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Role of the Extracellular Ca2+/cyclic AMP-Adenosine Signaling Pathways in Cardioprotection

  • March 2017
Authors:
Francisco Sandro Menezes Rodrigues at Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil
Francisco Sandro Menezes Rodrigues
  • Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil
José Gustavo Padrão Tavares at Faculdade Pitágoras de Teixeira de Freitas
José Gustavo Padrão Tavares
  • Faculdade Pitágoras de Teixeira de Freitas
Paolo Ruggero Errante at Universidade Federal de São Paulo
Paolo Ruggero Errante
Enio Rodrigues Vasques at University of São Paulo
Enio Rodrigues Vasques
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Role of the Extracellular Ca2+/cyclic AMP-Adenosine Signaling Pathways in
Cardioprotection
Francisco Sandro Menezes-Rodrigues1, José Gustavo Padrão Tavares1, Paolo Ruggero Errante1, Ênio Rodrigues Vasques2, Maria do Carmo Maia Reis3,
Bráulio Luna-Filho3, Fulvio Alexandre Scorza4, Afonso Caricati-Neto1 and Leandro Bueno Bergantin1*
1Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Brazil
2Departament of Gastroenterology, LIM 37, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
3Department of Cardiology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Brazil
4Department of Neuroscience, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Brazil
*Corresponding author: Dr. Leandro Bueno Bergantin, Department of Pharmacology, Escola Paulista de Medicina-Universidade Federal de São Paulo (UNIFESP),
Brazil, Tel: 551155764973, Email: leanbio39@yahoo.com.br
Received date: Feb 27, 2017, Accepted date: Mar 3, 2017, Published date: Mar 6, 2017
Copyright: © 2017 Menezes-Rodrigues FS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Editorial
Ischemic cardiac diseases (ICD) produce immense health and
economic burdens in the United States, and globally [1,2]. Among the
ICD, acute myocardial infarction (AMI) represents the commonest
cause of morbidity and mortality worldwide [2,3]. e cardiac muscle
can tolerate short periods of severe and total ischemia, which occur in
coronary vasospasm (e.g. angina pectoris and acute myocardial
infarction). Moreover, it is known that short periods of ischemia are
not associated with increased cardiac myocyte death. However, if there
is an increasing of duration, and severity of cardiac ischemia, it may be
developed great myocardial damage, and susceptibility to further
injury during reperfusion (R). us, the combined damage of ischemia
(I) with clearing of artery (e.g. catheterization) may compromise
cardiac structure and function, especially excitation-contraction
coupling [2-4].
e excitation-contraction coupling in cardiac myocytes depends
on ionic homeostasis, especially by a precise adjustment of the
intracellular calcium ([Ca2+]i) which maintains the strength, and
frequency, of cardiac function [5]. In cardiac sarcolemmal, the T-
tubules presented in myocytes make closely contact with junctional
sarcoplasmic reticulum (SR), where the L-type Ca2+ channels (LTCCs)
are highly expressed, and are in close proximity to cardiac ryanodine
receptors (RyR2), which are responsible to release Ca2+ from SR [5].
is LTCC-RyR2 implies that Ca2+ ions, which enter via LTCC, cause
high increase of [Ca2+] due to Ca2+ release from SR by opening RyR2
during excitation-contraction coupling. is event is called Ca2+-
induced Ca2+-release, which causes Ca2+ eux from the SR during
cardiac contraction (systole) [5].
In addition, Ca2+ acts as an intracellular second messenger that
amplies the cellular response, for example, by interacting with other
second messengers, such as cyclic AMP (cAMP). us, the ionic
imbalance produced by cardiac I/R injury, especially the cytosolic Ca2+
overload, has been implicated as a major cause of severe, and lethal,
cardiac arrhythmias due to ICD, such as AMI. Indeed, the cytosolic
Ca2+ and mitochondrial overload, and bioenergetics collapse,
compromise the excitation-contraction coupling, favoring the
development of cardiac arrhythmias, such as ventricular arrhythmia
and atrioventricular blockade, and death [6-8].
Interestingly, the increased entry of Ca2+ via LTCC acts as a negative
regulator on the eect of β-AR stimulation due to inhibition of
adenylyl cyclase (AC) activity. Increases of intracellular cAMP,
produced by β-adrenergic stimulation in the cardiac muscle, are higher
when extracellular Ca2+ is lowered, such as by the LTCC blockade with
Ca2+ channel blockers (CCBs) [9]. ese CCBs produce increase in the
intracellular cAMP of the smooth muscles [10], neuron cell [11-13],
skeletal muscle due to reducing the inux of extracellular Ca2+,
promoting desinhibition of the AC5 and AC6 isoforms activities [14].
