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1.  An Unsuspected Property of Natriuretic Peptides: Promotion of Calcium-Dependent Catecholamine Release via Protein Kinase G-Mediated Phosphodiesterase Type 3 Inhibition 
Circulation  2011;125(2):298-307.
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.
doi:10.1161/CIRCULATIONAHA.111.059097
PMCID: PMC3287346  PMID: 22158783
catecholamines; heart failure; natriuretic peptides
2.  Targeting Cardiac Mast Cells: Pharmacological Modulation of the Local Renin-Angiotensin System 
Current Pharmaceutical Design  2011;17(34):3744-3752.
Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local reninangiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.
PMCID: PMC3298860  PMID: 22103845
arrhythmias; cardiac renin-angiotensin system; histamine H3-receptors; mast-cell renin; myocardial ischemia-reperfusion; norepinephrine; sensory and sympathetic nerve endings; sodium-proton exchanger
3.  Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells 
Circulation  2010;122(8):771-781.
Background
Renin released by ischemia/reperfusion (I/R) from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (VT/VF), making RAS a new therapeutic target in myocardial ischemia.
Methods and Results
We investigated whether ischemic preconditioning (IPC) prevents cardiac RAS activation in guinea-pig hearts ex-vivo. When I/R (20-min ischemia/30-min reperfusion) was preceded by IPC (2×5-min I/R cycles), renin and norepinephrine release and VT/VF duration were markedly decreased, a cardioprotective anti-RAS effect. Activation and blockade of adenosine A2b/A3-receptors, and activation and inhibition of PKCε, mimicked and prevented, respectively, the anti-RAS effects of IPC. Moreover, activation of A2b/A3-receptors, or activation of PKCε, prevented degranulation and renin release elicited by peroxide in cultured mast cells (HMC-1). Activation and inhibition of mitochondrial aldehyde dehydrogenase type-2 (ALDH2) also mimicked and prevented, respectively, the cardioprotective anti-RAS effects of IPC. Furthermore, ALDH2 activation inhibited degranulation and renin release by reactive aldehydes in HMC-1. Notably, PKCε and ALDH2 were both activated by A2b/A3-receptor stimulation in HMC-1, and PKCε inhibition prevented ALDH2 activation.
Conclusions
The results uncover a signaling cascade initiated by A2b/A3-receptors, which triggers PKCε-mediated ALDH2 activation in cardiac mast cells, contributing to IPC-induced cardioprotection by preventing mast-cell renin release and the dysfunctional consequences of local RAS activation. Thus, unlike classical IPC where cardiac myocytes are the main target, cardiac mast cells are the critical site at which the cardioprotective anti-RAS effects of IPC develop.
doi:10.1161/CIRCULATIONAHA.110.952481
PMCID: PMC2927811  PMID: 20697027
Renin; Ischemia; Reperfusion; Norepinephrine; Arrhythmia
4.  Cardioprotective Effect of Histamine H3-Receptor Activation: Pivotal Role of Gβγ-Dependent Inhibition of Voltage-Operated Ca2+ Channels 
We previously showed that activation of Gi/o-coupled histamine H3-receptors (H3R) is cardioprotective since it attenuates excessive norepinephrine release from cardiac sympathetic nerves. This action is characterized by a marked decrease in intraneuronal Ca2+ ([Ca2+]i), as Gαi impairs the adenylyl cyclase-cAMP-PKA pathway, and this decreases Ca2+ influx via voltage-operated Ca2+ channels (VOCC). Yet, the Gi/o-derived βγ dimer could directly inhibit VOCC, and the subsequent reduction in Ca2+ influx would be responsible for the H3R-mediated attenuation of transmitter exocytosis. Here, we tested this hypothesis in nerve-growth factor-differentiated rat pheochromocytoma cells (PC12) stably transfected with H3R (PC12-H3) and with the Gβγ scavenger β-ARK1-(495−689)-polypeptide (PC12-H3/β-ARK1). Thus, we evaluated the effects of H3R activation directly on: 1) Ca2+ current (ICa) using the whole-cell patch-clamp technique, and 2) K+-induced exocytosis of endogenous dopamine. H3R activation attenuated both peak ICa and dopamine exocytosis in PC12-H3, but not in PC12-H3/β-ARK1 cells. Moreover, a membrane permeable phosducin-like Gβγ scavenger also prevented the anti-exocytotic effect of H3R activation. In contrast, the H3R-induced attenuation of cAMP accumulation and dopamine exocytosis in response to forskolin were the same in both PC12-H3 and PC12-H3/β-ARK1 cells. Our findings reveal that while Gαi participates in the H3-mediated anti-exocytotic effect when the adenylyl cyclase-cAMP-PKA pathway is stimulated, a direct Gβγ-induced inhibition of VOCC, resulting in an attenuation of ICa plays a pivotal role in the H3R-mediated decrease in [Ca2+]i and associated cardioprotective anti-exocytotic effects. The discovery of this H3R signaling step may offer new therapeutic approaches to cardiovascular diseases characterized by hyperadrenergic activity.
doi:10.1124/jpet.108.137919
PMCID: PMC2577049  PMID: 18523159
5.  Histamine H3-Receptor Signaling in Cardiac Sympathetic Nerves: Identification of a Novel MAPK-PLA2-COX-PGE2-EP3R Pathway 
Biochemical pharmacology  2007;73(8):1146-1156.
