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Energetics of failing and nonfailing human myocardium
J Mol Cell Cardiol 24 (Supplement
October 3,1992 Readjustment or Impairment
V) (1992)
Oral presentation I (Minisymposium of Energy Balance in Heart Failure
IX): 8.00 - 9.40
257 OXYGEN CONSUMPTION AND CYTOPLASMIC CALCIUM IN ISOLATED BAT VENTRICULAR MYOCYTES Jan WT Fiolet, Ton Baartscheer, Cees A Schumacher. Department of Experimental Cardiology, University of Amsterdam, The Netherlands. Mitochondrial state-3 respiration of disrupted myocytes strongly depends on cytoplasmic CCa2+l (Cal”). Also in intact myocytes 0, consumption is subject to regulation by Ca,“. The Na /Cal’-exchanger thermodynamically controls steady state Ca,” at least in resting cells. Ca,, may be manipulated by several interventions in the resting myocytes: 1) by an abrupt decrease of extracellular CNa’j, 2) by increasing sarcolemmal Na*-conductance by veratridine, an opener of the fast sodium channel, and 3) by increasing Ca-conductance using a Ca-ionophore. These interventions affect the thermodynamic condition of the Na*/Ca”-exchanger in a different manner. Electrical stimulation poises time-averaged Cain, frequency dependently, in a more physiological manner. In these conditions v0, and Ca,, were measured simultaneously. An abrupt decrease of extracellular CNa’l causes a concentration dependent transient increase of both v0, and and the Ca-ionophore both dose-dependently cause a monophasic increase Cal”* Veratridine of v0, and Ca,,. The relationships between v0, and Ca,, obtained in these different interventions were essentially the same. With field stimulation over a range of frequencies the relationship between steady state time averaged Ca,, and v0, seems rather similar. We conclude that Ca,, is a major regulator of myocardial oxygen consumption. Ca,, is poised by the thermodynamic condition of the sarcolemmal Na’/Ca”-exchanger.
282
Influence of inotropic interventions on efficiency of cardiomyocyte contraction Horst Rose, Stefanie Pijpping, Stefan Mmck, Helmut Kammermeier, lnstitut fiir Physiologic, Med. FakultY RWTH Aachen, Pauwelsstr. 30, W-5100 Aachen, FRG. Positive inokopic effects can be elicited in principle via an increased intracellular Ca2+ availabilty and/or via an increased myofibrillar sensitivity to Caz+ However, when evaluating the. potential benefit of a positive inotropic intervention, one should not only consider the enhanced performance achieved, but also its energetic costs. Beat dependent cardiac energy consumption consists of two components: (i) redistribution of ions to maintain homeostasis (ion cycling) and (ii) the acto-myosin ATPase energy transformation.Mechanismsleading to an increasedCa2+ availability involve both components, whwith enhanced Ca-sensitivity only the second should contribute to the higher energy consumption. We investigated these correlations with electrically stimulated isolated cardiac myocytes from rats where the increase in contraction and oxygen consumption per beat (vbG2) were measured. By inhibition of AM-ATF’ase (BDM-method J. Pbysiol. (1989) 414 :433-53). the two components could be measured sqerakly. Depending on the conditions used, the costs of ion-cycling amounled to 20 to almost 60 % of the beat related energy consumption of the (unloaded) myocytes. Positive inotropic interventions such as increasing Ibe extracellular Ca2+ or adding Isoprenaline enhanced vbG2 by a higher factor than contraction amplitude. The Ca2+-sensitizer FMD 57033 increased vbG2 by a lower factor than contraction amplitude. At pH 7.0 EMD 57033 increased vbG2 by a still smaller factor relative to contraction. These observations are indicative of an enhanced efficiency of contraction under the influence of the Ca2+- sensitizer. The time course of contraction also exhibited characteristic differences in the three types of interventions. Taken together, this findings suggest that the action of F&ID 57033 involves an alterations of crossbridge kinetics. Our method allows to analyze the energetin of contraction in cardiomyocytes within a
physiologicalbeating rate and without the limitations of diffusiveexchange.Supportedby DFG (Ro 755/l-2).
