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.

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.

Na+/Ca2+ exchange inhibition protects the rat heart from ischemia-reperfusion injury by blocking energy-wasting processes

2005 ◽  
Vol 288 (4) ◽  
pp. H1699-H1707 ◽  
Author(s):  
Hiroji Hagihara ◽  
Yoshiro Yoshikawa ◽  
Yoshimi Ohga ◽  
Chikako Takenaka ◽  
Ken-ya Murata ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mechanical Energy ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Reverse Mode ◽  
Rat Hearts ◽  
Total Mechanical Energy ◽  
Contractile Failure

We have recently reported that exposure of rat hearts to high Ca2+ produces a Ca2+ overload-induced contractile failure in rat hearts, which was associated with proteolysis of α-fodrin. We hypothesized that contractile failure after ischemia-reperfusion (I/R) is similar to that after high Ca2+ infusion. To test this hypothesis, we investigated left ventricular (LV) mechanical work and energetics in the cross-circulated rat hearts, which were subjected to 15 min global ischemia and 60 min reperfusion. Sixty minutes after I/R, mean systolic pressure-volume area (PVA; a total mechanical energy per beat) at midrange LV volume (mLVV) (PVAmLVV) was significantly decreased from 5.89 ± 1.55 to 3.83 ± 1.16 mmHg·ml·beat−1·g−1 ( n = 6). Mean myocardial oxygen consumption per beat (Vo2) intercept of (Vo2-PVA linear relation was significantly decreased from 0.21 ± 0.05 to 0.15 ± 0.03 μl O2·beat−1·g−1 without change in its slope. Initial 30-min reperfusion with a Na+/Ca2+ exchanger (NCX) inhibitor KB-R7943 (KBR; 10 μmol/l) significantly reduced the decrease in mean PVAmLVV and Vo2 intercept ( n = 6). Although Vo2 for the Ca2+ handling was finally decreased, it transiently but significantly increased from the control for 10–15 min after I/R. This increase in Vo2 for the Ca2+ handling was completely blocked by KBR, suggesting an inhibition of reverse-mode NCX by KBR. α-Fodrin proteolysis, which was significantly increased after I/R, was also significantly reduced by KBR. Our study shows that the contractile failure after I/R is similar to that after high Ca2+ infusion, although the contribution of reverse-mode NCX to the contractile failure is different. An inhibition of reverse-mode NCX during initial reperfusion protects the heart against reperfusion injury.

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.

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.

NHE-1 participates in isoproterenol-induced downregulation of SERCA2a and development of cardiac remodeling in rat hearts

2011 ◽  
Vol 301 (5) ◽  
pp. H2154-H2160 ◽  
Author(s):  
Munetaka Shibata ◽  
Daisuke Takeshita ◽  
Koji Obata ◽  
Shinichi Mitsuyama ◽  
Haruo Ito ◽  
...  
Keyword(s):  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Mechanical Energy ◽  
Systolic Pressure ◽  
Beneficial Effects ◽  
Rat Hearts ◽  
Total Mechanical Energy ◽  
Male Wistar Rats ◽  
Lv Volume

Impaired Ca2+ handling is one of the main characteristics in heart failure patients. Recently, we reported abnormal expressions of Ca2+-handling proteins in isoproterenol (ISO)-induced hypertrophied rat hearts. On the other hand, Na+/H+ exchanger (NHE)-1 inhibitor has been demonstrated to exert beneficial effects in ischemic-reperfusion injury and in the development of cardiac remodeling. The aims of the present study are to investigate the role of NHE-1 on Ca2+ handling and development of cardiac hypertrophy in ISO-infused rats. Male Wistar rats were randomly divided into vehicle [control (CTL)] and ISO groups without or with pretreatment with a selective NHE-1 inhibitor, BIIB-723. ISO infusion for 1 wk significantly increased the ratios of heart to body weight and left ventricle (LV) to body weight and collagen accumulation. All of these increases were antagonized by coadministration with BIIB-723. The ISO-induced significant increase in LV wall thickness was suppressed significantly ( P < 0.05) by BIIB-723. ISO-induced decreases in cardiac stroke volume and a total mechanical energy per beat index, systolic pressure-volume area at midrange LV volume, were normalized by BIIB-723. The markedly higher expression of NHE-1 protein in the ISO group than that in CTL group was suppressed ( P < 0.05) by BIIB-723. Surprisingly, ISO induced downregulation of the important Ca2+-handling protein sarcoplasmic reticulum Ca2+-ATPase 2a, the expression of which was also normalized by BIIB-723 without changes in phosphorylated phospholamban (PLB)/PLB expression. We conclude that NHE-1 contributes to ISO-induced abnormal Ca2+ handling associated with cardiac hypertrophy. Inhibition of NHE-1 ameliorates cardiac Ca2+-handling impairment and prevents the development of cardiac dysfunction in ISO-infused rats.

