Interaction between Sensory C-fibers and Cardiac Mast Cells in Ischemia/Reperfusion: Activation of a Local Renin-Angiotensin System Culminating in Severe Arrhythmic Dysfunction

Morrey, Christopher; Brazin, Jacqueline; Seyedi, Nahid; Corti, Federico; Silver, Randi B.; Levi, Roberto

doi:10.1124/jpet.110.172262

Cited by 37 publications

(42 citation statements)

References 46 publications

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“…These observations emphasize a close relationship between sensory nerve fibres and vascularity, also seen between C fibres and cardiac mast cells. 38) Further studies are needed in a larger number of patients to investigate any relationship of Na v 1.8-immunoreactive nerve fibres and gene variation in cardiac ischaemia or pain.…”

Section: Discussionmentioning

confidence: 99%

Localisation of SCN10A Gene Product Nav1.8 and Novel Pain-Related Ion Channels in Human Heart

et al. 2011

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SummaryWe have shown that the gene SCN10A encoding the sodium channel Na v 1.8 is a susceptibility factor for heart block and serious ventricular arrhythmia. Since Na v 1.8 is known to be present in nerve fibres that mediate pain, it may be related to both cardiac pain and dysrhythmia. The localisation of Na v 1.8 and other key nociceptive ion channels, including Na v 1.7, Na v 1.9, capsaicin receptor TRPV1, and purinergic receptor P2X 3 , have not been reported in human heart. The aim of this study was to determine the distribution of Na v 1.8, related sodium and other sensory channels in human cardiac tissue, and correlate their density with sympathetic nerves, regenerating nerves (GAP-43), and vascularity. Human heart atrial appendage tissues (n = 13) were collected during surgery for valve disease. Tissues were investigated by immunohistology using specific antibodies to Na v 1.8 and other markers. Na v 1.8 immunoreactivity was detected in nerve fibres and fascicles in the myocardium, often closely associated with small capillaries. Na v 1.8 nerve fibres per mm 2 correlated significantly with vascular markers. Na v 1.8-immunoreactivity was present also in cardiomyocytes with a similar distribution pattern to that seen with connexins, the specialised gap junction proteins of myocardial intercalated discs. Na v 1.5-immunoreactivity was detected in cardiomyocytes but not in nerve fibres. Na v 1.7, Na v 1.9, TRPV1, P2X 3 /P2X 2 , and GAP43 positive nerve fibres were relatively sparse, whereas sympathetic innervation and connexin43 were abundant. We conclude that sodium channel Na v 1.8 is present in sensory nerves and cardiomyocytes of human heart. Na v 1.8 and other pain channels provide new targets for the understanding and treatment of cardiac pain and dysrhythmia. (Int Heart J 2011; 52: 146-152)

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Section: Discussionmentioning

confidence: 99%

Localisation of SCN10A Gene Product Nav1.8 and Novel Pain-Related Ion Channels in Human Heart

et al. 2011

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“…This, in fact, suggested that H 3 Rs may influence neuronal AT 1 R expression in hearts subjected to I/R. Inasmuch as cardiac synaptosomes probably include cholinergic, purinergic, and sensory C-fiber terminals (Seyedi et al, 1999;Morrey et al, 2010), we tested whether H 3 R activation would influence AT 1 R expression in PC12-H 3 cells, which once differentiated with NGF express a typical sympathetic neuron phenotype (Taupenot, 2007;Morrey et al, 2008;Corti et al, 2011). Indeed, we found that activation of H 3 R with imetit markedly diminished AT 1 R protein abundance in these cells, an action that was abolished by the H 3 R antagonist clobenpropit.…”

Section: Discussionmentioning

confidence: 99%

Histamine 3 Receptor Activation Reduces the Expression of Neuronal Angiotensin II Type 1 Receptors in the Heart

