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1.
Am J Physiol Heart Circ Physiol ; 327(2): H351-H363, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38847755

ABSTRACT

Right ventricular (RV) function is an important prognostic indicator for pulmonary arterial hypertension (PAH), a vasculopathy that primarily and disproportionally affects women with distinct pre- and postmenopausal clinical outcomes. However, most animal studies have overlooked the impact of sex and ovarian hormones on RV remodeling in PAH. Here, we combined invasive measurements of RV hemodynamics and morphology with computational models of RV biomechanics in sugen-hypoxia (SuHx)-treated male, ovary-intact female, and ovariectomized female rats. Despite similar pressure overload levels, SuHx induced increases in end-diastolic elastance and passive myocardial stiffening, notably in male SuHx animals, corresponding to elevated diastolic intracellular calcium. Increases in end-systolic chamber elastance were largely explained by myocardial hypertrophy in male and ovary-intact female rats, whereas ovariectomized females exhibited contractility recruitment via calcium transient augmentation. Ovary-intact female rats primarily responded with hypertrophy, showing fewer myocardial mechanical alterations and less stiffening. These findings highlight sex-related RV remodeling differences in rats, affecting systolic and diastolic RV function in PAH.NEW & NOTEWORTHY Combining hemodynamic and morphological measurements from male, female, and ovariectomized female pulmonary arterial hypertension (PAH) rats revealed distinct adaptation mechanisms despite similar pressure overload. Males showed the most diastolic stiffening. Ovariectomized females had enhanced myocyte contractility and calcium transient upregulation. Ovary-intact females primarily responded with hypertrophy, experiencing milder passive myocardial stiffening and no changes in myocyte shortening. These findings suggest potential sex-specific pathways in right ventricular (RV) adaptation to PAH, with implications for targeted interventions.


Subject(s)
Disease Models, Animal , Ovariectomy , Pulmonary Arterial Hypertension , Rats, Sprague-Dawley , Ventricular Function, Right , Ventricular Remodeling , Animals , Female , Male , Pulmonary Arterial Hypertension/physiopathology , Pulmonary Arterial Hypertension/metabolism , Pulmonary Arterial Hypertension/etiology , Sex Factors , Hypertrophy, Right Ventricular/physiopathology , Hypertrophy, Right Ventricular/etiology , Hypertrophy, Right Ventricular/metabolism , Hypertrophy, Right Ventricular/pathology , Rats , Ventricular Dysfunction, Right/physiopathology , Ventricular Dysfunction, Right/metabolism , Ventricular Dysfunction, Right/etiology , Pulmonary Artery/physiopathology , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Models, Cardiovascular , Calcium Signaling , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/etiology , Hemodynamics
2.
Nat Nanotechnol ; 17(3): 292-300, 2022 03.
Article in English | MEDLINE | ID: mdl-34949774

ABSTRACT

Electrical impulse generation and its conduction within cells or cellular networks are the cornerstone of electrophysiology. However, the advancement of the field is limited by sensing accuracy and the scalability of current recording technologies. Here we describe a scalable platform that enables accurate recording of transmembrane potentials in electrogenic cells. The platform employs a three-dimensional high-performance field-effect transistor array for minimally invasive cellular interfacing that produces faithful recordings, as validated by the gold standard patch clamp. Leveraging the high spatial and temporal resolutions of the field-effect transistors, we measured the intracellular signal conduction velocity of a cardiomyocyte to be 0.182 m s-1, which is about five times the intercellular velocity. We also demonstrate intracellular recordings in cardiac muscle tissue constructs and reveal the signal conduction paths. This platform could provide new capabilities in probing the electrical behaviours of single cells and cellular networks, which carries broad implications for understanding cellular physiology, pathology and cell-cell interactions.


