• acidic metabolic environment
• cardiac differentiation
• lactate
• pH value
• stem cells

• Acidosis
• Hypoxia
• Ischemia
• Metabolism
• Purines
• pH

• Mice
• Animals
• Ischemia
• Reperfusion
• Metabolome
• Hypoxia
• Hydrogen-Ion Concentration

• R01 HL071158 NHLBI NIH HHS
• T32 GM068411 NIGMS NIH HHS

• PKCε
• carbonic anhydrase
• ethoxzolamide
• ischemia-reperfusion
• mitochondria
• myocardium
• p38MAPK

• Animals
• Benzophenanthridines/pharmacology
• Calcium/metabolism
• Carbonic Anhydrase Inhibitors/pharmacology
• Enzyme Inhibitors/pharmacology
• Ethoxzolamide/pharmacology
• Heart/drug effects
• Imidazoles/pharmacology
• Isolated Heart Preparation
• Membrane Potential, Mitochondrial/drug effects
• Mitochondria, Heart/drug effects
• Mitochondria, Heart/metabolism
• Mitochondrial Permeability Transition Pore/metabolism
• Myocardial Reperfusion Injury
• Myocardium/metabolism
• Protein Kinase C/antagonists & inhibitors
• Pyridines/pharmacology
• Rats
• p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors

• Universidad Nacional de La Plata

• NHE1
• PDE5A
• cardiac mechanism
• intracellular pathways
• sildenafil

• Calcium overload
• Cardiac diseases
• Myocardial ischemia-reperfusion injury
• Sodium bicarbonate cotransporter
• pH regulation

• Cardiac myocytes
• Sodium/bicarbonate cotransporter
• Soluble adenylyl cyclase
• cAMP

• Alcalinizing transporters
• cardiac myocyte
• cardiac remodeling
• cardiovascular pathophysiology

• Drp1
• Ischemia-reperfusion
• NBCe1
• OPA1
• p38MAPK

To investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na⁺-HCO₃^- cotransporter is cardioprotective during in vivo ischemia-reperfusion (IR) injury.

An NBCe1 (Slc4a4 gene) conditional knockout mouse (KO) model was prepared by gene targeting. Cardiovascular performance of wildtype (WT) and cardiac-specific NBCe1 KO mice was analyzed by intraventricular pressure measurements, and changes in cardiac gene expression were determined by RNA Seq analysis. Response to in vivo IR injury was analyzed after 30 min occlusion of the left anterior descending artery followed by 3 h of reperfusion.

Loss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation under basal conditions or in response to β-adrenergic stimulation, and caused only limited changes in gene expression patterns, such as those for electrical excitability. However, following ischemia and reperfusion, KO heart sections exhibited significantly fewer apoptotic nuclei than WT sections.

These studies indicate that cardiac-specific loss of NBCe1 does not impair cardiovascular performance, causes only minimal changes in gene expression patterns, and protects against IR injury in vivo .

• Deep sequencing
• Ischemic
• Apoptosis
• Slc4a4
• NBCe1

• Na+, HCO3− cotransport
• Na+/H+ exchange
• acid-base transport
• ischaemia
• resistance arteries
• vascular smooth muscle cells

• GPR30
• aldosterone
• electrogenic
• heart
• sodium/bicarbonate cotransporter

• Aldosterone
• Cardiomyocytes
• GPR30
• Sodium/bicarbonate cotransporter

• blood pressure
• carbonic anhydrase
• intermittent hypoxia
• obstructive sleep apnea

Bicarbonate is one of the major anions in mammalian tissues and extracellular fluids. Along with accompanying H⁺, HCO₃^- is generated from CO₂ and H₂O, either spontaneously or via the catalytic activity of carbonic anhydrase. It serves as a component of the major buffer system, thereby playing a critical role in pH homeostasis. Bicarbonate can also be utilized by a variety of ion transporters, often working in coupled systems, to transport other ions and organic substrates across cell membranes. The functions of HCO₃^- and HCO₃^--transporters in epithelial tissues have been studied extensively, but their functions in heart are less well understood. Here we review studies of the identities and physiological functions of Cl^-/HCO₃^- exchangers and Na⁺/HCO₃^- cotransporters of the SLC4A and SLC26A families in heart. We also present RNA Seq analysis of their cardiac mRNA expression levels. These studies indicate that slc4a3 (AE3) is the major Cl^-/HCO₃^- exchanger and plays a protective role in heart failure, and that Slc4a4 (NBCe1) is the major Na⁺/HCO₃^- cotransporter and affects action potential duration. In addition, previous studies show that HCO₃^- has a positive inotropic effect in the perfused heart that is largely independent of effects on intracellular Ca²⁺. The importance of HCO₃^- in the regulation of contractility is supported by experiments showing that isolated cardiomyocytes exhibit sharply enhanced contractility, with no change in Ca²⁺ transients, when switched from Hepes-buffered to HCO₃^-- buffered solutions. These studies demonstrate that HCO₃^- and HCO₃^--handling proteins play important roles in the regulation of cardiac function.

