A sensitive radioimmunoassay for atrial natriuretic peptide was used to examine the relation between circulating atrial natriuretic peptide and cardiac filling pressure in normal human subjects, in patients with cardiovascular disease and normal cardiac filling pressure, and in patients with cardiovascular disease and elevated cardiac filling pressure with and without congestive heart failure. The present studies establish a normal range for atrial natriuretic peptide in normal human subjects. These studies also establish that elevated cardiac filling pressure is associated with increased circulating concentrations of atrial natriuretic peptide and that congestive heart failure is not characterized by a deficiency in atrial natriuretic peptide, but with its elevation.

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.

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Impaired insulin secretion in type 2 diabetes is characterized by decreased first-phase insulin secretion, an increased proinsulin-to-insulin molar ratio in plasma, abnormal pulsatile insulin release, and heightened disorderliness of insulin concentration profiles. In the present study, we tested the hypothesis that these abnormalities are at least partly reversed by a period of overnight suspension of beta-cell secretory activity achieved by somatostatin infusion. Eleven patients with type 2 diabetes were studied twice after a randomly ordered overnight infusion of either somatostatin or saline with the plasma glucose concentration clamped at approximately 8 mmol/l. Controls were studied twice after overnight saline infusions and then at a plasma glucose concentration of either 4 or 8 mmol/l. We report that in patients with type 2 diabetes, 1) as in nondiabetic humans, insulin is secreted in discrete insulin secretory bursts; 2) the frequency of pulsatile insulin secretion is normal; 3) the insulin pulse mass is diminished, leading to decreased insulin secretion, but this defect can be overcome acutely by beta-cell rest with somatostatin; 4) the reported loss of orderliness of insulin secretion, attenuated first-phase insulin secretion, and elevated proinsulin-to-insulin molar ratio also respond favorably to overnight inhibition by somatostatin. The results of these clinical experiments suggest the conclusion that multiple parameters of abnormal insulin secretion in patients with type 2 diabetes mechanistically reflect cellular depletion of immediately secretable insulin that can be overcome by beta-cell rest.