In addition, studies demonstrated the existence of the eux of cAMP
mediated by multidrug resistance proteins transporters in cardiac
myocytes [15] and skeletal muscle [16]. According to the most
experimental evidences, the blockade of adenosine receptors in skeletal
muscle reduces the negative inotropic eect promoted by extracellular
adenosine due to eux of intracellular cAMP signaling pathways [17].
Following this line of reasoning, we may propose that pharmacological
modulation of the extracellular Ca2+/cAMP-adenosine signaling
pathways may be used to produce cardioprotective eects in patients
with ICD, such as AMI.
Acknowledgments
Research supported by CNPq, FAPESP and CAPES.
References
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Editorial OMICS International
J rombo Cir, an open access journal Volume 3 • Issue 1 • 1000e106
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Pharmacol Exp er 341: 820-828.
Citation: Menezes-Rodrigues FS, Tavares JGP, Errante PR, Vasques ER, do Carmo MRM, et al. (2017) Role of the Extracellular Ca2+/cyclic
AMP-Adenosine Signaling Pathways in Cardioprotection. J Thrombo Cir 3: e106.
Page 2 of 2
J rombo Cir, an open access journal Volume 3 • Issue 1 • 1000e106

Supplementary resource (1)

role-of-the-extracellular-ca2cyclic-ampadenosine-signaling-pathways-incardioprotection
Data
March 2017
Francisco Sandro Menezes Rodrigues · José Gustavo Padrão Tavares · Paolo Ruggero Errante · Enio Rodrigues Vasques · Leandro Bueno Bergantin
... In addition to this action on the plasmalemmal NCX, LMWHs can stimulate cAMP transport from cardiac cells to the extracellular medium, where they are rapidly converted by ecto-phosphodiesterases and ectonucleotides to ADO that, in turn, activates cardiac A1R resulting in the attenuation of the positive chronotropic response produced by stimulation of cardiac β1-adrenoceptors (β1-AR) by catecholamines or other stimuli that increase cardiac activity [25,[46][47][48]. It has been proposed that this modulatory role of A1R on cardiac function finely adjusts cardiac chronotropism, and thus reduces the incidence of cardiac arrhythmias [5,17,49]. ...
... The increase in extracellular levels of ADO generated by the enzymatic degradation of ATP released from intracardiac sympathetic neurons, combined with the transport of cAMP to the extracellular medium from cardiac cells during stimulation, produces an increase in the activation of cardiac A1R and attenuates the positive chronotropic response stimulated by β1AR [17,50]. Several lines of evidence suggest that this adrenergic-purinergic communication involved in the regulation of cardiac chronotropism contributes importantly to cardioprotective responses in different pathophysiological conditions [17,46,47]. In the present work, we showed that the A1R-antagonist DPCPX blocked the cardioprotective effects of ENOX, indicating the involvement of this ADO receptor in these effects. ...
Citation: Academic Editors: Saverio Muscoli Pharmacological Modulation by Low Molecular Weight Heparin of Purinergic Signaling in Cardiac Cells Prevents Arrhythmia and Lethality Induced by Myocardial Infarction
Article
Full-text available
  • Feb 2023
Background: Although several studies suggest that heparins prevent arrhythmias caused by acute myocardial infarction (AMI), the molecular mechanisms involved remain unclear. To investigate the involvement of pharmacological modulation of adenosine (ADO) signaling in cardiac cells by a low-molecular weight heparin (enoxaparin; ENOX) used in AMI therapy, the effects of ENOX on the incidences of ventricular arrhythmias (VA), atrioventricular block (AVB), and lethality (LET) induced by cardiac ischemia and reperfusion (CIR) were evaluated, with or without ADO signaling blockers. Methods: To induce CIR, adult male Wistar rats were anesthetized and subjected to CIR. Electrocardiogram (ECG) analysis was used to evaluate CIR-induced VA, AVB, and LET incidence, after treatment with ENOX. ENOX effects were evaluated in the absence or presence of an ADO A1-receptor antagonist (DPCPX) and/or an inhibitor of ABC transporter-mediated cAMP efflux (probenecid, PROB). Results: VA incidence was similar between ENOX-treated (66%) and control rats (83%), but AVB (from 83% to 33%) and LET (from 75% to 25%) incidences were significantly lower in rats treated with ENOX. These cardioprotective effects were blocked by either PROB or DPCPX. Conclusion: These results indicate that ENOX was effective in preventing severe and lethal arrhythmias induced by CIR due to pharmacological modulation of ADO signaling in cardiac cells, suggesting that this cardioprotective strategy could be promising in AMI therapy.