• SLC4
• SLC26
• Slc26a6
• AE1
• AE2
• NBCn1

• R01 ES017263 NIEHS NIH HHS
• R01 HL061974 NHLBI NIH HHS

• Acidosis/metabolism
• Acidosis, Lactic/metabolism
• Animals
• Cation Transport Proteins/metabolism
• Heart Arrest/metabolism
• Humans
• Hydrogen-Ion Concentration
• Hypoxia/metabolism
• Myocardium/metabolism
• Rats
• Sepsis/metabolism
• Shock, Hemorrhagic/metabolism
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers/metabolism

• Infarct size
• Ischemia–Reperfusion
• NBCe1
• NBCe1 antibodies
• S0859

The sodium/bicarbonate cotransporter (NBC) is one of the major alkalinizing mechanisms in the cardiomyocytes. It has been demonstrated the existence of at least two functional isoforms, one that promotes the co-influx of 1 molecule of Na⁺ per 1 molecule of HCO⁻₃ (electroneutral isoform; NBCn1) and the other one that generates the co-influx of 1 molecule of Na⁺ per 2 molecules of HCO⁻₃ (electrogenic isoform; NBCe1). Both isoforms are important to maintain intracellular pH (pH_i) and sodium concentration ([Na⁺]_i). In addition, NBCe1 generates an anionic repolarizing current that modulates the action potential duration (APD). The renin-angiotensin-aldosterone system (RAAS) is implicated in the modulation of almost all physiological cardiac functions and is also involved in the development and progression of cardiac diseases. It was reported that angiotensin II (Ang II) exhibits an opposite effect on NBC isoforms: it activates NBCn1 and inhibits NBCe1. The activation of NBCn1 leads to an increase in pH_i and [Na⁺]_i, which indirectly, due to the stimulation of reverse mode of the Na⁺/Ca²⁺ exchanger (NCX), conduces to an increase in the intracellular Ca²⁺ concentration. On the other hand, the inhibition of NBCe1 generates an APD prolongation, potentially representing a risk of arrhythmias. In the last years, the potentially altered NBC function in pathological scenarios, as cardiac hypertrophy and ischemia-reperfusion, has raised increasing interest among investigators. This review attempts to draw the attention on the relevant regulation of NBC activity by RAAS, since it modulates pH_i and [Na⁺]_i, which are involved in the development of cardiac hypertrophy, the damage produced by ischemia-reperfusion and the generation of arrhythmic events, suggesting a potential role of NBC in cardiac diseases.

• aldosterone
• angiotensin II
• heart
• hypertrophy
• sodium bicarbonate cotransporter

• Cardiac hypertrophy
• Cardiac myocytes
• Na+–HCO3- cotransporter

• Ammonium Compounds/metabolism
• Angiotensin II
• Angiotensin II Type 1 Receptor Blockers/pharmacology
• Animals
• Antihypertensive Agents/pharmacology
• Bicarbonates/metabolism
• Cardiomegaly/chemically induced
• Cardiomegaly/metabolism
• Cardiomegaly/pathology
• Disease Models, Animal
• Down-Regulation
• Endosomes/metabolism
• Hydrogen-Ion Concentration
• Hyperkalemia/metabolism
• Hypertension/drug therapy
• Hypertension/metabolism
• Hypertension/pathology
• Losartan/pharmacology
• Male
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• Potassium/metabolism
• Protein Transport
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Renin-Angiotensin System/drug effects
• Sarcolemma/metabolism
• Sarcolemma/pathology
• Sodium-Bicarbonate Symporters/metabolism
• Time Factors