Left ventricular function of isoproterenol-induced hypertrophied rat hearts perfused with blood: mechanical work and energetics

2009 ◽  
Vol 297 (5) ◽  
pp. H1736-H1743 ◽  
Author(s):  
Chikako Nakajima-Takenaka ◽  
Guo-Xing Zhang ◽  
Koji Obata ◽  
Kiyoe Tohne ◽  
Hiroko Matsuyoshi ◽  
...  
Keyword(s):  
Relaxation Rate ◽  
Diastolic Pressure ◽  
Mechanical Energy ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Mechanical Work ◽  
Linear Relations ◽  
Rat Hearts ◽  
Total Mechanical Energy ◽  
Heart Preparation

We investigated left ventricular (LV) mechanical work and energetics in the cross-circulated (blood-perfused) isoproterenol [Iso 1.2 mg·kg−1·day−1 for 3 days (Iso3) or 7 days (Iso7)]-induced hypertrophied rat heart preparation under isovolumic contraction-relaxation. We evaluated pressure-time curves per beat, end-systolic pressure-volume and end-diastolic pressure-volume relations, and myocardial O2 consumption per beat (V̇o2)-systolic pressure-volume area (PVA; a total mechanical energy per beat) linear relations at 240 beats/min, because Iso-induced hypertrophied hearts failed to completely relax at 300 beats/min. The LV relaxation rate at 240 beats/min in Iso-induced hypertrophied hearts was significantly slower than that in control hearts [saline 24 μl/day for 3 and 7 days (Sa)] with unchanged contraction rate. The V̇o2-intercepts (composed of basal metabolism and Ca2+ cycling energy consumption in excitation-contraction coupling) of V̇o2-PVA linear relations were unchanged associated with their unchanged slopes in Sa, Iso3, and Iso7 groups. The oxygen costs of LV contractility were also unchanged in all three groups. The amounts of expression of sarcoplasmic reticulum Ca2+-ATPase, phospholamban (PLB), phosphorylated-Ser16 PLB, phospholemman, and Na+-K+-ATPase are significantly decreased in Iso3 and Iso7 groups, although the amount of expression of NCX1 is unchanged in all three groups. Furthermore, the marked collagen production (types I and III) was observed in Iso3 and Iso7 groups. These results suggested the possibility that lowering the heart rate was beneficial to improve mechanical work and energetics in isoproterenol-induced hypertrophied rat hearts, although LV relaxation rate was slower than in normal hearts.

Sensitivities of cardiac O2 consumption and contractility to catecholamines in dogs

1991 ◽  
Vol 261 (1) ◽  
pp. H196-H205 ◽  
Author(s):  
Y. Ohgoshi ◽  
Y. Goto ◽  
S. Futaki ◽  
H. Yaku ◽  
H. Suga
Keyword(s):  
Mechanical Energy ◽  
Plasma Catecholamines ◽  
Systolic Pressure ◽  
Plasma Catecholamine ◽  
Catecholamine Level ◽  
Oxygen Cost ◽  
O2 Consumption ◽  
Total Mechanical Energy ◽  
Plasma Catecholamine Level ◽  
Stimulation Of

