Ca(2+)-free, high-Ca2+ coronary perfusion suppresses contractility and excitation-contraction coupling energy

1995 ◽  
Vol 268 (3) ◽  
pp. H1061-H1070 ◽  
Author(s):  
J. Araki ◽  
M. Takaki ◽  
T. Namba ◽  
M. Mori ◽  
H. Suga
Keyword(s):  
Systolic Pressure ◽  
Left Ventricular ◽  
Ultrastructural Changes ◽  
Coronary Perfusion ◽  
Oxygen Cost ◽  
Tyrode Solution ◽  
Coupling Energy ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Contractile Failure

We studied the mechanoenergetic effects of a short-term Ca(2+)-free, high-Ca2+ Tyrode solution coronary perfusion in eight excised, cross-circulated canine hearts. The perfusion protocol consisted of coronary perfusion with Ca(2+)-free Tyrode solution for 10 min followed by high-Ca2+ (16 mM) Tyrode solution for 5 min. This new protocol successfully induced acute contractile failure in seven hearts, without myocardial ultrastructural changes. We studied the end-systolic pressure-volume relation (slope = Emax, a contractility index) and the relation between oxygen consumption per beat (VO2) and systolic pressure-volume area (PVA) in these failing hearts. These hearts had no increase in end-diastolic pressure at a given volume, a 40% decrease in Emax and a proportional decrease in the PVA-independent VO2 for 1–4 h, but no decrease in the oxygen cost of PVA, defined as the slope of the VO2-PVA relation. The oxygen cost of Emax for Ca2+ handling, defined as the slope of the relation between PVA-independent VO2 and Emax, was unchanged in the failing hearts. We conclude that the present protocol induced left ventricular contractile failure, primarily involving the suppression of Ca2+ handling energy for excitation-contraction coupling.

Rat cardiac contractile dysfunction induced by Ca2+ overload: possible link to the proteolysis of α-fodrin

2001 ◽  
Vol 281 (3) ◽  
pp. H1286-H1294 ◽  
Author(s):  
Tsuyoshi Tsuji ◽  
Yoshimi Ohga ◽  
Yoshiro Yoshikawa ◽  
Susumu Sakata ◽  
Takehisa Abe ◽  
...  
Keyword(s):  
Mechanical Energy ◽  
Systolic Pressure ◽  
Calpain Inhibitor ◽  
Contractile Dysfunction ◽  
Area Index ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Total Mechanical Energy ◽  
Cardiac Contractile Dysfunction ◽  
Contractile Failure

The aim of the present study was to examine the mechanisms of Ca2+ overload-induced contractile dysfunction in rat hearts independent of ischemia and acidosis. Experiments were performed on 30 excised cross-circulated rat heart preparations. After hearts were exposed to high Ca2+, there was a contractile failure associated with a parallel downward shift of the linear relation between myocardial O2 consumption per beat and systolic pressure-volume area (index of a total mechanical energy per beat) in left ventricles from all seven hearts that underwent the protocol. This result suggested a decrease in O2consumption for total Ca2+ handling in excitation-contraction coupling. In the hearts that underwent the high Ca2+ protocol and had contractile failure, we found marked proteolysis of a cytoskeleton protein, α-fodrin, whereas other proteins were unaffected. A calpain inhibitor suppressed the contractile failure by high Ca2+, the decrease in O2 consumption for total Ca2+ handling, and membrane α-fodrin degradation. We conclude that the exposure to high Ca2+ may induce contractile dysfunction possibly by suppressing total Ca2+ handling in excitation-contraction coupling and degradation of membrane α-fodrin via activation of calpain.

