An Unsuspected Property of Natriuretic Peptides: Promotion of Calcium-Dependent Catecholamine Release via Protein Kinase G-Mediated Phosphodiesterase Type 3 Inhibition
Background—Although natriuretic peptides are considered cardioprotective, clinical heart failure trials with recombinant BNP (nesiritide) failed to prove it. Unsuspected proadrenergic effects might oppose the anticipated benefits of natriuretic peptides.
Methods and Results—We investigated whether natriuretic peptides induce catecholamine release in isolated hearts, sympathetic nerve endings (cardiac synaptosomes) and PC12 cells bearing a sympathetic neuron phenotype. Perfusion of isolated guinea pig hearts with BNP elicited a 3-fold increase in norepinephrine release which doubled in ischemia/reperfusion conditions. BNP and ANP also released norepinephrine from cardiac synaptosomes and dopamine from nerve-growth-factor-differentiated PC12 cells in a concentration-dependent manner. These catecholamine-releasing effects were associated with an increase in intracellular calcium, and abolished by blockade of calcium channels and calcium transients, demonstrating a calcium-dependent exocytotic process. Activation of the guanylyl cyclase-cGMP-protein-kinase-G system with nitroprusside or membrane-permeant cGMP analogs mimicked the proexocytotic effect of natriuretic peptides, an action associated with an increase in intracellular cAMP and protein-kinase-A activity. cAMP enhancement resulted from an inhibition of phosphodiesterase-type-3-induced cAMP hydrolysis. Collectively, these findings indicate that, by inhibiting phosphodiesterase-type-3, natriuretic peptides sequentially enhance intracellular cAMP levels, protein-kinase-A activity, intracellular calcium and catecholamine exocytosis.
Conclusions—Our results show that natriuretic peptides, at concentrations likely to be reached at cardiac sympathetic nerve endings in advanced congestive heart failure, promote norepinephrine release via a protein-kinase-G-induced inhibition of phosphodiesterase-type-3-mediated cAMP hydrolysis. We propose that this proadrenergic action may counteract the beneficial cardiac and hemodynamic effects of natriuretic peptides, and thus explain the ineffectiveness of nesiritide as a cardiac failure medication.
- Received July 28, 2011.
- Accepted December 5, 2011.
- Copyright © 2011, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited