Cardiac sympathetic overstimulation is characteristic of advanced heart failure, which was recently found not to be improved by the administration of recombinant brain natriuretic peptide (BNP; nesiritide), despite the predicated beneficial effects of natriuretic peptides. It is possible that the lack of improvement was related to a proadrenergic effect of natriuretic peptides. The purpose of the present study was to search for novel means to prevent the proadrenergic effects of natriuretic peptides. The findings show that activation of neuronal H3- and H4-receptors inhibits the release of catecholamines elicited by BNP in cardiac synaptosomes and differentiated PC12 cells. Selective H3- and H4-receptor agonists each synergized with a protein kinase G (PKG) inhibitor and with a phosphodiesterase 3 (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 H3- and H4-receptor-mediated attenuation of BNP-induced catecholamine release. Because excessive catecholamine release is likely to offset the desirable effects of natriuretic peptides, these findings suggest a novel means to alleviate their adverse effects and to improve their therapeutic potential.
See article at J Pharmacol Exp Ther 2012, 343:568–577.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics