Natriuretic Peptide-Induced Catecholamine Release from Cardiac Sympathetic Neurons: Inhibition by Histamine H₃ and H₄ Receptor Activation

Abstract

We reported previously that natriuretic peptides, including brain natriuretic peptide (BNP), promote norepinephrine release from cardiac sympathetic nerves and dopamine release from differentiated pheochromocytoma PC12 cells. These proexocytotic effects are mediated by an increase in intracellular calcium secondary to cAMP/protein kinase A (PKA) activation caused by a protein kinase G (PKG)-mediated inhibition of phosphodiesterase type 3 (PDE3). The purpose of the present study was to search for novel means to prevent the proadrenergic effects of natriuretic peptides. For this, we focused our attention on neuronal inhibitory G␣ i/o -coupled histamine H 3 and H 4 receptors. Our findings show that activation of neuronal H 3 and H 4 receptors inhibits the release of catecholamines elicited by BNP in cardiac synaptosomes and differentiated PC12 cells. This effect results from a decrease in intracellular Ca 2ϩ due to reduced intracellular cAMP/PKA activity, caused by H 3 and H 4 receptor-mediated PKG inhibition and consequent PDE3-induced increase in cAMP metabolism. Indeed, selective H 3 and H 4 receptor agonists each synergized with a PKG inhibitor and a PDE3 activator in attenuating BNP-induced norepinephrine release from cardiac sympathetic nerve endings. This indicates that PKG inhibition and PDE3 stimulation are pivotal for the H 3 and H 4 receptor-mediated attenuation of BNP-induced catecholamine release. Cardiac sympathetic overstimulation is characteristic of advanced heart failure, which was recently found not to be improved by the administration of recombinant BNP (nesiritide), despite the predicated beneficial effects of natriuretic peptides. Because excessive catecholamine release is likely to offset the desirable effects of natriuretic peptides, our findings suggest novel means to alleviate their adverse effects and improve their therapeutic potential.

The histamine H4-receptor and the central and peripheral nervous system: A critical analysis of the literature

“…The K þ -and BNP (brain natriuretic peptide)-induced release of norepinephrine (NE) from cardiac synaptosomes was inhibited by methimepip (H 3 R agonist) as well as by the H 2 R/H 4 R agonist 4-MH. The 4-MH-induced effect was effectively blocked by the H 4 R antagonist A 943931, which suggests that it was not caused by unspecific H 2 R activation (Chan et al, 2012). Unfortunately, however, Chan et al (2012) did not record a complete concentrationeeffect curve for 4-MH, and therefore, concentration dependency of the effect could not be established.…”

“…Moreover, Chan et al (2012) conclude from a Western blot analysis that PC12 rat pheochromocytoma cells constitutively express H 4 R, but as already mentioned several times in our article, antibody staining results should be interpreted with caution. Unfortunately, H 4 R-free cells (e.g.…”

“…This hypothesis was tested in experiments with rat pheochromocytoma cells and guinea pig cardiac sympathetic nerve endings (Chan et al, 2012). The K þ -and BNP (brain natriuretic peptide)-induced release of norepinephrine (NE) from cardiac synaptosomes was inhibited by methimepip (H 3 R agonist) as well as by the H 2 R/H 4 R agonist 4-MH.…”

Histamine H4-Receptors Inhibit Mast Cell Renin Release in Ischemia/Reperfusion via Protein Kinase Cε-Dependent Aldehyde Dehydrogenase Type-2 Activation

“…We recently ascertained the presence of H 4 Rs in cardiac sympathetic nerve endings where, similar to H 3 Rs, H 4 Rs inhibit NE release (Chan et al, 2012). This effect could complement the reduction of NE release ultimately resulting from H 4 R-mediated actions at the MC level.…”

“…Lastly, in addition to the heart, H 4 R-mediated protective mechanisms may impact other organs (e.g., brain, liver, and kidney) that have renin-containing MCs (Reid et al, 2007;Biran et al, 2008;Veerappan et al, 2008), can suffer ischemic episodes (Kaneko et al, 1998;Guo et al, 2004;Chen et al, 2009), and have been shown to be protected by IPC (Nandagopal et al, 2001;Adachi et al, 2006;Chan et al, 2012;Kukreja, 2012). Fig.…”