Subject(s)
Electrophysiological Phenomena , Myocytes, Cardiac , Action Potentials , Cell Communication
3.
Sci Adv ; 7(20)2021 05.
Article in English | MEDLINE | ID: mdl-33990324

ABSTRACT

Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCREs) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further found cardiovascular disease-associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.


Subject(s)
Heart , Regulatory Sequences, Nucleic Acid , Humans , Promoter Regions, Genetic , Regulatory Sequences, Nucleic Acid/genetics , Transcription Factors/metabolism
4.
Int J Cardiol ; 104(1): 59-66, 2005 Sep 15.
Article in English | MEDLINE | ID: mdl-16137511

ABSTRACT

BACKGROUND: To study the cellular mechanisms governing cardiac atrial arrhythmias initiated by ectopic focus (or foci) from pulmonary veins (PVs). METHODS: In the present in vitro study, we applied the conventional microelectrode technique to record intracellular action potentials in PV sleeves from dogs. RESULTS: In 80 normal healthy dogs, all action potentials recorded in cardiomyocytes from PV sleeves were fast-response. The pharmacological responses to quinidine, nisoldipine, D-sotalol, 4-aminopyridine, isoproterenol, acetylcholine, and adenosine were characteristic of those in atrial cells. Diastolic depolarization and spontaneous activity could be induced by 1 mmol/L Ba2+ in all the 22 PV specimens being tested, but only in 3 of 11 of left atrial specimens (p<0.0001). In the presence of 1 mmol/L Ba2+, the diastolic slope was only slightly affected by Ni2+ (500 micromol/L), but was significantly suppressed by Cd2+ (200 micromol/L). Ryanodine (2 micromol/L) caused a transient increase, followed by a marked decrease of Ba2+-induced spontaneous activity. Isoproterenol shortened and acetylcholine prolonged the cycle length of the Ba2+-induced automatic activity. In the presence of isoproterenol, washout of acetylcholine induced a rebound phenomenon, which triggered a short period of spontaneous activity. The results suggest an important role of intracellular cytoplasmic Ca2+ loading. Under conditions that mimic ischemia/hypoxia, the resting membrane potential depolarized, upstroke of the action potential became depressed and the action potential duration shortened. In the presence of isoproterenol and elevated external K+, spontaneous activity was generated. CONCLUSIONS: These findings indicate a lack of arrhythmogenic activity in normal healthy PV sleeves. Abnormal automaticity and triggered activity occurred exclusively under simulated pathologic conditions. Ba2+-induced automaticity was more easily induced in PV than in the left atrium. The same conditions might also favor the genesis of reentry in the in vivo condition.


Subject(s)
Myocardial Contraction , Myocardium/metabolism , Pulmonary Veins/metabolism , Action Potentials/drug effects , Adrenergic alpha-Antagonists/pharmacology , Animals , Atrial Function/drug effects , Disease Models, Animal , Dogs , Electrophysiologic Techniques, Cardiac , Heart Atria/metabolism , Heart Atria/physiopathology , Hypoxia/chemically induced , Hypoxia/physiopathology , Microelectrodes , Myocardial Contraction/drug effects , Myocardial Ischemia/chemically induced , Myocardial Ischemia/physiopathology , Neurotransmitter Agents/pharmacology , Parasympathetic Nervous System/drug effects , Pulmonary Veins/physiopathology , Receptors, Purinergic P1/drug effects , Stimulation, Chemical , Sympathetic Nervous System/drug effects , Vasodilator Agents/pharmacology
5.
J Biomed Sci ; 11(3): 303-14, 2004.
Article in English | MEDLINE | ID: mdl-15067213

