Néstor G Pérez

Néstor G Pérez
National University of La Plata | UNLP · Centro de Investigaciones Cardiovasculares (CIC)

PhD

About

101
Publications
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Publications

Publications (101)
Article
Background Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue, and both can be activated by corticosteroids. MR activation, in acute myocardial infarction (AMI), worsens cardiac function, and increase NHE activity contributing to the deleterious process. In contrast, effects of GR activation are not full...
Article
Introduction: Acute corticosteroid therapy has been used in the prophylaxis against atrial fibrillation following cardiac surgery or acute myocardial infarction (AMI). Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue. While MR activation during AMI was linked to Na ⁺ /H ⁺ exchanger (NHE1) activation-me...
Article
Full-text available
The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank–Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. An important step in the chain of events leadi...
Article
Full-text available
The cardiac Na+/H+ exchanger (NHE1) is a membrane glycoprotein fundamental for proper cell functioning due its multiple housekeeping tasks, including regulation of intracellular pH, Na+ concentration, and cell volume. In the heart, hyperactivation of NHE1 has been linked to the development of different pathologies. Several studies in animal models...
Article
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Current evidence reveals that cardiac mineralocorticoid receptor (MR) activation following myocardial stretch plays an important physiological role in adapting developed force to sudden changes in hemodynamic conditions. Its underlying mechanism involves a previously unknown nongenomic effect of the MR that triggers redox-mediated Na ⁺ /H ⁺ exchang...
Article
Previously, we have shown that an increased cGMP-activated protein Kinase (PKG) activity after phosphodiesterase 5 (PDE5) inhibition by Sildenafil (SIL), leads to myocardial Na⁺/H⁺ exchanger (NHE1) inhibition preserving its basal homeostatic function. Since NHE1 is hyperactive in the hypertrophied myocardium of spontaneous hypertensive rats (SHR),...
Article
Pathological cardiac hypertrophy (PCH) can be triggered by epidermal growth factor receptor (EGFR) transactivation. Progression of PCH can be prevented by inhibition of hyperactive Na+/H+ exchanger isoform 1 (NHE1). We first aimed, to limit PCH of spontaneously hypertensive rats (SHR) by specific and localized silencing of cardiac EGFR, and second...
Article
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Abstract Background/Aims: Myocardial stretch increases cardiac force in two consecutive phases: The first one due to Frank-Starling mechanism, followed by the gradually developed slow force response (SFR). The latter is the mechanical counterpart of an autocrine/paracrine mechanism involving the release of angiotensin II (Ang II) and endothelin (ET...
Article
Since the original description as potent antianginal compounds, phosphodiesterase 5A inhibitors have continuously increased their possible therapeutic applications. In the heart, Sildenafil was shown to protect against an ischemic insult by decreasing cardiac Na ⁺ /H ⁺ exchanger (NHE1) activity, action that was mediated by protein kinase G. p38 mit...
Article
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During ischemia, increased anaerobic glycolysis results in intracellular acidosis. Activation of alkalinizing transport mechanisms associated with carbonic anhydrases (CA) leads to myocardial intracellular Ca2+ increase. We characterize the effects of inhibition of CA with benzolamide (BZ) during cardiac ischemia-reperfusion (I/R). Langendorff perf...
Article
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RNAi is a widely used methodology for gene silencing. The action mechanism of siRNA molecules has been well studied in recent years, and the technique has been optimized in terms of safety and effectiveness. Cardiovascular diseases have a high incidence in the current population, and despite of the extensive research, safe and efficient therapeutic...
Data
Figure S1. Myocardial distribution of the lentivirus. Representative confocal images (4×) of myocardial slices from hearts injected with shRNA‐EGFR or shRNA‐SCR lentiviral vectors, as well as from a sham‐operated rat. Characteristic patchy distribution of red fluorescence by DsRed protein can be observed. The second column presents confocal capture...
