Characterization of natriuretic peptide production by adult heart atria

OGAWA T; VATTA MS; BRUNEAU B; DE BOLD AJ

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY

AMER PHYSIOLOGICAL SOC

Año: 1999 vol. 45 p. 1977 - 1986

0363-6135

The cardiacpolypeptide hormones atrial natriuretic factor (ANF) andbrain natriuretic peptide (BNP) are synthesized and costoredby atrial cardiocytes and share receptors and many biologicproperties. Although some aspects of their synthesis andrelease are specific for each peptide, it is not clear whetherthey share intracellular sorting and secretory mechanisms.In the present work we take advantage of a stable isolated ratatrial preparation that allows, for the first time, long-termstudy of synthesis, trafficking, targeting, and secretion ofANF and BNP by adult atrial muscle. Three model stimuli ofsecretion were used: increased intra-atrial pressure, endothelin-1 (ET-1), and phenylephrine (PE), representing mechanical,hormonal, and a1-adrenergic stimuli, respectively. Togain further insight into the secretory process under basaland agonist-induced secretion, we employed agents known toinhibit protein synthesis (cycloheximide) or to interfere withthe vectorial transport of protein targeted for secretion(brefeldin A and monensin). All these agents induced significantchanges in ANF and BNP release. Cycloheximide decreasednatriuretic peptide secretion under basal and stimulatedconditions. Brefeldin A dramatically increased basal aswell as stimulated secretion of ANF and BNP. Monensinpartially decreased basal ANF and BNP secretion and completelyblocked stimulated secretion. None of these agentsmodified proteolytic processing as assessed by reverse-phaseHPLC analysis. Double-label pulse-chase experiments using[3H]- and [14C]leucine demonstrated that the secretory responseto ET-1, in contrast to the response to muscle stretch,is based on peptide other than newly synthesized or relativelynewly stored ANF. It is concluded that, in adult atrialcardiocytes, ANF and BNP are sorted to constitutive andregulated pathways in a manner that is substantially uniquefor atrial cardiocytes. In particular, it appears that basal andstimulated ANF and BNP secretion may have a large ??constitutive-like?? component, as previously defined in other endocrinesystems. This type of secretion is based on the preferentialrelease of hormone through vesicles arising from immaturesecretory granules. The capacity of the atria to release ANFand BNP in response to stimuli, therefore, may depend moreon stimulation of the rate of formation of immature granulesthan on the amount of stored hormone.