Role of potassium channels in stretch-promoted atrial natriuretic factor secretion.

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.

Angiotensin II receptor antagonism reverts the selective cardiac BNP upregulation and secretion observed in myocarditis.

The cardiac natriuretic peptides atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are discoordinately regulated in myocardial inflammation associated with acute allograft rejection in humans and during in vitro exposure of cardiocyte cultures to some proinflammatory cytokines. We used experimental autoimmune myocarditis (EAM) to determine whether the discoordinate regulation of ANF and BNP was specific to the situations above or was generally associated with other types of myocardial inflammation. The dependency of this process to angiotensin signaling was also determined, given that previous work demonstrated beneficial effects of the angiotensin receptor blocker olmesartan in myocarditis. Histopathological changes, plasma and cardiac ANF, BNP, and selected cytokines gene expression as well as plasma cytokine levels using a cytokine array were determined in EAM, angiotensin receptor blocker-treated, and control rats. It was found that EAM specifically increases BNP but not ANF circulating levels, thus mimicking the findings in acute cardiac allograft rejection and the effect of some proinflammatory cytokines on cardiocyte cultures in vitro. Plasma cytokine array and real-time PCR revealed that lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, and tissue inhibitor of metalloproteinase-1 were increased in plasma and in the myocardium of EAM rats. Olmesartan treatment reversed virtually all neuroendocrine and histopathological cardiac changes induced by EAM, thus providing a mechanistic insight into this phenomenon. It is concluded that the inflammatory process contributes specific cytokines, leading to the disregulation of cardiac ANF and BNP production observed during myocardial inflammation, and that this process is angiotensin receptor 1 dependent.

Natriuretic peptide system gene expression in human coronary arteries.

The natriuretic peptides (NPs) ANF, BNP, and CNP have potent anti-proliferative and anti-migratory effects on vascular smooth muscle cells (SMCs). These properties make NPs relevant to the study of human coronary atherosclerosis because vascular cell proliferation and migration are central to the pathophysiology of atherosclerosis. However, the existence and cytological distribution of NPs and their receptors in human coronary arteries remain undetermined. This has hampered the development of hypotheses regarding the possible role of NPs in human coronary disease. We determined the pattern of expression of NPs and their receptors (NPRs) in human coronary arteries with atherosclerotic lesions classified by standard histopathological criteria as fatty streak/early atherosclerotic lesions, intermediate plaques, or advanced lesions. The investigation was carried out using a combination of immunocytochemistry (ICC), in situ hybridization (ISH), and semi-quantitative polymerase chain reaction (PCR). Both by ICC and ISH, ANF was found in the intimal and medial layers of all lesions. BNP was highly expressed in advanced lesions where it was particularly evident by a strong ISH signal but weak ICC staining. CNP was demonstrable in all types of lesions, giving a strong signal by ISH and ICC. This peptide was particularly demonstrable in the endothelium, as well as in the SMCs of the intima, media, and vasa vasorum of the adventitia and in macrophages. By ISH, NPR-A was not detectable in any of the lesions but both NPR-B and NPR-C were found in the intimal and the inner medial layers. By RT-PCR, mRNA levels of all NPs tended to be increased in macroscopically diseased arteries, but only the values for BNP were significantly so. No significant changes in NPR mRNA levels were detected by PCR. In general, the signal intensity given by the NPs and their receptors by ICC or ISH appeared dependent on the type of lesion, being strongest in intermediate plaques and decreasing with increasing severity of the lesion. This study constitutes the first demonstration of NPs and NPR mRNAs in human coronary arteries and supports the existence of an autocrine/paracrine NP system that is actively modulated during the progression of atherosclerotic coronary disease. This suggests that the coronary NP system is involved in the pathobiology of intimal plaque formation in humans and may be involved in vascular remodeling.