Article
Full-text available
Background Myocardial stretch increases force biphasically: the Frank‐Starling mechanism followed by the slow force response (SFR). Based on pharmacological strategies, we proposed that epidermal growth factor (EGF) receptor (EGFR or ErbB1) activation is crucial for SFR development. Pharmacological inhibitors could block ErbB4, a member of the ErbB...
Article
Background: Two potent carbonic anhydrase (CA) inhibitors with widely differing membrane permeability, poorly diffusible benzolamide (BZ), and highly diffusible ethoxzolamide (ETZ) were assessed to determine whether they can reduce cardiac dysfunction in rats subjected to coronary artery ligation (CAL)-induced myocardial infarction. Methods and r...
Article
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Cells are constantly exposed to mechanical forces that play a role in modulating cellular structure and function. The cardiovascular system experiences physical forces in the form of shear stress and stretch associated with blood flow and contraction, respectively. These forces are sensed by endothelial cells and cardiomyocytes and lead to response...
Article
The adult heart contains a population of cardiac progenitor cells (CPCs). Growing and collecting an adequate number of CPCs demands complex culture media containing growth factors. Since activated macrophages secrete many growth factors, we investigated if activated isolated heart cells seeded on a feeder layer of activated peritoneal macrophages (...
Article
Background: The involvement of NHE-1 hyperactivity, critical for pathological cardiac hypertrophy (CH), in physiological CH has not been elucidated yet. Stimulation of NHE-1 increases intracellular Na(+) and Ca(2+) favouring calcineurin activation. Since myocardial stretch, an activator of NHE-1, is common to both types of CH, we speculate that NH...
Article
Mechanical stretch is an important physiological and pathological stimulus to the heart. Stretch induces a biphasic increase in myocardial force generation: A first phase due to the Frank-Starling mechanism, followed by a slower increase in force called slow force response (SFR). The SFR is blunted by AT1 or ETA receptor blockade, by NHE1 inhibitio...
Article
Myocardial stretch triggers an angiotensin II-dependent autocrine/paracrine loop of intracellular signals, leading to reactive oxygen species-mediated activation of redox-sensitive kinases. Based on pharmacological strategies, we previously proposed that mineralocorticoid receptor (MR) is necessary for this stretch-triggered mechanism. Now, we aime...
Article
Full-text available
The stretch of cardiac muscle increases developed force in two phases. The first phase, which occurs rapidly, constitutes the well-known Frank-Starling mechanism and it is generally attributed to enhanced myofilament responsiveness to Ca2+. The second phase or slow force response (SFR) occurs gradually and is due to an increase in the calcium trans...
Article
Full-text available
Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intrac...
Article
Full-text available
Myocardial stretch is an established signal that leads to hypertrophy. Myocardial stretch induces a first immediate force increase followed by a slow force response (SFR), which is a consequence of increased Ca(2+) transient that follows the NHE1 Na(+)/H(+) exchanger activation. Carbonic anhydrase II (CAII) binds to extreme C-terminus of NHE1 and r...
Chapter
Full-text available
The link between the Anrep effect -the increase in cardiac contractility that develops 10–15 min following myocardial stretch- and myocardial hypertrophy and failure was not appreciated until we proposed it in the 2005 edition of the book “Mechanosensitivity in Cells and Tissues”. In this new version of the chapter we will present the updated exper...
Article
The stretch-induced increase of cardiac force is biphasic. A first abrupt increase (Farnk-Starling mechanism) is followed by a slower response that takes minutes to develop, which is believed to be the in vitro manifestation of the Anrep effect. This slow force response (SFR) is due to an increase in the intracellular Ca ²⁺ transient. Although the...
Article
Full-text available
Myocardial stretch elicits a rapid increase in developed force, which is mainly caused by an increase in myofilament calcium sensitivity (Frank Starling mechanism). Over the ensuing 10-15 minutes, a second gradual increase in force takes place. This slow force response to stretch is known to be the result of an increase in the calcium transient amp...