We tested the hypothesis that the histamine H3-receptor (H3R)-mediated attenuation of norepinephrine (NE) exocytosis from cardiac sympathetic nerves results not only from a Gαi-mediated inhibition of the adenylyl cyclase-cAMP-PKA pathway, but also from a Gβγi-mediated activation of the MAPK-PLA2 cascade, culminating in formation of an arachidonate metabolite with anti-exocytotic characteristics (e.g., PGE2). We report in Langendorff-perfused guinea-pig hearts and isolated sympathetic nerve endings (cardiac synaptosomes), H3R-mediated attenuation of K+-induced NE exocytosis was prevented by MAPK and PLA2 inhibitors, and by cyclooxygenase and EP3-receptor (EP3R) antagonists. Moreover, H3R activation resulted in MAPK phosphorylation in H3R-transfected SH-SY5Y neuroblastoma cells, and in PLA2 activation and PGE2 production in cardiac synaptosomes; H3R-induced MAPK phosphorylation was prevented by an anti-βγ peptide. Synergism between H3R and EP3R agonists (i.e., imetit and sulprostone, respectively) suggested PGE2 may be a downstream effector of the anti-exocytotic effect of H3R activation. Furthermore, the anti-exocytotic effect of imetit and sulprostone was potentiated by the N-type Ca2+-channel antagonist ω-conotoxin GVIA, and prevented by an anti-Gβγ peptide. Our findings suggest an EP3R Gβγi-induced decrease in Ca2+ influx through N-type Ca2+-channels is involved in PGE2/EP3R-mediated attenuation of NE exocytosis elicited by H3R activation. Conceivably, activation of the Gβγi subunit of H3R and EP3R may also inhibit Ca2+ entry directly, independent of MAPK intervention. As heart failure, myocardial ischemia and arrhythmic dysfunction are associated with excessive local NE release, attenuation of NE release by H3R activation is cardioprotective. Thus, the uncovering of a novel H3R signaling pathway may ultimately bear therapeutic significance in hyper-adrenergic states.
doi:10.1016/j.bcp.2007.01.001
PMCID: PMC1893009  PMID: 17266940
6.  The plasminogen activator system modulates sympathetic nerve function 
The Journal of Experimental Medicine  2006;203(9):2191-2200.
Sympathetic neurons synthesize and release tissue plasminogen activator (t-PA). We investigated whether t-PA modulates sympathetic activity. t-PA inhibition markedly reduced contraction of the guinea pig vas deferens to electrical field stimulation (EFS) and norepinephrine (NE) exocytosis from cardiac synaptosomes. Recombinant t-PA (rt-PA) induced exocytotic and carrier-mediated NE release from cardiac synaptosomes and cultured neuroblastoma cells; this was a plasmin-independent effect but was potentiated by a fibrinogen cleavage product. Notably, hearts from t-PA–null mice released much less NE upon EFS than their wild-type (WT) controls (i.e., a 76.5% decrease; P < 0.01), whereas hearts from plasminogen activator inhibitor-1 (PAI-1)–null mice released much more NE (i.e., a 275% increase; P < 0.05). Furthermore, vasa deferentia from t-PA–null mice were hyporesponsive to EFS (P < 0.0001) but were normalized by the addition of rt-PA. In contrast, vasa from PAI-1–null mice were much more responsive (P < 0.05). Coronary NE overflow from hearts subjected to ischemia/reperfusion was much smaller in t-PA–null than in WT control mice (P < 0.01). Furthermore, reperfusion arrhythmias were significantly reduced (P < 0.05) in t-PA–null hearts. Thus, t-PA enhances NE release from sympathetic nerves and contributes to cardiac arrhythmias in ischemia/reperfusion. Because the risk of arrhythmias and sudden cardiac death is increased in hyperadrenergic conditions, targeting the NE-releasing effect of t-PA may have valuable therapeutic potential.
doi:10.1084/jem.20060077
PMCID: PMC2118409  PMID: 16940168
7.  Cardiac mast cell–derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion 
Journal of Clinical Investigation  2006;116(4):1063-1070.
Having identified renin in cardiac mast cells, we assessed whether its release leads to cardiac dysfunction. In Langendorff-perfused guinea pig hearts, mast cell degranulation with compound 48/80 released Ang I–forming activity. This activity was blocked by the selective renin inhibitor BILA2157, indicating that renin was responsible for Ang I formation. Local generation of cardiac Ang II from mast cell–derived renin also elicited norepinephrine release from isolated sympathetic nerve terminals. This action was mediated by Ang II-type 1 (AT1) receptors. In 2 models of ischemia/reperfusion using Langendorff-perfused guinea pig and mouse hearts, a significant coronary spillover of renin and norepinephrine was observed. In both models, this was accompanied by ventricular fibrillation. Mast cell stabilization with cromolyn or lodoxamide markedly reduced active renin overflow and attenuated both norepinephrine release and arrhythmias. Similar cardioprotection was observed in guinea pig hearts treated with BILA2157 or the AT1 receptor antagonist EXP3174. Renin overflow and arrhythmias in ischemia/reperfusion were much less prominent in hearts of mast cell–deficient mice than in control hearts. Thus, mast cell–derived renin is pivotal for activating a cardiac renin-angiotensin system leading to excessive norepinephrine release in ischemia/reperfusion. Mast cell–derived renin may be a useful therapeutic target for hyperadrenergic dysfunctions, such as arrhythmias, sudden cardiac death, myocardial ischemia, and congestive heart failure.
doi:10.1172/JCI25713
PMCID: PMC1421347  PMID: 16585966

Results 1-7 (7)