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An analysis of the failing heart
J Mol
S4&3
Cell RATE
Cardiol
24 (Supplement
OF DEVELOPMENT
I) (1992) OF RIGOR
IN RAT CARDIAC
TRABECULAE
DURING
METABOLIC
INHIBITION
Henk E.D.J.ter Keurs, Wei Dong Gao, and Tin Nguyen. Dept of Medicine, University of Calgary, Canada. Metabolic inhibition (MI) causes development of unstimulated force (Fu). We have shown ureviouslv that maximal Fu (Fu,,) reflects rigor due.10 ATP depletion. We assessed the relative contributions of twitch for& (Fa), excitation contraction coupling (XC) and basal metabolism (EM) to depletion of ATT during MI. Trabeculae from rat heart were mounted between a-force transducer and motor arm and superfused with modified Krebs-Hens&it solution (pH 7.4.30 “C, Ca++ 1.5 mM, stim 1H.z). Trabeculae were depleted of glycogen prior to experiments by lo-15 min exposure to CN(2 mM) and N2. After complete recovery, the muscles were exposed to CN- and N, to achieve MI. During MI, Fa was controlled by afterloading the muscle. ECC was changed by varying [Ca++],. The integral of Fa over time (IFa) was used to express the load encountered by the muscles. We used l/Fu,,, to indicate the rate of ATP depletion. The main results arc shown in the Figure. IFa accounted for -1530% of ATP consumption (AATP), AATP by BM -25%.AATP by ECC varied from 35% to 50%. depending on [Ca++],. A sigmoid relationship existed between l/Fu,, and [Ca++], at zero load. Propranolol(5 *M) at 1.5 mM [Ca*+], significantly delayed Fu max as compared with control muscles at the same [Ca++],. Myofibrillar energy conversion efficiency was -67%. These results show that: (1) during MI, IFa, ECC, and BM all contribute to AATP. ECC and BM dominated AATP. (2) The increased AATP by ECC is in part due to increased Ca++ cycling as a result of endogenous catecholamine release during MI. (3) The energy conversion efficiency was not changed during MI.
S-O&4
AN ANALYBIB OF THE FAIUNG HEART Norman R Alpert, Gerd Hasenfuss, Lou Mulieri, Dave Warshaw, Bruce Leavttt, Frank lttleman, Paul Allen. Department of Physiology and Biophysics, University of Vermont, Burlington, Vermont 05465 In human heart failure there is a depressed relation between diastolic filling pressure and stroke volume. Insight into the subcellular basis for the depressed stroke volume is provided by using isometric force and heat measurements (isolated myocardial strips, 37C, 1 Hz) to evaluate alterations from normal in the contractile and excitation contraction coupling systems in end stage failing dilated cardiomyopathy. In the failing myocardium peak isometric twitch tension, maximum rate of tension rise and maximum rate of relaxation were reduced by 46%, 51% and 46%, respectively. Tension dependent heat (TDH) and the force time integral (IPdt) in the failing heart was reduced by 61% and 4696, respectively. The average myosin crossbridge force time integral (calculated from the economy (IPdt/TDH)) was increased by 34% in the failing hearts. From the motility assay measurements, with comparable altered crossbrldge force time integral and isometric force, calculations of the power output was shown to be markedly depressed in the failing heart. Excitation contraction coupling was assessed by using the tension independent heat (TIH). In the failing strips, TIH and TIH rate were reduced by 66% and 71%, respectively, indicating a marked reduction in the amount of calcium released as well as the rate of calcium uptake in each twitch. The increase in the myosin crossbridge force time integral and the decrease in amount and rate of calcium cycling are offfered as an explanation for the depressed mechanical peformance in heart failure.
