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.

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.

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.

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.

Calpain inhibitor-1 protects the rat heart from ischemia-reperfusion injury: analysis by mechanical work and energetics

2005 ◽  
Vol 288 (4) ◽  
pp. H1690-H1698 ◽  
Author(s):  
Yoshiro Yoshikawa ◽  
Hiroji Hagihara ◽  
Yoshimi Ohga ◽  
Chikako Nakajima-Takenaka ◽  
Ken-ya Murata ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mechanical Energy ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Mechanical Work ◽  
Lv Function ◽  
Calpain Inhibitor ◽  
Lv Volume

We hypothesized that calpain inhibitor-1 protected left ventricular (LV) function from ischemia-reperfusion injury by inhibiting the proteolysis of α-fodrin. To test this hypothesis, we investigated the effect of calpain inhibitor-1 on LV mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion ( n = 9). After ischemia-reperfusion with calpain inhibitor-1, mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at midrange LV volume (total mechanical energy per beat) were hardly changed, although they were significantly ( P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. Mean myocardial oxygen consumption per beat (Vo2) intercepts (PVA-independent Vo2; Vo2 for the total Ca2+ handling in excitation-contraction coupling and basal metabolism) of Vo2-PVA linear relations were also unchanged after ischemia-reperfusion with calpain inhibitor-1, although they were significantly ( P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. There were no significant differences in O2 costs of LV PVA and contractility among the hearts in control (or normal) postischemia-reperfusion and postischemia-reperfusion with calpain inhibitor-1. Western blot analysis of α-fodrin and the immunostaining of 150-kDa products of α-fodrin confirmed that calpain inhibitor-1 almost completely protected the proteolysis of α-fodrin. Our results indicate that calpain inhibitor-1 prevents the heart from ischemia-reperfusion injury associated with the impairment of total Ca2+ handling by directly inhibiting the proteolysis of α-fodrin.

Cardiac dysfunction in terms of left ventricular mechanical work and energetics in hypothyroid rats

2002 ◽  
Vol 283 (2) ◽  
pp. H631-H641 ◽  
Author(s):  
Yoshimi Ohga ◽  
Susumu Sakata ◽  
Chikako Takenaka ◽  
Takehisa Abe ◽  
Tsuyoshi Tsuji ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Cardiac Dysfunction ◽  
Myocardial Oxygen Consumption ◽  
Left Ventricular ◽  
Mechanical Work ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Plasmic Reticulum ◽  
Heart Preparation ◽  
Whole Heart

We hypothesized that cardiac dysfunction in hypothyroidism is mainly caused by the impairment of Ca2+ handling in excitation-contraction coupling. To prove this hypothesis, we investigated left ventricular (LV) mechanical work and energetics without interference of preload and afterload in an excised, blood-perfused whole heart preparation from hypothyroid rats. We found that LV inotropism and lusitropism were significantly depressed, and these depressions were causally related to decreased myocardial oxygen consumption for Ca2+ handling and for basal metabolism. The oxygen costs of LV contractility for Ca2+ and for dobutamine in the hypothyroid rats did not differ from those in age-matched normal rats. The expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) significantly decreased and that of phospholamban significantly increased. The present results revealed that changes in LV energetics associated with decreased mechanical work in hypothyroid rats are mainly caused by the impairment of Ca2+ uptake via SERCA2. We conclude that the impairment of Ca2+ uptake plays an important role in the pathogenesis of cardiac dysfunction in hypothyroidism.

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.

Effects of Intracoronary Fentanyl on Left Ventricular Mechanoenergetics in the Excised Cross-circulated Canine Heart (Revised Publication)

1997 ◽  
Vol 87 (3) ◽  
pp. 658-666 ◽  
Author(s):  
Kunihisa Kohno ◽  
Miyako Takaki ◽  
Kazunari Ishioka ◽  
Yasunori Nakayama ◽  
Shunsuke Suzuki ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Energy Use ◽  
Mechanical Energy ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Canine Heart ◽  
Loading Conditions ◽  
Wide Range ◽  
Total Mechanical Energy ◽  
Lv Volumes

Background It is still unclear whether fentanyl directly alters left ventricular (LV) contractility and oxygen consumption. This is because of the difficulty in defining and evaluating contractility and energy use independently of ventricular loading conditions and heart rate in beating whole hearts. Methods This study was conducted to clarify the mechanoenergetic effects of intracoronary fentanyl in six excised cross-circulated canine hearts. The authors used the framework of the Emax (a contractility index)-PVA (systolic pressure-volume area, a measure of total mechanical energy)-VO2 (myocardial oxygen consumption per beat) relationship practically independent of ventricular loading conditions. The authors measured LV pressure, volume, coronary flow, and arteriovenous oxygen content difference to calculate Emax, PVA, and VO2. They first obtained the VO2-PVA relationship for varied LV volumes at control Emax. The authors then obtained the VO2-PVA relationship at a constant LV volume, whereas coronary blood fentanyl concentration was increased in steps up to 240 ng/ml. Finally, they obtained the VO2-PVA relationship for varied LV volumes at the final dose of fentanyl. Results Fentanyl at any concentrations did not significantly change Emax, PVA, and VO2 from the control. The linear end-systolic pressure-volume relations and their slopes were virtually the same between the control and fentanyl volume loading in each heart. Further, either the slope (oxygen cost of PVA) or the VO2 intercept (unloaded VO2) of the linear VO2-PVA relationship remained unchanged by fentanyl. Conclusions These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.

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.

Effects of Intracoronary Fentanyl on Left Ventricular Mechanoenergetics in the Excised Cross-circulated Canine Heart 

1997 ◽  
Vol 86 (6) ◽  
pp. 1350-1358 ◽  
Author(s):  
Kunihisa Kohno ◽  
Miyako Takaki ◽  
Kazunari Ishioka ◽  
Yasunori Nakayama ◽  
Shunsuke Suzuki ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Energy Use ◽  
Mechanical Energy ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Canine Heart ◽  
Loading Conditions ◽  
Wide Range ◽  
Total Mechanical Energy ◽  
Lv Volumes

Background It is still unclear whether fentanyl directly alters left ventricular (LV) contractility and oxygen consumption. This is because of the difficulty in defining and evaluating contractility and energy use independently of ventricular loading conditions and heart rate in beating whole hearts. Methods This study was conducted to clarify the mechanoenergetic effects of intracoronary fentanyl in six excised cross-circulated canine hearts. The authors used the framework of the E(max) (a contractility index)-PVA (systolic pressure-volume area, a measure of total mechanical energy)-VO2 (myocardial oxygen consumption per beat) relationship practically independent of ventricular loading conditions. The authors measured LV pressure, volume, coronary flow, and arteriovenous oxygen content difference to calculate E(max), PVA, and VO2. They first obtained the VO2-PVA relationship for varied LV volumes at control E(max). The authors then obtained the VO2-PVA relationship at a constant LV volume, whereas coronary blood fentanyl concentration was increased in steps up to 240 ng/ml. Finally, they obtained the VO2-PVA relationship for varied LV volumes at the final dose of fentanyl. Results Fentanyl at any concentrations did not significantly change E(max), PVA, and VO2 from the control. The linear end-systolic pressure-volume relations and their slopes were virtually the same between the control and fentanyl volume loading in each heart. Further, either the slope (oxygen cost of PVA) or the VO2 intercept (unloaded VO2) of the linear VO2-PVA relationship remained unchanged by fentanyl. Conclusions These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.

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.

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