Hashikawa-Hobara¹,

Chan²,

Levi³

2011

J Pharmacol Exp Ther

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In severe myocardial ischemia, histamine 3 (H 3 ) receptor activation affords cardioprotection by preventing excessive norepinephrine release and arrhythmias; pivotal to this action is the inhibition of neuronal Na ϩ /H ϩ exchanger (NHE). Conversely, angiotensin II, formed locally by mast cell-derived renin, stimulates NHE via angiotensin II type 1 (AT 1 ) receptors, facilitating norepinephrine release and arrhythmias. Thus, ischemic dysfunction may depend on a balance between the NHE-modulating effects of H 3 receptors and AT 1 receptors. The purpose of this investigation was therefore to elucidate the H 3 /AT 1 receptor interaction in myocardial ischemia/reperfusion. We found that H 3 receptor blockade with clobenpropit increased norepinephrine overflow and arrhythmias in Langendorff-perfused guinea pig hearts subjected to ischemia/reperfusion. This coincided with increased neuronal AT 1 receptor expression. NHE inhibition with cariporide prevented both increases in norepinephrine release and AT 1 receptor expression. Moreover, norepinephrine release and AT 1 receptor expression were increased by the nitric oxide (NO) synthase inhibitor N G -methyl-L-arginine and the protein kinase C activator phorbol myristate acetate. H 3 receptor activation in differentiated sympathetic neuron-like PC12 cells permanently transfected with H 3 receptor cDNA caused a decrease in protein kinase C activity and AT 1 receptor protein abundance. Collectively, our findings suggest that neuronal H 3 receptor activation inhibits NHE by diminishing protein kinase C activity. Reduced NHE activity sequentially causes intracellular acidification, increased NO synthesis, and diminished AT 1 receptor expression. Thus, H 3 receptor-mediated NHE inhibition in ischemia/reperfusion not only opposes the angiotensin II-induced stimulation of NHE in cardiac sympathetic neurons, but also down-regulates AT 1 receptor expression. Cardioprotection ultimately results from the combined attenuation of angiotensin II and norepinephrine effects and alleviation of arrhythmias.

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“…The renin-angiotensin system (RAS) is a key regulator of blood pressure and fluid homeostasis (Peach, 1977;Morrey et al, 2010). Angiotensin (Ang) II is a main effector molecule of the RAS, produced from the substrate angiotensinogen through sequential enzymatic cleavages by renin and angiotensin-converting enzyme.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II Type 1 Receptor Antagonist Attenuates Lung Fibrosis in Hyperoxia-Exposed Newborn Rats

Chou

Lang

Wang³

et al. 2011

J Pharmacol Exp Ther

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Bronchopulmonary dysplasia (BPD) remains a major cause of morbidity and mortality during the first year of life, and many infants have significant respiratory problems throughout childhood. Currently no effective therapy is clinically available to prevent the long-term pulmonary sequelae of BPD. Previous research has demonstrated that the renin-angiotensin system is up-regulated in human lung fibroblasts. Angiotensin II type 1 receptor (AT 1 R) antagonists and AT 1 R short interfering RNA diminished hyperoxia-increased collagen expression, whereas AT 2 R antagonists did not have any effects on these hyperoxiainduced changes. The in vivo therapeutic effects of AT 1 R antagonists on hyperoxia-induced lung fibrosis remain unknown. The present study assessed the effects of an AT 1 R antagonist (losartan) on preventing hyperoxia-induced lung fibrosis in newborn rats. Rat pups were exposed to 7 days of Ͼ95% O 2 and an additional 2 weeks of 60% O 2 . AT 1 R antagonist-treated pups were injected intraperitoneally with losartan at a dose of 10 mg/kg/day from postnatal days 1 to 7 and a dose of 5 mg/kg/day from postnatal days 8 to 21. Control group pups were injected with an equal volume of normal saline. AT 1 R antagonist treatment attenuated the hyperoxia-induced lung fibrosis on postnatal days 7 and 21 and also decreased the hyperoxia-induced expression of extracellular signal-regulated protein kinase and ␣-smooth muscle actin. AT 1 R antagonist treatment did not affect body weight or lung weight of the rats. These data suggest that AT 1 R antagonist may offer a novel therapeutic strategy for preventing hyperoxia-induced lung fibrosis.

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Interaction between Sensory C-fibers and Cardiac Mast Cells in Ischemia/Reperfusion: Activation of a Local Renin-Angiotensin System Culminating in Severe Arrhythmic Dysfunction

Cited by 37 publications

References 46 publications

Localisation of SCN10A Gene Product Nav1.8 and Novel Pain-Related Ion Channels in Human Heart

Localisation of SCN10A Gene Product Nav1.8 and Novel Pain-Related Ion Channels in Human Heart

Histamine 3 Receptor Activation Reduces the Expression of Neuronal Angiotensin II Type 1 Receptors in the Heart

Angiotensin II Type 1 Receptor Antagonist Attenuates Lung Fibrosis in Hyperoxia-Exposed Newborn Rats

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