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Proadrenergic effects of cardiac natriuretic peptides: inhibition by histamine H3‐receptor (H3R) activation

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. Also, mice lacking NP receptor‐A are resistant to endotoxic shock. Further, a recombinant NP (nesiritide) was shown to increase death risk in heart failure patients. Excessive norepinephrine (NE) release may have been pivotal in these unexpected events. Langendorff guinea‐pig hearts were perfused with NP; this resulted in a ≈ 73% increase in NE overflow. NP treatment of guinea‐pig cardiac synaptosomes and NGF‐differentiated PC12 cells also increased NE and dopamine release (≈ 34% and ≈ 48% increase, respectively). Thus, we investigated the mechanisms of the pro‐adrenergic effect of NP. We found that NP markedly increased PKG activity, cAMP levels and PKA activity in differentiated PC12 cells; these effects derived from a cGMP/PKG‐mediated prevention of cAMP hydrolysis by PDE3. Because of the antiexocytotic properties of H3R, we next questioned whether H3R activation might inhibit the proadrenergic effects of NP. Activation of H3R, constitutively expressed in heart synaptosomes and permanently transfected in PC12 cells, inhibited NP‐induced catecholamine release and prevented the increases in cAMP level and PKA activity. Since the clinical use of NP in congestive heart failure (CHF) remains controversial, our findings may foster the design of selective H3R agonists to enable a safe and effective treatment of CHF with NP.