ABSTRACT

The effect of cisapride on L-type Ca(2+) current (I(Ca,L)) was studied in guinea pig ventricular myocytes using a whole-cell voltage-clamp technique and a conventional action potential recording method. Myocytes were held at -40 mV, and internally dialyzed and externally perfused with Na(+)- and K(+)-free solutions; cisapride elicited a concentration-dependent block of peak I(Ca,L), with a half-maximum inhibition concentration (IC(50)) of 46.9 microM. There was no shift in the reversal potential, nor any change in the shape of the current-voltage relationship of I(Ca,L) in the presence of cisapride. Inhibition of cisapride was not associated with its binding to serotonin or to alpha-adrenergic receptors because ketanserin, SB203186, and prazosin had no effect on the inhibitory action of cisapride on I(Ca,L). Cisapride elicited a tonic block and a use-dependent block of I(Ca,L). These blocking effects were voltage dependent as the degree of inhibition at -40 mV was greater than that at -70 mV. Cisapride shifted the steady-state inactivation curve of I(Ca,L) in the negative direction, but had no effect on the steady-state activation curve. Cisapride also delayed the kinetics of recovery of I(Ca,L) from inactivation. At a slow stimulation frequency (0.1 Hz), the action potential duration in guinea pig papillary muscles showed biphasic effects; it was prolonged by lower concentrations of cisapride, but shortened by higher concentrations. These findings suggest that cisapride preferentially binds to the inactivated state of L-type Ca(2+) channels. The inhibitory effect of cisapride on I(Ca,L) might play an important role in its cardiotoxicity under pathophysiological conditions, such as myocardial ischemia.


Subject(s)
Calcium Channels, L-Type/drug effects , Cisapride/pharmacology , Heart Ventricles/drug effects , Action Potentials , Animals , Calcium Channels, L-Type/physiology , Guinea Pigs , Ventricular Function
6.
Cardiovasc Res ; 62(1): 96-104, 2004 Apr 01.
Article in English | MEDLINE | ID: mdl-15023556

ABSTRACT

OBJECTIVE: Myocardial swelling occurs during endotoxic shock. The hypothesis that swelling-activated Cl- current (ICl,swell) activates during endotoxic shock was tested. METHODS: Endotoxic shock was induced by intravenous lipopolysaccharides (10 mg/kg) in guinea pigs. The effects of ICl,swell blockers on the cardiac action potentials in papillary muscles and on the ICl,swell in single ventricular myocytes were tested. RESULTS: Action potential duration (APD) at 90% of repolarization (APD90) was significantly shortened after 5-h endotoxic shock in guinea pig papillary muscles. I(Cl,swell) blockers, 9-anthracene carboxylic acid (9-AC) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), dose-dependently prolonged the shortened APD90. Inducible nitric oxide synthase (iNOS) inhibitors, L-N6-(1-iminoethyl) lysine (L-NIL) and N-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide (1400 W), also prolonged the APD90. Protein kinase C (PKC) activators, 4beta-phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-didecanoate (PDD), also prolonged the APD. The addition of glibenclamide (an ATP-sensitive K+ channel blocker) on top of these ICl,swell blockers hastened the recovery of APD90 compared to the use of ICl,swell blockers alone. Whole-cell voltage-clamp study in single ventricular myocytes from endotoxic shock heart disclosed activation of a DIDS- and 9-AC-sensitive current. These currents displayed outward rectification with reversal potentials similar to the calculated Nernst potential for Cl-. The reversal potentials tracked the ECl closely when the Cl- gradient was changed, suggesting that Cl- was the major charged carrier. CONCLUSIONS: We have shown for the first time that ICl,swell activates in guinea pig heart in endotoxic shock. The change in this membrane current, together with the activation of ATP-sensitive K+ current, contributes to the electrophysiological derangement in endotoxic shock.