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... Recently, we discovered that the functional interaction between intracellular signaling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP signaling interaction) plays an important role in the regulation of the several cellular responses, including neurotransmitter/hormone release and neuroprotection [8][9][10][11][12][13][14] . It is well established that the free Ca 2+ in the cytosol regulates adenylate cyclase (AC) activity and consequently cAMP production 9-13 . ...
... We have proposed that the combined use of the L-type CCB and cAMP-enhancer compounds to pharmacologically modulate the Ca 2+ /cAMP signaling interaction could be used as a new therapeutic strategy for neurological and psychiatric disorders related to neurotransmission deficit, and neuronal death, such as Alzheimer's and Parkinson's diseases 9-13 . In addition, this pharmacological modulation could attenuate cardiac arrhythmias and myocardial lesions caused by ischemia and reperfision in patients with acute myocardial infarction 14 . ...
View
... Recently, we discovered that the functional interaction between intracellular signaling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP signaling interaction) plays an important role in the regulation of the several cellular responses, including neurotransmitter/hormone release and neuroprotection [8][9][10][11][12][13][14] . It is well established that the free Ca 2+ in the cytosol regulates adenylate cyclase (AC) activity and consequently cAMP production 9-13 . ...
... We have proposed that the combined use of the L-type CCB and cAMP-enhancer compounds to pharmacologically modulate the Ca 2+ /cAMP signaling interaction could be used as a new therapeutic strategy for neurological and psychiatric disorders related to neurotransmission deficit, and neuronal death, such as Alzheimer's and Parkinson's diseases 9-13 . In addition, this pharmacological modulation could attenuate cardiac arrhythmias and myocardial lesions caused by ischemia and reperfision in patients with acute myocardial infarction 14 . ...
View
... Recently, we discovered that the functional interaction between intracellular signaling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP signaling interaction) plays an important role in the regulation of the several cellular responses, including neurotransmitter/hormone release and neuroprotection [8][9][10][11][12][13][14] . It is well established that the free Ca 2+ in the cytosol regulates adenylate cyclase (AC) activity and consequently cAMP production 9-13 . ...
... We have proposed that the combined use of the L-type CCB and cAMP-enhancer compounds to pharmacologically modulate the Ca 2+ /cAMP signaling interaction could be used as a new therapeutic strategy for neurological and psychiatric disorders related to neurotransmission deficit, and neuronal death, such as Alzheimer's and Parkinson's diseases 9-13 . In addition, this pharmacological modulation could attenuate cardiac arrhythmias and myocardial lesions caused by ischemia and reperfision in patients with acute myocardial infarction 14 . ...
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... In addition, activation of β1/2-AR stimulates the increment of intracellular cAMP concentration in cardiac cells, which in turn, increases the cAMP efflux mediated by multidrug resistance protein transporters and elevates the extracellular cAMP concentration and adenosine, thus culminating in activation of adenosine receptors [42]. These cellular responses mediated β-AR reduce cytosolic Ca 2+ overload, oxygen consumption and ATP deficit [67][68][69][70]. ...
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Ischemic heart diseases (IHD) are the leading cause of death worldwide. Although the principal form of treatment of IHD is myocardial reperfusion, the recovery of coronary blood flow after ischemia can cause severe and fatal cardiac dysfunctions, mainly due to the abrupt entry of oxygen and ionic deregulation in cardiac cells. The ability of these cells to protect themselves against injury including ischemia and reperfusion (I/R), has been termed "cardioprotection". This protective response can be stimulated by pharmacological agents (adenosine, catecholamines and others) and non-pharmacological procedures (conditioning, hypoxia and others). Several intracellular signaling pathways mediated by chemical messengers (enzymes, protein kinases, transcription factors and others) and cytoplasmic organelles (mitochondria, sarcoplasmic reticulum, nucleus and sarcolemma) are involved in cardioprotective responses. Therefore, advancement in understanding the cellular and molecular mechanisms involved in the cardioprotective response can lead to the development of new pharmacological and non-pharmacological strategies for cardioprotection, thus contributing to increasing the efficacy of IHD treatment. In this work, we analyze the recent advances in pharmacological and non-pharmacological strategies of cardioprotection.
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... In addition, activation of β1/2-AR stimulates the increment of intracellular cAMP concentration in cardiac cells, which in turn, increases the cAMP efflux mediated by multidrug resistance protein transporters and elevates the extracellular cAMP concentration and adenosine, thus culminating in activation of adenosine receptors [42]. These cellular responses mediated β-AR reduce cytosolic Ca 2+ overload, oxygen consumption and ATP deficit [67][68][69][70]. ...
