title: An unsuspected property of natriuretic peptides: promotion of calcium-dependent catecholamine release via protein kinase G-mediated phosphodiesterase type 3 inhibition.
abstract: BACKGROUND
  Although natriuretic peptides are considered cardioprotective, clinical heart failure trials with recombinant brain natriuretic peptide (nesiritide) failed to prove it. Unsuspected proadrenergic effects might oppose the anticipated benefits of natriuretic peptides.
  
  
  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 brain natriuretic peptide elicited a 3-fold increase in norepinephrine release, which doubled in ischemia/reperfusion conditions. Brain natriuretic peptide and atrial natriuretic peptide 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-cyclic GMP-protein-kinase-G system with nitroprusside or membrane-permeant cyclic GMP analogs mimicked the proexocytotic effect of natriuretic peptides, an action associated with an increase in intracellular cyclic AMP (cAMP) and protein-kinase-A activity. Cyclic AMP 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.
authors.affiliation: Dept of Pharmacology, Weill Cornell Medical College, 1300 York Ave, New York, NY 10065-4896, USA.
authors.forename: Noel Yan-Ki
authors.initials: NY
authors.lastname: Chan
authors.forename: Nahid
authors.initials: N
authors.lastname: Seyedi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Takano
authors.forename: Roberto
authors.initials: R
authors.lastname: Levi
mesh_terms: D000818:Animals; D002118:Calcium; D002395:Catecholamines / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D006321:Heart; D006333:Heart Failure; D045283:Natriuretic Agents; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology*; D045265:Natriuretic Peptides / Q000502:physiology*; D016716:PC12 Cells; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D051381:Rats; D013564:Sympathetic Nervous System
chemical_list: D002395:Catecholamines; D045283:Natriuretic Agents; D045265:Natriuretic Peptides; D058987:Phosphodiesterase 3 Inhibitors; D020097:Natriuretic Peptide, Brain; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D002118:Calcium