Article
Non-technical summary Myocardial stretch increases force in two phases. The first one is immediate and attributed to an increase in myofilament Ca²⁺ responsiveness (Frank–Starling mechanism). The second phase gradually develops and is known as slow force response (SFR) or Anrep effect due to an increase in intracellular Ca²⁺ transient. We previousl...
Article
Full-text available
Growing in vitro evidence suggests NHE-1, a known target for reactive oxygen species (ROS), as a key mediator in cardiac hypertrophy (CH). Moreover, NHE-1 inhibition was shown effective in preventing CH and failure; so has been the case for AT1 receptor (AT1R) blockers. Previous experiments indicate that myocardial stretch promotes angiotensin II r...
Article
Full-text available
Myocardial stretch induces a biphasic force response: a first abrupt increase followed by a slow force response (SFR), believed to be the in vitro manifestation of the Anrep effect. The SFR is due to an increase in Ca²⁺ transient of unclear mechanism. We proposed that Na⁺/H⁺ exchanger (NHE-1) activation is a key factor in determining the contractil...
Article
Full-text available
Cardiac Na(+)/H(+) exchanger (NHE1) hyperactivity is a central factor in cardiac remodeling following hypertension, myocardial infarction, ischemia-reperfusion injury, and heart failure. Treatment of these pathologies by inhibiting NHE1 is challenging because specific drugs that have been beneficial in experimental models were associated with undes...
Article
Full-text available
Myocardial strain triggers an autocrine/paracrine mechanism known to participate in myocardial hypertrophy development. After the onset of stretch, there is a rapid augmentation in developed tension due to an increase in myofilament calcium sensitivity (the Frank Starling mechanism) followed by a gradual increase in tension over the next 10-15 min....
Article
Flow restoration to ischemic myocardium reduces infarct size (IS), but it also promotes reperfusion injury. A burst of reactive oxygen species (ROS) and/or NHE-1 reactivation were proposed to explain this injury. Our study was aimed to shed light on this unresolved issue. Regional infarction (40 min-ischemia/2 hs-reperfusion) was induced in isolate...
Article
Full-text available
This study aimed to identify the signaling pathway for the proposed link between phosphodiesterase-5A (PDE5A) inhibition and decreased cardiac Na(+)/H(+) exchanger (NHE-1) activity. NHE-1 activity was assessed in rat isolated papillary muscles by the Na(+)-dependent initial pH(i) recovery from a sustained acidosis (ammonium prepulse). ERK1/2, p90RS...
Article
Myocardial stretch elicits a biphasic contractile response: the Frank-Starling mechanism followed by the slow force response (SFR) or Anrep effect. In this study we hypothesized that the SFR depends on epidermal growth factor receptor (EGFR) transactivation after the myocardial stretch-induced angiotensin II (Ang II)/endothelin (ET) release. Experi...
Chapter
Full-text available
In this chapter the enhanced activity of the cardiac Na+/H+ exchanger (NHE-1) after myocardial stretch is considered a key step of the intracellular signaling pathway leading to the slow force response to stretch as well as an early signal for the development of cardiac hypertrophy. We propose that the chain of events triggered by stretch begins wi...
Article
To the Editor: Pokreisz et al1 recently published an interesting article in which they show increased cardiac left ventricular phosphodiesterase-5A (PDE5A) expression in patients with heart failure. They also generated a PDE5A transgenic mouse in which overexpression of this cGMP-selective phosphodiesterase worsened ventricular remodeling and func...
Article
The enhanced activity of the cardiac Na+/H+ exchanger (NHE-1) after myocardial stretch is considered a key step of the intracellular signaling pathway leading to the slow force response to stretch as well as an early signal for the development of cardiac hypertrophy. We propose that the chain of events triggered by stretch begins with the release o...
Article
Full-text available
When the length of the myocardium is increased, a biphasic response to stretch occurs involving an initial rapid increase in force followed by a delayed slow increase called the slow force response (SFR). Confirming previous findings involving angiotensin II in the SFR, it was blunted by AT1 receptor blockade (losartan). The SFR was accompanied by...