Subject(s)
Chloride Channels/metabolism , Myocytes, Cardiac/metabolism , Shock, Septic/metabolism , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Action Potentials/physiology , Animals , Anthracenes/pharmacology , Chloride Channels/drug effects , Female , Guinea Pigs , Heart Ventricles , Lipopolysaccharides , Male , Models, Animal , Myocytes, Cardiac/drug effects , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type II , Patch-Clamp Techniques , Phorbol Esters/pharmacology , Protein Kinase C/antagonists & inhibitors , Tetradecanoylphorbol Acetate/pharmacology
7.
Int J Cardiol ; 89(2-3): 187-95, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12767542

ABSTRACT

Pulmonary veins may serve as source of ectopic focus (or foci) in initiating atrial tachyarrhythmias in human beings. However, the animal model for such focal atrial fibrillation is still lacking and cellular mechanism for arrhythmias remains to be studied. Recently, a series of reports of cellular electrophysiological characterization of pulmonary vein sleeves demonstrated an extremely high incidence of automaticity (varied from 40 to 76%) and triggered activity (from 0 to 44%) in normal healthy control dogs and rabbits. The present study was therefore designed to re-investigate the cellular electrophysiological properties of canine pulmonary veins. Intracellular action potentials were characterized in pulmonary vein sleeves in 50 normal healthy dogs. Conventional glass microelectrode recording technique was used. Experiments were focused on the incidence of automaticity and triggered activity in pulmonary vein sleeve tissues. Surprisingly, our results showed that all pulmonary vein sleeves tissues in these dogs displayed fast-response action potentials under the well-controlled experimental condition (100%, n=50). No spontaneous pacemaking activities, early or delayed afterdepolarisations were observed (0%, n=50). No high-frequency spikes or irregular rhythm could be recorded in all experiments (0%, n=50). Both the frequency response and membrane responsiveness of the pulmonary vein action potentials were characterized. No electrophysiological inhomogeneity between the distal and the proximal part of the sleeves was observed. In conclusion, canine pulmonary vein sleeves do not display arrhythmogenic activities under normal physiological conditions. The possible explanations for the controversy in pulmonary veins electrophysiology were discussed.


Subject(s)
Action Potentials/physiology , Myocytes, Cardiac/physiology , Pulmonary Veins/physiology , Animals , Atrial Fibrillation/physiopathology , Dogs , Electrophysiology , In Vitro Techniques , Models, Animal , Muscle, Smooth, Vascular/physiology , Reaction Time/physiology
8.
J Biomed Sci ; 9(4): 321-6, 2002.
Article in English | MEDLINE | ID: mdl-12145529

ABSTRACT

Genistein is an isoflavone with potent inhibitory activity on protein tyrosine kinase. Previous studies have shown that genistein has additional effects, among which the direct blocking effects on various ionic channels have recently been disclosed. Using whole-cell voltage clamp and current clamp techniques, we demonstrate that micromolar concentrations of genistein dose-dependently and reversibly inhibit the inward rectifying K(+) current, and depolarize the resting membrane potential, resulting in abnormal automaticity in guinea pig ventricular myocytes. Interestingly, another potent tyrosine kinase inhibitor, tyrphostin 51, did not produce the same inhibitory effect, while the inactive analogue of genistein, daidzein, had a similar blocking effect. We suggest that genistein directly blocks the inward rectifying K(+) current in ventricular myocytes, and one should be cautious of its pro-arrhythmic effect in clinical use.


Subject(s)
Genistein/pharmacology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Potassium Channel Blockers/pharmacology , Potassium Channels, Inwardly Rectifying/metabolism , Action Potentials/drug effects , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Female , Guinea Pigs , Isoflavones/pharmacology , Male , Patch-Clamp Techniques , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Tyrphostins/pharmacology
9.
Cardiovasc Res ; 55(2): 290-9, 2002 Aug 01.
Article in English | MEDLINE | ID: mdl-12123768