Cardioprotective effects of a novel calpain inhibitor SNJ-1945 for reperfusion injury after cardioplegic cardiac arrest

2010 ◽  
Vol 298 (2) ◽  
pp. H643-H651 ◽  
Author(s):  
Yoshiro Yoshikawa ◽  
Guo-Xing Zhang ◽  
Koji Obata ◽  
Yoshimi Ohga ◽  
Hiroko Matsuyoshi ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mechanical Energy ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Calpain Inhibitor ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
The Mean

We have previously indicated that calpain inhibitor-1 prevents the heart from ischemia- reperfusion injury associated with the impairment of total Ca2+ handling by inhibiting the proteolysis of α-fodrin. However, this inhibitor is insoluble with water and inappropriate for clinical application. The aim of the present study was to investigate the protective effect of a newly developed calpain inhibitor, SNJ-1945 (SNJ), with good aqueous solubility on left ventricular (LV) mechanical work and energetics in the cross-circulated rat hearts. SNJ (150 μM) was added to KCl (30 meq) cardioplegia (CP). Mean end-systolic pressure at midrange LV volume (ESPmLVV) and systolic pressure-volume area (PVA) at mLVV (PVAmLVV; a total mechanical energy per beat) were hardly changed after CP plus SNJ arrest-reperfusion (post-CP + SNJ), whereas ESPmLVV and PVAmLVV in post-CP group were significantly ( P < 0.01) decreased. Mean myocardial oxygen consumption for the total Ca2+ handling in excitation-contraction coupling did not significantly decrease in post-CP + SNJ group, whereas it was significantly ( P < 0.01) decreased in post-CP group. The mean amounts of 145- and 150-kDa fragments of α-fodrin in the post-CP group were significantly larger than those in normal and post-CP + SNJ groups. In contrast, the mean amounts of L-type Ca2+ channel and sarcoplasmic reticulum Ca2+-ATPase were not significantly different among normal, post-CP, and post-CP + SNJ groups. Our results indicate that soluble SNJ attenuates cardiac dysfunction due to CP arrest-reperfusion injury associated with the impairment of the total Ca2+ handling in excitation-contraction coupling by inhibiting the proteolysis of α-fodrin.

Decrease in oxygen cost of contractility during hypocapnic alkalosis in canine hearts

1996 ◽  
Vol 270 (6) ◽  
pp. H1905-H1913
Author(s):  
K. Onishi ◽  
K. Sekioka ◽  
R. Ishisu ◽  
H. Tanaka ◽  
M. Nakamura ◽  
...  
Keyword(s):  
Energy Cost ◽  
Mechanical Energy ◽  
Systolic Pressure ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Oxygen Cost ◽  
Contraction Coupling ◽  
Total Mechanical Energy ◽  
Volume Relation ◽  
Hypocapnic Alkalosis

Ca2+ sensitization of contractile machinery could theoretically enhance the mechanoenergetics of the heart. We studied the effects of alkalosis with Ca2+ sensitization on mechanoenergetics within the framework of the relationships of left ventricular pressure-volume area (PVA; a measure of the total mechanical energy), myocardial oxygen consumption per beat (VO2), and the contractility index [E(max) (slope of end-systolic pressure-volume relation)] in 10 excised, cross-circulated canine hearts. Alkalosis was stably maintained without hypoxia (mean pH 7.66). Alkalosis increased E(max) without changing the slope of the VO2-PVA relation, a reflected contractile efficiency. The incremental ratio of unloaded VO2 to E(max) in alkalosis was significantly lower than that in Ca2+ sensitization (0.0012 +/- 0.0010 vs. 0.0062 +/- 0.0030 ml O2 . mmHg-1 . ml . beat-1 . 100 g LV-2; P < 0.01). Basal metabolism under KCl arrest was unchanged by alkalosis, indicating the decreased energy cost of the excitation-contraction coupling by alkalosis. Compared with the control, alkalosis increased E(max) during the Ca2+ infusion of various concentrations without any further increase in unloaded VO2. Thus we demonstrated a decreased oxygen cost of contractility during alkalosis, presumably due to Ca2+ sensitization.