Article
Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1), detected by the almost null intracellular pH recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of phosphoglycerate kinase-1 (KT5823) restored norma...
Article
Full-text available
In this review, the enhanced activity of the cardiac Na+/H+ exchanger is considered to be a key step in the intracellular signaling pathway leading to cardiac hypertrophy, and the inhibition of the exchanger is a pharmacological tool to prevent or regress it. This enhanced activity has been demonstrated after stretching neonatal rat cardiomyocytes...
Article
Reactive oxygen species (ROS) have been linked to hypertrophy, remodeling and abnormal excitation-contraction coupling. Previous data demonstrated that an increase in oxidative stress is associated to the pathogenesis of congestive heart failure (CHF). We examined whether inhibition of the superoxide anion (*O2(-))-generating enzyme xanthine oxidas...
Article
The stretch of adult papillary muscle elicits a chain of autocrine/paracrine events in which the Na(+)/H(+) exchanger (NHE-1) activation is the central step. This activation is induced by a sequential angiotensin II-endothelin (Ang II-ET) release and results in an increase in intracellular Na(+) (Na(+)(i)) without significant changes in intracellul...
Article
Full-text available
Myocardial stretch elicits a biphasic increase in developed force with a first rapid force response and a second slow force response (SFR). The rapid phase is due to an increase in myofilament Ca(2+) responsiveness; the SFR, analyzed here, is ascribed to a progressive increase in Ca(2+) transients. Experiments were performed in cat papillary muscle...
Article
Myocardial stretch promotes an increase in developed force (DF) in two phases: a rapid initial phase, and a slowly developing second phase called the slow force response (SFR) to myocardial stretch. The SFR results from an autocrine/paracrine mechanism of angiotensin II and endothelin (ET) release that is triggered by the stretch. To explore whethe...
Article
This study aimed to explore the signaling pathways involved in the positive inotropic effect (PIE) of low doses of endothelin-1 (ET-1). Cat papillary muscles were used for force and intracellular Na(+) concentration (Na(+)(i)) measurements, and isolated cat ventricular myocytes for patch-clamp experiments. ET-1 (5 nmol/L) induced a PIE and an assoc...
Chapter
Full-text available
The stretch of cardiac muscle elicits a chain of autocrine/paracrine events in which the Na+/H+ exchanger activation is the central step. This activation is induced by a sequential angiotensin II-endothelin release and results in an increase in intracellular Na+ [Na+]i without significant changes in intracellular pH. The increase in [Na+]i negative...
Article
The present study was attempted to determine whether LV midwall mechanics yielded different conclusions about LV systolic function than the assessment of endocardial LV mechanics by echocardiography in spontaneously hypertensive rats (SHR). Thirty-six (18 Wistar normotensive (W), 18 [SHR]) anesthetized rats were studied with two-dimensional directe...
Article
Full-text available
In our studies with spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Wistar rats, we observed normotensive WKY rats with cardiac hypertrophy determined by a greater left ventricular (LV) mass (LVM)-to-body weight (BW) ratio (LVM/BW) than that of normotensive Wistar rats. Thus we compared the following parameters in SHR, WKY, and Wistar rat...
Article
Full-text available
Collagen degradation is suggested to be responsible for long-term contractile dysfunction in different cardiomyopathies, but the effects of acute and specific collagen type I removal (main type in the heart muscle) on tension have not been studied. We determined the diastolic and developed tension length relations in isometric contracting perfused...
Article
Previous work demonstrated that the slow force response (SFR) to stretch is due to the increase in calcium transients (Ca2+T) produced by an autocrine-paracrine mechanism of locally produced angiotensin II/endothelin activating Na+-H+ exchange. Although a rise in pHi is presumed to follow stretch, it was observed only in the absence of extracellula...
