ABSTRACT
The cardiac polypeptide hormone atrial natriuretic factor (ANF) plays important roles in the regulation of blood volume and pressure. Few specific details are known about basal or stretch-promoted ANF secretion. Here, we investigated the involvement of K(+) channels in ANF secretion based on investigations of their nature as revealed by oligonucleotide microarray analysis and on protein-protein interactions evidenced by a yeast two-hybrid approach using a heterotrimeric Galphao-1 G protein subunit, which is particularly abundant in the atrium. Based on these data, we investigated the effect of drugs known to pharmacologically affect the function of specific K(+) channels on ANF secretion from the isolated rat atrium. These included adenosine triphosphate-sensitive K(+) channels, TWIK-related K(+) channel 1 (TREK-1), and the Ca(+2)-activated intermediate conductance K(+) channel (SK4). The sulfonylurea ligands tolbutamide and repaglinide, but not glibenclamide, increased stretch-promoted ANF secretion. The channel openers diazoxide, pinacidil, and cromakalim all decreased this type of stimulated ANF secretion. TRAM 34, a specific SK4 inhibitor, and oleylamine, a nonspecific TREK-1 inhibitor, significantly decreased or increased respectively, both basal and stretch-stimulated ANF secretion. Inhibition of Gi/o by pretreatment with Pertussis toxin often significantly affected the effect of these treatments. We concluded that the atria express K(+) channels that are related to Gi/o protein signaling and that significantly affect the endocrine function of the heart. These findings are significant for the development of therapeutic drugs with properties related to the manipulation of ANF plasma levels.