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Ischemic heart diseases (IHD) are the leading cause of death worldwide. Although the principal form of treatment of IHD is myocardial reperfusion, the recovery of coronary blood flow after ischemia can cause severe and fatal cardiac dysfunctions, mainly due to the abrupt entry of oxygen and ionic deregulation in cardiac cells. The ability of these cells to protect themselves against injury including ischemia and reperfusion (I/R), has been termed "cardioprotection". This protective response can be stimulated by pharmacological agents (adenosine, catecholamines and others) and non-pharmacological procedures (conditioning, hypoxia and others). Several intracellular signaling pathways mediated by chemical messengers (enzymes, protein kinases, transcription factors and others) and cytoplasmic organelles (mitochondria, sarcoplasmic reticulum, nucleus and sarcolemma) are involved in cardioprotective responses. Therefore, advancement in understanding the cellular and molecular mechanisms involved in the cardioprotective response can lead to the development of new pharmacological and non-pharmacological strategies for cardioprotection, thus contributing to increasing the efficacy of IHD treatment. In this work, we analyze the recent advances in pharmacological and non-pharmacological strategies of cardioprotection.
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Pharmacological implications of the Ca 2+ /cAMP signaling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders
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In this review, we discussed pharmacological implications of the Ca 2+ /cAMP signaling interaction in the antihypertensive and neurological/psychiatric disorders therapies. Since 1975, several clinical studies have reported that acute and chronic administration of L-type voltage-activated Ca 2+ channels (VACCs) blockers, such as nifedipine, produces reduction in peripheral vascular resistance and arterial pressure associated with an increase in plasma noradrenaline levels and heart rate, typical of sympathetic hyperactivity. Despite this sympathetic hyperactivity has been initially attributed to adjust reflex of arterial pressure, the cellular and molecular mechanisms involved in this apparent sympathomimetic effect of the L-type VACCs blockers remained unclear for decades. In addition, experimental studies using isolated tissues richly inner-vated by sympathetic nerves (to exclude the influence of adjusting reflex) showed that neurogenic responses were completely inhibited by L-type VACCs blockers in concentrations above 1 lmol/L, but paradoxically potentiated in concentrations below 1 lmol/L. During almost four decades, these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical increase in sympathetic activity produced by L-type VACCs blocker is due to interaction of the Ca 2+ /cAMP signaling pathways. Then, the pharmacological manipulation of the Ca 2+ /cAMP interaction produced by combination of the L-type VACCs blockers used in the antihypertensive therapy, and cAMP accumulating compounds used in the antidepressive therapy, could represent a potential cardiovascular risk for hypertensive patients due to increase in sympathetic hyperactivity. In contrast, this pharmacological manipulation could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases.
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Contribution of the Extracellular cAMP-Adenosine Pathway to Dual Coupling of 2-Adrenoceptors to Gs and Gi Proteins in Mouse Skeletal Muscle
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Calcium influx through L-type channels attenuates skeletal muscle contraction via inhibition of adenylyl cyclases
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Skeletal muscle contraction is triggered by acetylcholine induced release of Ca(2+) from sarcoplasmic reticulum. Although this signaling pathway is independent of extracellular Ca(2+), L-type voltage-gated calcium channel (Cav) blockers have inotropic effects on frog skeletal muscles which occur by an unknown mechanism. Taking into account that skeletal muscle fiber expresses Ca(+2)-sensitive adenylyl cyclase (AC) isoforms and that cAMP is able to increase skeletal muscle contraction force, we investigated the role of Ca(2+) influx on mouse skeletal muscle contraction and the putative crosstalk between extracellular Ca(2+) and intracellular cAMP signaling pathways. The effects of Cav blockers (verapamil and nifedipine) and extracellular Ca(2+) chelators EGTA were evaluated on isometric contractility of mouse diaphragm muscle under direct electrical stimulus (supramaximal voltage, 2ms, 0.1Hz). Production of cAMP was evaluated by radiometric assay while Ca(2+) transients were assessed by confocal microscopy using L6 cells loaded with fluo-4/AM. Ca(2+) channel blockers verapamil and nifedipine had positive inotropic effect, which was mimicked by removal of extracellular Ca(+2) with EGTA or Ca(2+)-free Tyrode. While phosphodiesterase inhibitor IBMX potentiates verapamil positive inotropic effect, it was abolished by AC inhibitors SQ22536 and NYK80. Finally, the inotropic effect of verapamil was associated with increased intracellular cAMP content and mobilization of intracellular Ca(2+), indicating that positive inotropic effects of Ca(2+) blockers depend on cAMP formation. Together, our results show that extracellular Ca(2+) modulates skeletal muscle contraction, through inhibition of Ca(2+)-sensitive AC. The cross-talk between extracellular calcium and cAMP-dependent signaling pathways appears to regulate the extent of skeletal muscle contraction responses.
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