Article
This work was aimed to prove that release/formation of endogenous endothelin acting in an autocrine/paracrine fashion contributes to the increase in contractility promoted by a low dose of angiotensin II. Isolated cat papillary muscles were used for force, pH(i), [Na(+)](i) and [Ca(2+)](i) measurements and isolated cat myocytes for patch-clamp expe...
Article
Full-text available
The stretch of the cardiac muscle is immediately followed by an increase in the contraction strength after which occurs a slow force increase (SFR) that takes several minutes to fully develop. The SFR was detected in a wide variety of experimental preparations including isolated myocytes, papillary muscles and/or trabeculae, left ventricle strips o...
Article
We have recently reported that the inhibition of the Na(+)/H(+) exchanger (NHE) during 1 month in spontaneously hypertensive rats (SHR) is followed by regression of cardiomyocyte hypertrophy but not of myocardial fibrosis. The aim of this study was to evaluate whether a treatment of longer duration could reduce myocardial fibrosis and stiffness. SH...
Article
Na+/H+ exchanger (NHE) is hyperactive in the hypertensive hypertrophied myocardium. Regression of cardiac hypertrophy (CH) induced by prolonged antihypertensive therapy with compounds of different pharmacological profiles (angiotensin converting enzyme inhibition, slow calcium channel and angiotensin II type 1 receptor blockade) normalizes the hyp...
Article
An autocrine/paracrine mechanism is triggered by stretching the myocardium. This mechanism involves the release of angiotensin II (Ang II), the release/increased formation of endothelin (ET), the activation of the Na+/H+ exchanger (NHE), the increase in intracellular Na+ concentration ([Na+]i), and the increase in the Ca2+ transient that underlies...
Chapter
When the heart is subjected to a brief but severe episode of ischemia, a prolonged contractile dysfunction becomes evident upon reperfusion, despite the absence of irreversible tissue damage. This acute and fully reversible form of pump failure has been called “myocardial stunning” and is characterized by a decreased myofilament Ca2+ responsiveness...
Chapter
The sarcolemmal Na+/H+ exchanger (NHE) extrudes intracellular H+ in exchange for extracellular Na+ and has a role in the regulation of not only intracellular pH (pHi) but also intracellular Na+ (Na+i homeostasis. Both H+ and Na+ are important determinants of cardiac contractility and therefore, the level of NHE activity may become relevant to many...
Article
Rats exposed to prolonged administration of the NHE-1 inhibitor cariporide showed enhanced activity of the exchanger in cardiac tissue, as assessed by the rise in the steady-state pHi value in the absence of bicarbonate (7.15+/-0.01 in control vs 7.49+/-0.06 and 7.41+/-0.05 in cariporide-treated for 1 or 2 months, respectively, P<0.05). In the pres...
Article
Experiments were performed to examine the effect of chronic inhibition of the Na(+)/H(+) exchanger isoform-1 (NHE-1) on cardiac hypertrophy of spontaneously hypertensive rats (SHR). SHR were orally treated during 1 month with two different doses (0.3 and 3.0 mg/kg/day) of the NHE-1 inhibitor, cariporide, or nifedipine (10.0 mg/kg/day). The two dose...
Article
Full-text available
An autocrine/paracrine mechanism is triggered by stretching the myocardium. This mechanism involves release of angiotensin II, release/increased formation of endothelin, activation of the Na(+)/H(+) exchanger, increase in intracellular Na(+), and the increase in the Ca(2+) transient that underlies the slow force response to stretch. The autocrine/p...
Article
This study was designed to gain additional insight into the mechanism of the slow force response (SFR) to stretch of cardiac muscle. SFR and changes in intracellular Na(+) concentration ([Na(+)](i)) were assessed in cat papillary muscles stretched from 92% to approximately 98% of L(max). The SFR was 120+/-0.6% (n=5) of the rapid initial phase and c...
Article
This study was undertaken to investigate the mechanism of altered contractility in hearts from transgenic mice overexpressing the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a). In particular, we sought to determine whether the reported increase in contractility is frequency-dependent, as might be expected if attributable to changes in SR Ca2+ l...