A cardioprotective agent of a novel calpain inhibitor, SNJ-1945, exerts β1 actions on left ventricular mechanical work and energetics

2010 ◽  
Vol 299 (2) ◽  
pp. H396-H401 ◽  
Author(s):  
Yoshiro Yoshikawa ◽  
Guo-Xing Zhang ◽  
Koji Obata ◽  
Hiroko Matsuyoshi ◽  
Keiji Asada ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Mechanical Energy ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Water Soluble ◽  
Mechanical Work ◽  
Calpain Inhibitor ◽  
Excitation Contraction Coupling ◽  
Linear Relations ◽  
Contraction Coupling

We have previously shown that a newly developed calpain inhibitor, SNJ-1945 (SNJ), with good aqueous solubility prevents the heart from KCl arrest-reperfusion injury associated with the impairment of total Ca2+ handling by inhibiting the proteolysis of α-fodrin as a cardioplegia. The aim of the present study was to investigate certain actions of this calpain inhibitor, SNJ, on left ventricular (LV) mechanical work and energetics in cross-circulated excised rat hearts undergoing blood perfusion with 40 μM SNJ. Mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at mLVV (a total mechanical energy/beat) were significantly increased by SNJ perfusion ( P < 0.01). Mean myocardial oxygen consumption per beat (V̇o2) intercepts (V̇o2 for the total Ca2+ handling in excitation-contraction coupling and basal metabolism) of V̇o2-PVA linear relations were significantly increased ( P < 0.01) with unchanged mean slopes of V̇o2-PVA linear relations. Pretreatment with the selective β1-blocker landiolol (10 μM) blocked these effects of SNJ perfusion. There were no significant differences in mean basal metabolic oxygen consumption among normal, 40 μM SNJ, and 10 μM landiolol + 40 μM SNJ groups. Our results indicate that water-soluble SNJ exerted positive actions on mechanical work and energetics mediated via β1-adrenergic receptors associated with the enhancement of total Ca2+ handling in excitation-contraction coupling and with unchanged contractile efficiency. In clinical settings, this pharmacological action of SNJ is beneficial as an additive agent for cardioplegia.

scholarly journals Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yankun Lyu ◽  
Vipin K. Verma ◽  
Younjee Lee ◽  
Iosif Taleb ◽  
Rachit Badolia ◽  
...  
Keyword(s):  
Heart Function ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Excitation Contraction Coupling ◽  
Transverse Tubular System ◽  
Contraction Coupling ◽  
Senescent Phenotype ◽  
Cellular Microstructure ◽  
T System

AbstractIt is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF. Using left ventricular myocardium from donors and HF patients with ages between 19 and 75 years, we established a library of 3D reconstructions of the t-system as well as ryanodine receptor (RyR) and junctophilin 2 (JPH2) clusters. Aging was characterized by t-system alterations and sarcolemmal dissociation of RyR clusters. This remodeling was less pronounced than in HF and accompanied by major alterations of JPH2 arrangement. Our study indicates that targeting sarcolemmal association of JPH2 might ameliorate age-associated deficiencies of heart function.

scholarly journals Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

2014 ◽  
Vol 306 (7) ◽  
pp. H1018-H1024 ◽  
Author(s):  
N. T. Boardman ◽  
J. M. Aronsen ◽  
W. E. Louch ◽  
I. Sjaastad ◽  
F. Willoch ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Left Ventricular ◽  
Lv Function ◽  
Mechanical Function ◽  
Transport Mechanisms ◽  
Working Capacity ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Plasmic Reticulum ◽  
The Relationship

Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 transports Ca2+ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca2+ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca2+ handling in the cardiomyocyte. Previous studies using cardiomyocyte-specific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca2+ transient amplitude and induces compensatory Ca2+ transport mechanisms that may lead to more inefficient Ca2+ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MV̇o2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca2+ transient amplitude in cardiomyocytes from SERCA2 KO mice, work-independent MV̇o2 was decreased due to a reduced energy cost of excitation-contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, work-dependent MV̇o2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modeling-based studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction.

