxing factor and/or enhanced synthesis and release of an endothelium-derived contracting factor. Endothelin is an endothelium-derived vasoconstrictor and mitogenic peptide that is present in normal plasma, and its circulating concentrations are elevated in disease states that are characterized by abnormal endothelium-dependent relaxation to acetylcholine. The current studies were designed to test the hypotheses that experimental hypercholesterolemia results in elevation of plasma and tissue endothelin immunoreactivity and that the abnormal acetylcholine-evoked coronary vasoconstriction in the hypercholesterolemic animals is associated with further elevation of plasma endothelin. METHODS AND RESULTS Plasma concentrations and molecular forms of endothelin immunoreactivity were determined following 2% cholesterol diet for 4 months in pigs and during intracoronary acetylcholine administration. Second, we assessed the presence of endothelin in the coronary vascular wall by using immunohistochemistry. Hypercholesterolemia elevated plasma endothelin concentration and enhanced coronary artery tissue endothelin immunoreactivity. The endothelium-dependent vasodilator acetylcholine further increases plasma endothelin in hypercholesterolemia in association with coronary vasoconstriction. The predominant molecular form of endothelin in hypercholesterolemia is the biological active endothelin-1. CONCLUSIONS This study suggests a role for endothelin as an early participant and a marker for the endothelial dysfunction in hypercholesterolemia as well as a participant in the atherogenic process.

BACKGROUND beta-Atrial natriuretic factor (beta-ANF) is an antiparallel dimer of alpha-ANF (alpha-ANF) with diminished cyclic GMP generation in vitro. To date, the presence of beta-ANF in the circulation of humans with severe congestive heart failure (CHF) remains controversial. The current study was designed to determine the presence and magnitude of circulating beta-ANF in severe CHF, to correlate plasma beta-ANF with the degree of ventricular dysfunction, and to investigate the role of human plasma and atrial tissue in the degradation of beta-ANF. METHODS AND RESULTS Venous plasma samples were obtained from patients (n = 12) with severe CHF and normal volunteers (n = 8). Total plasma ANF was measured by radioimmunoassay. alpha-ANF and beta-ANF in nonextracted plasma were separated by gel filtration chromatography using a P-6 column. Right atrial tissue samples (n = 5) were collected from a different group of patients at the time of open-heart surgery. 125I beta-ANF and I125 ANF were incubated with atrial tissue or plasma. The corresponding peak areas of beta-ANF were determined by Tamaya Digital Planimeter. beta-ANF represented 61% of total plasma ANF in CHF patients and was not detected in normal human plasma. The elevation of beta-ANF correlated with the severity of ventricular dysfunction. Thirty percent of beta-ANF and 100% alpha-ANF were converted to smaller peptide fragments in atrial tissue no conversion in plasma. CONCLUSIONS beta-ANF is the principal form of circulating ANF in patients with severe CHF and correlates with the degree of left ventricular dysfunction. beta-ANF is not generated from alpha-ANF and may be degraded rapidly in atrial tissue to smaller peptide fragments that do not occur in plasma. As beta-ANF is reported to have reduced biological action, the current studies may support the conclusion that the ANF system in CHF has reduced functional activity despite increases in circulation concentrations.

BACKGROUND Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are a family of structurally related peptides that participate in the integrated control of renal and cardiovascular function. Previous studies suggest a functional role for these hormonal peptides in cardiorenal regulation in congestive heart failure (CHF). METHODS AND RESULTS The present studies were performed in normal subjects (n = 6) and in patients with mild (New York Heart Association [NYHA] class I to II, n = 20) and severe (NYHA class III to IV, n = 20) CHF by use of radioimmunoassay and immunohistochemical staining (IHCS). Plasma ANP was significantly increased in both mild and severe CHF compared with normal subjects. In contrast, plasma BNP was only moderately increased in the severe CHF group, and plasma CNP concentration was unchanged in CHF compared with normal subjects. Atrial tissue concentrations of the natriuretic peptides did not parallel circulating concentrations. ANP predominated in normal atrial tissue, but BNP predominated in CHF. In ventricular tissue, IHCS staining was present for all three peptides in normal ventricular myocardium and was markedly enhanced in CHF. CONCLUSIONS These studies support a differential regulation of ANP, BNP, and CNP circulating concentrations and tissue activity in human CHF.

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

As both fluid flow measurement techniques and computer simulation methods continue to improve, there is a growing need for numerical simulation approaches that can assimilate experimental data into the simulation in a flexible and mathematically consistent manner. The problem of interest here is the simulation of blood flow in the left ventricle with the assimilation of experimental data provided by ultrasound imaging of microbubbles in the blood. The weighted least-squares finite element method is used because it allows data to be assimilated in a very flexible manner so that accurate measurements are more closely matched with the numerical solution than less accurate data. This approach is applied to two different test problems: a flexible flap that is displaced by a jet of fluid and blood flow in the porcine left ventricle. By adjusting how closely the simulation matches the experimental data, one can observe potential inaccuracies in the model because the simulation without experimental data differs significantly from the simulation with the data. Additionally, the assimilation of experimental data can help the simulation capture certain small effects that are present in the experiment, but not modeled directly in the simulation.