ABSTRACT

OBJECTIVES: Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect of sildenafil on cardiac repolarization. METHODS: We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs. RESULTS: Action potential duration at 90% repolarization (APD(90)) was not affected by sildenafil in the therapeutic ranges (< or =1 microM), but shortened by higher concentration (> or =10 microM) in both guinea pig papillary muscles and canine Purkinje fibers. D-Sotalol prolonged APD(90) in the same preparations with concentrations > or =1 microM in a reverse frequency-dependent manner. Co-administration of sildenafil (10 and 30 microM) abolished the APD-prolonging effects of D-sotalol (30 microM) and amiodarone (100 microM). Sildenafil, with concentrations up to 30 microM, had no significant effect on both the rapid (I(Kr)) and the slow (I(Ks)) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. Sildenafil dose-dependently blocked L-type Ca(2+) current (I(Ca,L)), but had no effect on persistent Na(+) current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval by sildenafil (10 and 30 mg/kg orally). The QT-prolonging effects by D,L-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished by sildenafil (30 mg/kg). CONCLUSIONS: Sildenafil does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on I(Ca,L).


Subject(s)
Heart Conduction System/drug effects , Phosphodiesterase Inhibitors/pharmacology , Piperazines/pharmacology , Vasodilator Agents/pharmacology , Action Potentials/drug effects , Animals , Anti-Arrhythmia Agents/antagonists & inhibitors , Calcium/metabolism , Dogs , Dose-Response Relationship, Drug , Electrocardiography/drug effects , Female , Guinea Pigs , Male , Papillary Muscles/drug effects , Patch-Clamp Techniques , Potassium/metabolism , Purines , Purkinje Fibers/drug effects , Sildenafil Citrate , Sodium/metabolism , Sulfones
10.
Zhonghua Yi Xue Za Zhi (Taipei) ; 65(12): 570-9, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12636202

ABSTRACT

BACKGROUND: We have previously shown that an increase in NO activity activated ATP-sensitive potassium channel (K(ATP)) and shortened action potential duration (APD) in an endotoxic shock model. Because the increase in NO production and the decrease of APD appear to be downstream late events in endotoxic shock, we hypothesized that a common signaling pathway might mediate these effects. METHODS: Using a guinea pig model of endotoxic shock, we investigated the effect of genistein and tyrphostin AG 556 on the cardiac action potential. Adult Hartley guinea pigs (300 to 450 gm) were randomized into 2 treatment parts. In the chronic treatment part, guinea pigs were randomized to receive daily subcutaneous injection of one of the five agents: saline, genistein, tyrphostin AG 556, daidzein, and vehicle for 10 days. In the acute treatment part, these agents were administered by intraperitoneal injection 1 hour before endotoxic shock. The animals were then anesthetized and mechanically ventilated, and underwent 6-hour endotoxic shock or sham experiment. RESULTS: In the chronic treatment part, the plasma nitrate concentration, myocardial guanosine 3',5'-cyclic monophosphate (cGMP) content, and APD at 90% repolarization (APD90) of papillary muscle showed no difference in the five groups before endotoxic shock. After 6-hour endotoxic shock, the elevation of plasma nitrate concentration and myocardial cGMP content was found significant in the control, the daidzein, and the vehicle groups, but was blunted in the genistein and the tyrphostin groups. The shortening of APD90 of papillary muscle was also significant in the control, the daidzein, and the vehicle groups, but blunted in the genistein and tyrphostin groups. There were similar findings in the acute treatment part, except the weaker effect of genistein and tyrphostin. CONCLUSIONS: Genistein and tyrphostin AG 556, either administered chronically or acutely, significantly attenuate the cardiac APD shortening in endotoxic shock, presumably through the decrease in the plasma nitrate and the cardiac cGMP production. It is suggested that tyrosine kinase signaling plays an important role in the modulation of APD in endotoxic shock.


Subject(s)
Action Potentials/drug effects , Genistein/pharmacology , Heart/drug effects , Shock, Septic/physiopathology , Tyrphostins/pharmacology , Animals , Cyclic GMP/analysis , Female , Guinea Pigs , Heart/physiology , Male , Myocardium/chemistry , Nitrates/blood , Nitric Oxide/biosynthesis , Papillary Muscles/drug effects , Papillary Muscles/physiology , Potassium Channels/drug effects
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