A novel proadrenergic effect of cardiac natriuretic peptides: inhibition by histamine H3‐receptor activation

Abstract

Natriuretic peptides (NP) are generally viewed as cardioprotective. Yet, NP were recently found to increase myocardial infarct size in mice, while their deletion decreased it. Further, a recombinant NP (nesiritide) was shown to increase death risk in heart failure patients. Excessive norepinephrine release may have been pivotal in these unexpected events. Thus, we questioned by which mechanisms NP could exert a pro‐adrenergic effect and whether this could be inhibited by histamine H3‐receptor (H3R) activation. NP treatment of sympathetic nerve endings isolated from guinea‐pig hearts (cardiac synaptosomes) and NGF‐differentiated PC12 cells markedly increased cAMP levels and PKA activity, thus promoting catecholamine exocytosis. These pro‐adrenergic effects derived from a cGMP/PKG‐mediated prevention of cAMP hydrolysis by PDE3. Activation of H3R, constitutively expressed in synaptosomes and permanently transfected in PC12 cells, inhibited NP‐induced catecholamine release and prevented the increases in cAMP levels and PKA activity. These effects most likely resulted from a H3R‐mediated enhancement of PDE3 activity and/or PKG inhibition. These findings elucidate new means to control catecholamine exocytosis in the heart, and may foster the design of new agents (e.g., selective H3R agonists) to enable a safe and effective treatment of congestive heart failure with NP.This work was supported by NIH Grant HL 034215 and by a PhRMA Pre‐doctoral fellowship.