Transmembrane sodium (Na⁺) fluxes and intracellular sodium homeostasis are central players in the physiology of the cardiac myocyte, since they are crucial for both cell excitability and for the regulation of the intracellular calcium concentration. Furthermore, Na⁺ fluxes across the membrane of mitochondria affect the concentration of protons and calcium in the matrix, regulating mitochondrial function. In this review we first analyze the main molecular determinants of sodium fluxes across the sarcolemma and the mitochondrial membrane and describe their role in the physiology of the healthy myocyte. In particular we focus on the interplay between intracellular Ca²⁺ and Na⁺. A large part of the review is dedicated to discuss the changes of Na⁺ fluxes and intracellular Na⁺ concentration([Na⁺]_i) occurring in cardiac disease; we specifically focus on heart failure and hypertrophic cardiomyopathy, where increased intracellular [Na⁺]_i is an established determinant of myocardial dysfunction. We review experimental evidence attributing the increase of [Na⁺]_i to either decreased Na⁺ efflux (e.g. via the Na⁺/K⁺ pump) or increased Na⁺ influx into the myocyte (e.g. via Na⁺ channels). In particular, we focus on the role of the “late sodium current” (I_NaL), a sustained component of the fast Na⁺ current of cardiac myocytes, which is abnormally enhanced in cardiac diseases and contributes to both electrical and contractile dysfunction. We analyze the pathophysiological role of I_NaL enhancement in heart failure and hypertrophic cardiomyopathy and the consequences of its pharmacological modulation, highlighting the clinical implications.

The central role of Na⁺ fluxes and intracellular Na⁺ physiology and pathophysiology of cardiac myocytes has been highlighted by a large number of recent works. The possibility of modulating Na⁺ inward fluxes and [Na⁺]_i with specific I_NaL inhibitors, such as ranolazine, has made Na⁺a novel suitable target for cardiac therapy, potentially capable of addressing arrhythmogenesis and diastolic dysfunction in severe conditions such as heart failure and hypertrophic cardiomyopathy.

• calcium
• heart failure
• hypertrophic cardiomyopathy
• mitochondria
• sodium
• sodium current

The sodium/ bicarbonate cotransporter (NBC) is, with the Na⁺/H⁺ exchanger (NHE), an important alkalinizing mechanism that maintains cellular intracellular pH (pHi). In the heart exists at least three isoforms of NBC, one that promotes the co-influx of 1 molecule of Na⁺ per 1molecule of HCO₃^-(electroneutral isoform; nNBC) and two others that generates the co-influx of 1 molecule of Na⁺ per 2 molecules of HCO₃^- (electrogenic isoforms; eNBC). In addition, the eNBC generates an anionic repolarizing current that modulate the cardiac action potential (CAP), adding to such isoforms the relevance to modulate the electrophysiological function of the heart. Angiotensin II (Ang II) is one of the main hormones that regulate cardiac physiology. The alkalinizing mechanisms (NHE and NBC) are stimulated by Ang II, increasing pHi and intracellular Na⁺ concentration, which indirectly, due to the stimulation of the Na⁺/Ca²⁺ exchanger (NCX) operating in the reverse form, leads to an increase in the intracellular Ca²⁺ concentration. Interestingly, it has been shown that Ang II exhibits an opposite effect on NBC isoforms: it activates the nNBC and inhibits the eNBC. This inhibition generates a CAP prolongation, which could directly increase the intracellular Ca²⁺ concentration. The regulation of the intracellular Na⁺ and Ca²⁺ concentrations is crucial for the cardiac cellular physiology, but these ions are also involved in the development of cardiac hypertrophy and the damage produced by ischemia-reperfusion, suggesting a potential role of NBC in cardiac diseases.

• 2,3-butanedione monoxime
• 4,4-diisothiocyanatostilbene-2,2-disulfonate
• BDM
• Cardiac muscle
• DIDS
• Intracellular Ca(2+)
• Krebs–Henseleit
• K–H
• NBC
• NCX
• NHE
• Na(+)/Ca(2+)-exchanger
• Na(+)/H(+)-exchanger
• Na(+)/HCO(3)(−)-cotransporter
• Protons
• SFR
• SL
• SR
• Stretch
• sarcolemmal
• sarcoplasmic reticulum
• slow force response

• Angiotensin II/pharmacology
• Animals
• Bicarbonates/metabolism
• Biological Transport, Active
• Calcium/metabolism
• Extracellular Space/metabolism
• Heart/drug effects
• Heart/physiology
• Hydrogen/metabolism
• Hydrogen-Ion Concentration
• Myocardial Contraction/drug effects
• Myocardial Contraction/physiology
• Myocardium/metabolism
• Physical Stimulation
• Rats
• Sarcoplasmic Reticulum/metabolism
• Sodium/metabolism
• Stress, Mechanical

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 intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoK_ATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.

