Turnover studies on cardiac natriuretic peptides: methodological, pathophysiological and therapeutical considerations

Cardiac natriuretic peptide hormones (ANP and BNP) are synthesized and secreted by the heart, producing several biological effects, such as natriuresis, vasorelaxation, hypotension, and neuromodulation. Extensive studies conducted in both animals and humans have documented that cardiac natriuretic peptides (CNPs) are secreted into the circulatory system via the coronary sinus into the right atrium, and then rapidly degraded and removed from the blood by plasma proteases and specific clearance receptors. Usually, studies of CNPs kinetics have been carried out following an experimental protocol in which labeled or unlabeled hormone is administered (by constant infusion or bolus injection) and the corresponding concentration of the hormone is measured in peripheral venous blood. However, when a uniform intravascular concentration throughout artero-venous vessels is lacking due to the very rapid clearance of the substance being studied (such as CNPs), the classical compartmental or none compartmental approach may not be suitable for interpreting the experimental data. In this case, a more physiological circulatory model, which does not assume a uniform intravascular distribution of the hormone and comprises several anatomo-functional blocks arranged in a series and supplied by the same flow (cardiac output) should be adopted. Different experimental designs (infusion or bolus injection) as well as multiple sampling sites (aorta and pulmonary artery, inferior vena cava, femoral vein) were used in ANP kinetic studies. Using a circulatory approach, ANP has been demonstrated to be rapidly distributed and degraded; in healthy subjects about 50% of ANP secreted into the right atrium is extracted by the peripheral tissues during the first pass throughout the body. Since CNPs have important fluid-volume regulatory features, it has been postulated that they also play a key role in volume homeostasis in several pathophysiological states, such as congestive heart failure. Indeed, a markedly altered degradation and distribution of ANP in patients with cardiac failure who show a resistance to its natriuretic effects, even in those on the early stage of clinical disease, whose CNPs plasma levels are in the normal range, have been demonstrated. Recent studies indicate that some drugs, by inhibiting the degradation of CNPs by plasma proteases and can thus affect CNP kinetics, may be useful in the treatment of arterial hypertension and cardiac failure.