Effect of ischemic zone size on nonischemic zone function

1990 ◽  
Vol 258 (6) ◽  
pp. H1786-H1795 ◽  
Author(s):  
T. Aversano ◽  
P. N. Marino
Keyword(s):  
Systolic Pressure ◽  
Coronary Perfusion Pressure ◽  
Left Ventricular ◽  
Wall Thickening ◽  
Acute Ischemia ◽  
Coronary Perfusion ◽  
Zone Size ◽  
Reduced Pressure ◽  
Systolic Performance ◽  
Shortening Deactivation

To study the influence of ischemic zone size on function in nonischemic regions, wall thickening and the end-systolic pressure-thickness (ESPTR) relationship were measured before and during a 90-s coronary occlusion, which produced either a small or large (24 or 35% of left ventricular mass) area of ischemia. With both size ischemic areas, nonischemic zone isovolumic and ejection phase wall thickening increased during occlusion, primarily because of increased preload and, to a lesser extent, a reduced pressure component of afterload. The nonischemic region ESPTR was unchanged from preocclusion control with small ischemic mass. With larger ischemic mass, the nonischemic region ESPTR was shifted downward and to the left, indicating reduced end-systolic performance. The decline in the nonischemic zone ESPTR with large ischemic zone size was not due to reduced blood flow, shortening deactivation, reflex effects, or "tethering" but rather to the associated decline in coronary perfusion pressure. Thus the increase of nonischemic region wall thickening during acute ischemia is due to a change in ventricular loading conditions and not augmentation of contractile performance. Larger ischemic zone size can impair function in nonischemic myocardium by reducing the erectile component of end-systolic performance.

scholarly journals CaMKII inhibition reduces arrhythmogenic Ca2+ events in subendocardial cryoinjured rat living myocardial slices

2021 ◽  
Vol 153 (6) ◽  
Author(s):  
Eef Dries ◽  
Ifigeneia Bardi ◽  
Raquel Nunez-Toldra ◽  
Bram Meijlink ◽  
Cesare M. Terracciano
Keyword(s):  
High Resolution ◽  
Cardiac Injury ◽  
Left Ventricular ◽  
Decay Phase ◽  
High Resolution Imaging ◽  
Triggered Activity ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Specific Targeting ◽  
Resolution Imaging

Spontaneous Ca2+ release (SCR) can cause triggered activity and initiate arrhythmias. Intrinsic transmural heterogeneities in Ca2+ handling and their propensity to disease remodeling may differentially modulate SCR throughout the left ventricular (LV) wall and cause transmural differences in arrhythmia susceptibility. Here, we aimed to dissect the effect of cardiac injury on SCR in different regions in the intact LV myocardium using cryoinjury on rat living myocardial slices (LMS). We studied SCR under proarrhythmic conditions using a fluorescent Ca2+ indicator and high-resolution imaging in LMS from the subendocardium (ENDO) and subepicardium (EPI). Cryoinjury caused structural remodeling, with loss in T-tubule density and an increased time of Ca2+ transients to peak after injury. In ENDO LMS, the Ca2+ transient amplitude and decay phase were reduced, while these were not affected in EPI LMS after cryoinjury. The frequency of spontaneous whole-slice contractions increased in ENDO LMS without affecting EPI LMS after injury. Cryoinjury caused an increase in foci that generates SCR in both ENDO and EPI LMS. In ENDO LMS, SCRs were more closely distributed and had reduced latencies after cryoinjury, whereas this was not affected in EPI LMS. Inhibition of CaMKII reduced the number, distribution, and latencies of SCR, as well as whole-slice contractions in ENDO LMS, but not in EPI LMS after cryoinjury. Furthermore, CaMKII inhibition did not affect the excitation–contraction coupling in cryoinjured ENDO or EPI LMS. In conclusion, we demonstrate increased arrhythmogenic susceptibility in the injured ENDO. Our findings show involvement of CaMKII and highlight the need for region-specific targeting in cardiac therapies.

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