S-08-5
WHY INTACT MYOCARDIUM SHOWS NO FENN EFFECT Gijs Elzinga, Zolt6n Papp, Ger JM Stlenen. Laboratory for Physiology, Free University, van der Boechorststraat 7,lOSl BT Amsterdam. When varying arterial load, and thus stroke volume, at a given end-diastolic volume the highest energy turnover of the ventricle is found with isovohunic contractions. For isolated heart muscle comparable observations have been reported. In contrast, skeletal muscle may show an increase in energy turnover when shortening occurs. Fenn (19231 was the first to show this effect. The precise mechanism responsible for the Fenn effect is unknown, but it no doubt reflects the effect of shortening on cross bridge properties. In heart muscle the cross bridges are only partially activated. We therefore studied the effect of movement on myoBbrillar ATPase activity in skinned cardiac trabeculae at different degrees of activation. At maximum activation (pGa = 4.27) an increase of the ATEase activity was found with movement by 160 f 6 %. When the preparations were partially activated QKa = 5.1) no change was found while at pGa = 5.5 ATPase activity was reduced during movement to 33 f 3 %. The findings suggest that the degree of activation determines the occurrence of the Fenn effect in cardiac muscle. s.29
S4&3
Cell RATE
Cardiol
24 (Supplement
OF DEVELOPMENT
I) (1992) OF RIGOR
IN RAT CARDIAC
TRABECULAE
DURING
METABOLIC
INHIBITION
Henk E.D.J.ter Keurs, Wei Dong Gao, and Tin Nguyen. Dept of Medicine, University of Calgary, Canada. Metabolic inhibition (MI) causes development of unstimulated force (Fu). We have shown ureviouslv that maximal Fu (Fu,,) reflects rigor due.10 ATP depletion. We assessed the relative contributions of twitch for& (Fa), excitation contraction coupling (XC) and basal metabolism (EM) to depletion of ATT during MI. Trabeculae from rat heart were mounted between a-force transducer and motor arm and superfused with modified Krebs-Hens&it solution (pH 7.4.30 “C, Ca++ 1.5 mM, stim 1H.z). Trabeculae were depleted of glycogen prior to experiments by lo-15 min exposure to CN(2 mM) and N2. After complete recovery, the muscles were exposed to CN- and N, to achieve MI. During MI, Fa was controlled by afterloading the muscle. ECC was changed by varying [Ca++],. The integral of Fa over time (IFa) was used to express the load encountered by the muscles. We used l/Fu,,, to indicate the rate of ATP depletion. The main results arc shown in the Figure. IFa accounted for -1530% of ATP consumption (AATP), AATP by BM -25%.AATP by ECC varied from 35% to 50%. depending on [Ca++],. A sigmoid relationship existed between l/Fu,, and [Ca++], at zero load. Propranolol(5 *M) at 1.5 mM [Ca*+], significantly delayed Fu max as compared with control muscles at the same [Ca++],. Myofibrillar energy conversion efficiency was -67%. These results show that: (1) during MI, IFa, ECC, and BM all contribute to AATP. ECC and BM dominated AATP. (2) The increased AATP by ECC is in part due to increased Ca++ cycling as a result of endogenous catecholamine release during MI. (3) The energy conversion efficiency was not changed during MI.
S-O&4
AN ANALYBIB OF THE FAIUNG HEART Norman R Alpert, Gerd Hasenfuss, Lou Mulieri, Dave Warshaw, Bruce Leavttt, Frank lttleman, Paul Allen. Department of Physiology and Biophysics, University of Vermont, Burlington, Vermont 05465 In human heart failure there is a depressed relation between diastolic filling pressure and stroke volume. Insight into the subcellular basis for the depressed stroke volume is provided by using isometric force and heat measurements (isolated myocardial strips, 37C, 1 Hz) to evaluate alterations from normal in the contractile and excitation contraction coupling systems in end stage failing dilated cardiomyopathy. In the failing myocardium peak isometric twitch tension, maximum rate of tension rise and maximum rate of relaxation were reduced by 46%, 51% and 46%, respectively. Tension dependent heat (TDH) and the force time integral (IPdt) in the failing heart was reduced by 61% and 4696, respectively. The average myosin crossbridge force time integral (calculated from the economy (IPdt/TDH)) was increased by 34% in the failing hearts. From the motility assay measurements, with comparable altered crossbrldge force time integral and isometric force, calculations of the power output was shown to be markedly depressed in the failing heart. Excitation contraction coupling was assessed by using the tension independent heat (TIH). In the failing strips, TIH and TIH rate were reduced by 66% and 71%, respectively, indicating a marked reduction in the amount of calcium released as well as the rate of calcium uptake in each twitch. The increase in the myosin crossbridge force time integral and the decrease in amount and rate of calcium cycling are offfered as an explanation for the depressed mechanical peformance in heart failure.
S-08-5
WHY INTACT MYOCARDIUM SHOWS NO FENN EFFECT Gijs Elzinga, Zolt6n Papp, Ger JM Stlenen. Laboratory for Physiology, Free University, van der Boechorststraat 7,lOSl BT Amsterdam. When varying arterial load, and thus stroke volume, at a given end-diastolic volume the highest energy turnover of the ventricle is found with isovohunic contractions. For isolated heart muscle comparable observations have been reported. In contrast, skeletal muscle may show an increase in energy turnover when shortening occurs. Fenn (19231 was the first to show this effect. The precise mechanism responsible for the Fenn effect is unknown, but it no doubt reflects the effect of shortening on cross bridge properties. In heart muscle the cross bridges are only partially activated. We therefore studied the effect of movement on myoBbrillar ATPase activity in skinned cardiac trabeculae at different degrees of activation. At maximum activation (pGa = 4.27) an increase of the ATEase activity was found with movement by 160 f 6 %. When the preparations were partially activated QKa = 5.1) no change was found while at pGa = 5.5 ATPase activity was reduced during movement to 33 f 3 %. The findings suggest that the degree of activation determines the occurrence of the Fenn effect in cardiac muscle. s.29