We studied the effects of plasma catecholamines from the adrenal gland on systolic pressure-volume area (PVA)-independent O2 consumption (VO2) and contractility index (Emax) in the left ventricle of excised cross-circulated dog hearts. PVA is a measure of the total mechanical energy of contraction. Under baseline conditions, the PVA-independent VO2 correlated with plasma catecholamine level in the hearts (r = 0.84). Plasma epinephrine and norepinephrine levels increased gradually from 0.3 and 0.4 ng/ml to 10.3 and 2.7 ng/ml on average during adrenal sympathetic nerve stimulation of support dogs. Simultaneously, Emax and PVA-independent VO2 increased by 240 +/- 127 (SD) and 75 +/- 24%. Although their increases were monotonic in a given heart, their sensitivities to catecholamines were considerably variable among hearts. However, these two sensitivities were correlated (r = 0.96) with each other in the hearts, and the interheart variation of the sensitivity of the PVA-independent VO2 to Emax (i.e., oxygen cost of Emax) was smaller. We conclude that the oxygen cost of Emax is less variable among hearts despite large interheart variations of Emax and VO2 responses to plasma catecholamines.

Heart rate-independent energetics and systolic pressure-volume area in dog heart

1983 ◽  
Vol 244 (2) ◽  
pp. H206-H214 ◽  
Author(s):  
H. Suga ◽  
R. Hisano ◽  
S. Hirata ◽  
T. Hayashi ◽  
O. Yamada ◽  
...  
Keyword(s):  
Heart Rate ◽  
Oxygen Consumption ◽  
Left Ventricle ◽  
Mechanical Energy ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Canine Heart ◽  
Heart Rates ◽  
Dog Heart ◽  
Total Mechanical Energy

Left ventricular (LV) systolic pressure-volume area (PVA), a new measure of total mechanical energy for the contraction, linearly correlates with its oxygen consumption per beat (VO2) regardless of contraction mode in a canine heart with stable chronotropism and inotropism. PVA is the area in the pressure-volume (PV) diagram circumscribed by the end-systolic and end-diastolic PV relation curves and the systolic segment of the PV loop and has dimensions of energy. We investigated whether primary changes in heart rate would affect the VO2-PVA relation. In the excised cross-circulated canine heart with left ventricular load controlled with a servo pump, we changed heart rate by pacing to compare the VO2-PVA relations at low [124 +/- 17 (SD) min-1] and high (193 +/- 23) heart rates. In 15 left ventricles, VO2 (ml O2 X beat-1 X 100 g LV-1) was (1.75 +/- 0.57) X 10(-5) PVA (mmHg X ml X beat-1 X 100 g LV-1) + 0.031 +/- 0.011 (ml O2 X beat-1 X 100 g LV-1). The VO2-PVA relation was virtually independent of heart rate in individual hearts. We conclude that the load-independent VO2-PVA relationship is not affected by chronotropism in a given canine left ventricle.

Prospective prediction of O2 consumption from pressure-volume area in dog hearts

1987 ◽  
Vol 252 (6) ◽  
pp. H1258-H1264 ◽  
Author(s):  
H. Suga ◽  
Y. Yasumura ◽  
T. Nozawa ◽  
S. Futaki ◽  
Y. Igarashi ◽  
...  
Keyword(s):  
Mechanical Energy ◽  
Systolic Pressure ◽  
Regression Coefficients ◽  
Coefficient Of Determination ◽  
O2 Consumption ◽  
Ventricular Contraction ◽  
Individual Variations ◽  
Total Mechanical Energy ◽  
Myocardial O2 Consumption ◽  
The Individual

Systolic pressure-volume area (PVA) is the area circumscribed by the end-systolic pressure-volume (PV) line, the end-diastolic PV curve, and the systolic PV trajectory of the ventricle. PVA represents the total mechanical energy generated by ventricular contraction. Myocardial O2 consumption (VO2) linearly correlates with PVA under different pre- and afterloads in the dog left ventricle. The linear VO2-PVA relation parallel shifts with changes in contractility index Emax. We have retrospectively obtained VO2 = A X PVA + B . Emax + C, where A, B, and C are regression coefficients. We used this equation to prospectively predict VO2 from measured PVA and Emax in a new group of dog left ventricles. Coefficient of determination (CD) of measured VO2 from predicted VO2 was 0.86 +/- 0.09 (SD) in individual hearts, but decreased to 0.72 when data of the five hearts were pooled. These prospective CDs in individual hearts and all hearts were smaller than retrospective CDs in the individual hearts (0.90 +/- 0.06). Inter-individual variations of A,B, and C caused the lower prospective predictability.

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