Role of the Extracellular Ca2+/cyclic AMP-Adenosine Signaling Pathways in
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: email@example.com
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.
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
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 . 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 .
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+ eux from the SR during
cardiac contraction (systole) .
In addition, Ca2+ acts as an intracellular second messenger that
amplies 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 eect 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) . ese CCBs produce increase in the
intracellular cAMP of the smooth muscles , neuron cell [11-13],
skeletal muscle due to reducing the inux of extracellular Ca2+,
promoting desinhibition of the AC5 and AC6 isoforms activities .
In addition, studies demonstrated the existence of the eux of cAMP
mediated by multidrug resistance proteins transporters in cardiac
myocytes  and skeletal muscle . According to the most
experimental evidences, the blockade of adenosine receptors in skeletal
muscle reduces the negative inotropic eect promoted by extracellular
adenosine due to eux of intracellular cAMP signaling pathways .
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 eects in patients
with ICD, such as AMI.
Research supported by CNPq, FAPESP and CAPES.
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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.
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