• cardiac myocyte
• reactive oxygen species
• second messenger systems
• sodium-bicarbonate symporters
• sodium-hydrogen antiporter

• CA
• CBE
• CHE
• Ca(2+) transient
• CaT
• Cl(−)/HCO(3)(−) exchange
• Cl(−)/OH(−) exchange
• DAD
• LTCC
• MAPK
• MCT
• NBC
• NCX
• NHE
• Na(+)-HCO(3)(−) co-transport
• Na(+)-influx
• Na(+)/Ca(2+) exchange
• Na(+)/H(+) exchange
• PKC
• PMCA
• RyR
• SERCA
• SR
• acidosis
• carbonic anhydrase
• delayed after-depolarisation
• intracellular pH
• mitogen activated protein kinase
• monocarboxylic acid transporter
• pH regulatory proteins
• pH transporters
• pH(i)
• pH(i)-regulation
• plasmalemmal Ca(2+) ATPase
• protein kinase C
• ryanodine receptor
• sarcolemmal L-type Ca(2+) channel
• sarcoplasmic reticular Ca(2+) ATPase
• sarcoplasmic reticulum
• t-tubules
• transverse tubules

• Acid-Base Imbalance/metabolism
• Animals
• Cardiomegaly/metabolism
• Cation Transport Proteins/physiology
• Excitation Contraction Coupling
• Heart Failure/metabolism
• Heart Ventricles/metabolism
• Heart Ventricles/pathology
• Humans
• Myocardial Reperfusion Injury/metabolism
• Myocytes, Cardiac/physiology
• Protons
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers/physiology

• PG/12/2/29324 British Heart Foundation
• RG/08/016 British Heart Foundation
• RG/08/016/26423 British Heart Foundation

• Acidosis, Renal Tubular/genetics
• Acidosis, Renal Tubular/metabolism
• Animals
• Biological Evolution
• Chloride-Bicarbonate Antiporters/genetics
• Chloride-Bicarbonate Antiporters/metabolism
• Humans
• Molecular Sequence Data
• Sodium Bicarbonate/metabolism

• EY021646 NEI NIH HHS
• DK81567 NIDDK NIH HHS
• NS18400 NINDS NIH HHS
• Wellcome Trust
• HL090969 NHLBI NIH HHS
• HD032573 NICHD NIH HHS
• DK30344 NIDDK NIH HHS
• R01 HL090969 NHLBI NIH HHS

• Acidosis/chemically induced
• Acidosis/drug therapy
• Acidosis/mortality
• Acidosis/physiopathology
• Acidosis/veterinary
• Animals
• Cardiovascular System/drug effects
• Cardiovascular System/physiopathology
• Cation Transport Proteins/antagonists & inhibitors
• Cation Transport Proteins/genetics
• Familial Primary Pulmonary Hypertension
• Guanidines/administration & dosage
• Hemorrhage/chemically induced
• Hemorrhage/physiopathology
• Humans
• Hypertension, Pulmonary/chemically induced
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/physiopathology
• Hypertension, Pulmonary/veterinary
• Hypovolemia/chemically induced
• Hypovolemia/physiopathology
• Inflammation/drug therapy
• Inflammation/physiopathology
• Inflammation/veterinary
• Lactic Acid/toxicity
• Male
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers/antagonists & inhibitors
• Sodium-Hydrogen Exchangers/genetics
• Swine
• Vascular Resistance

• sodium
• ischemia-reperfusion
• heart failure
• calcium
• mitochondria
• ion transport

• Animals
• Heart Diseases/metabolism
• Humans
• Mitochondria/metabolism
• Sodium/metabolism
• Sodium Channels/metabolism
• Sodium-Hydrogen Exchangers/metabolism

• Z99 HL999999 Intramural NIH HHS
• British Heart Foundation