CONGESTWE HEART FAILURE Atrial natriuretic peptide in congestive heart failure in the dog : plasma levels , cyclic guanosine monophosphate , ultrastructure of atrial myoendocrine cells , and hemodynamic , hormonal , and renal effects

In an animal preparation of congestive heart failure in the dog, during the development of cardiac failure due to rapid right ventricular pacing we observed significant decreases in cardiac output and arterial pressure and increases in pulmonary arterial and right atrial pressure. We also observed a related increase in right atrial pressure and increases in plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (c-GMP). Ultrastructure changes in the atrial myoendocrine cells indicated extreme stimulation of the secretory apparatus of ANP. The response of hemodynamic, renal, and hormonal variables was investigated after incremental infusions (0.01, 0.03, 0.1, 0.3, and 0.6 ,ug/kg/min) of exogenous ANP. In healthy animals ANP significantly decreased mean arterial pressure, cardiac output, stroke volume, and right atrial pressure without changing heart rate or peripheral vascular resistance. As expected, we found a striking increase in urine flow and urinary excretion of sodium, chloride, magnesium and calcium and a smaller increase in potassium excretion. ANP suppressed renin secretion, and increased renal plasma flow, glomerular filtration rate, and filtration fraction. In dogs with heart failure ANP caused a small reduction in mean arterial pressure. No effect was seen on other hemodynamic variables or plasma renin concentration. The excretory effects on the kidneys were completely absent, and smaller increases in glomerular filtration rate and filtration fraction were observed. We found no difference between healthy dogs and animals with heart failure with respect to the secretion of c-GMP during ANP infusions in relation to the plasma levels of ANP. This suggests an intracellular defect that prevents the mediation of the hormonal signal into biological action in the presence of heart failure. Circulation 77, No. 2, 398-406, 1988. IN 1981 de Bold et al. demonstrated that intravenous administration of atrial extracts to intact rats induced profound natriuresis and diuresis. Injection of atrial natriuretic peptide (ANP) in human subjects causes diuresis and natriuresis and reduces blood pressure. 2, 3 It has been shown3 that ANP is elevated in the presence of heart failure in proportion to the severity of the disease, suggesting that ANP may be important in the pathophysiology of cardiac failure. It has been reported that in patients with severe chronic congestive heart From the Medizinische Universititsklinik Wurzburg and Anatomisches Institut der Universitat Heidelberg, F.R.G. Supported by the "Deutsche Forschungsgemeinschaft." Address for correspondence: Prof. G.A.J. Riegger, M.D., Medizinische Universitatsklinik, Josef Schneider Strasse 2, D8700 Wurzburg, F.R.G. Received Aug. 12, 1987; accepted Oct. 8, 1987 398 failure ANP infusions in pharmacologic doses have beneficial effects on cardiac function by reducing preload and afterload.46 However, in contrast to healthy volunteers, ANP at relatively high doses had no effects on urine and electrolyte excretion, or its effects were considerably attenuated,4 in these patients. 6To date, no studies have definitively investigated hemodynamic, renal, and hormonal responses to ANP in an experimental preparation of chronic heart failure. The present study was designed (1) to determine changes in endogenous ANP during the development of heart failure, (2) to determine whether the response to ANP administration is normal or abnormal in the presence of heart failure, (3) to determine the effect of ANP infusions on plasma renin concentration and cyclic guanosine monophosphate (c-GMP) before and CIRCULATION by gest on A ril 0, 2017 http://ciajournals.org/ D ow nladed from LABORATORY INVESTIGATION-CoNGESTIVE HEART FAILURE after heart failure has developed and (4) to describe ultrastructural changes in myoendocrine cells of the atria in dogs with heart failure as compared with those in normal control dogs. To characterize the effects of ANP more precisely, dose-response studies were performed with the use of synthetic ANP in healthy animals and dogs with congestive heart failure, and hemodynamic, hormonal, and renal changes were measured.