313 ENERGETICS
OF FAILING
AND NONFAILING
HUMAN
MYOCARDIUM
Gerd Hasenfuss, Louis A. Mulieri, Christian Holubarsch, Hanjiirg Just and Norman R. Alpert. Medizin. Klinik, Kardiologie, Universitgt Freiburg, F.R.G. and College of Medicine, University of Vermont, Burlington, Vermont, USA. Isometric force and heat were measured in left ventricular muscle strips from nonfailing human hearts (n = 14) and from hearts with end-stage failing dilated cardiomyopathy (DCM; n= 13). Peak twitch tension and tension-time integral (TTI) were reduced by 46% and 40%, respectively in DCM (~~0.05). Tension-independent heat (TIH) reflecting the amount of calcium cycling was reduced by 69% (~~0.05) in DCM. Economy of contraction (TIT/total heat) was increased significantly in DCM due to an increase in the individual crossbridge force-time integral (by 34%; ~~0.05). Application of isoproterenol in DCM increased peak twitch tension by 61%, TIH by 356%, did not influence crossbridge force-time integral, and decreased economy of contraction significantly. These data indicate that force production in DCM is reduced due to a decreased amount of calcium cycling, but economy of contraction is increased. Isoproterenol increases force production in DCM, but at the expense of reduced economy of contraction. s.110
October 3,1992 Readjustment or Impairment
V) (1992)
Oral presentation I (Minisymposium of Energy Balance in Heart Failure
IX): 8.00 - 9.40
257 OXYGEN CONSUMPTION AND CYTOPLASMIC CALCIUM IN ISOLATED BAT VENTRICULAR MYOCYTES Jan WT Fiolet, Ton Baartscheer, Cees A Schumacher. Department of Experimental Cardiology, University of Amsterdam, The Netherlands. Mitochondrial state-3 respiration of disrupted myocytes strongly depends on cytoplasmic CCa2+l (Cal”). Also in intact myocytes 0, consumption is subject to regulation by Ca,“. The Na /Cal’-exchanger thermodynamically controls steady state Ca,” at least in resting cells. Ca,, may be manipulated by several interventions in the resting myocytes: 1) by an abrupt decrease of extracellular CNa’j, 2) by increasing sarcolemmal Na*-conductance by veratridine, an opener of the fast sodium channel, and 3) by increasing Ca-conductance using a Ca-ionophore. These interventions affect the thermodynamic condition of the Na*/Ca”-exchanger in a different manner. Electrical stimulation poises time-averaged Cain, frequency dependently, in a more physiological manner. In these conditions v0, and Ca,, were measured simultaneously. An abrupt decrease of extracellular CNa’l causes a concentration dependent transient increase of both v0, and and the Ca-ionophore both dose-dependently cause a monophasic increase Cal”* Veratridine of v0, and Ca,,. The relationships between v0, and Ca,, obtained in these different interventions were essentially the same. With field stimulation over a range of frequencies the relationship between steady state time averaged Ca,, and v0, seems rather similar. We conclude that Ca,, is a major regulator of myocardial oxygen consumption. Ca,, is poised by the thermodynamic condition of the sarcolemmal Na’/Ca”-exchanger.
282
Influence of inotropic interventions on efficiency of cardiomyocyte contraction Horst Rose, Stefanie Pijpping, Stefan Mmck, Helmut Kammermeier, lnstitut fiir Physiologic, Med. FakultY RWTH Aachen, Pauwelsstr. 30, W-5100 Aachen, FRG. Positive inokopic effects can be elicited in principle via an increased intracellular Ca2+ availabilty and/or via an increased myofibrillar sensitivity to Caz+ However, when evaluating the. potential benefit of a positive inotropic intervention, one should not only consider the enhanced performance achieved, but also its energetic costs. Beat dependent cardiac energy consumption consists of two components: (i) redistribution of ions to maintain homeostasis (ion cycling) and (ii) the acto-myosin ATPase energy transformation.Mechanismsleading to an increasedCa2+ availability involve both components, whwith enhanced Ca-sensitivity only the second should contribute to the higher energy consumption. We investigated these correlations with electrically stimulated isolated cardiac myocytes from rats where the increase in contraction and oxygen consumption per beat (vbG2) were measured. By inhibition of AM-ATF’ase (BDM-method J. Pbysiol. (1989) 414 :433-53). the two components could be measured sqerakly. Depending on the conditions used, the costs of ion-cycling amounled to 20 to almost 60 % of the beat related energy consumption of the (unloaded) myocytes. Positive inotropic interventions such as increasing Ibe extracellular Ca2+ or adding Isoprenaline enhanced vbG2 by a higher factor than contraction amplitude. The Ca2+-sensitizer FMD 57033 increased vbG2 by a lower factor than contraction amplitude. At pH 7.0 EMD 57033 increased vbG2 by a still smaller factor relative to contraction. These observations are indicative of an enhanced efficiency of contraction under the influence of the Ca2+- sensitizer. The time course of contraction also exhibited characteristic differences in the three types of interventions. Taken together, this findings suggest that the action of F&ID 57033 involves an alterations of crossbridge kinetics. Our method allows to analyze the energetin of contraction in cardiomyocytes within a
physiologicalbeating rate and without the limitations of diffusiveexchange.Supportedby DFG (Ro 755/l-2).
313 ENERGETICS
OF FAILING
AND NONFAILING
HUMAN
MYOCARDIUM
Gerd Hasenfuss, Louis A. Mulieri, Christian Holubarsch, Hanjiirg Just and Norman R. Alpert. Medizin. Klinik, Kardiologie, Universitgt Freiburg, F.R.G. and College of Medicine, University of Vermont, Burlington, Vermont, USA. Isometric force and heat were measured in left ventricular muscle strips from nonfailing human hearts (n = 14) and from hearts with end-stage failing dilated cardiomyopathy (DCM; n= 13). Peak twitch tension and tension-time integral (TTI) were reduced by 46% and 40%, respectively in DCM (~~0.05). Tension-independent heat (TIH) reflecting the amount of calcium cycling was reduced by 69% (~~0.05) in DCM. Economy of contraction (TIT/total heat) was increased significantly in DCM due to an increase in the individual crossbridge force-time integral (by 34%; ~~0.05). Application of isoproterenol in DCM increased peak twitch tension by 61%, TIH by 356%, did not influence crossbridge force-time integral, and decreased economy of contraction significantly. These data indicate that force production in DCM is reduced due to a decreased amount of calcium cycling, but economy of contraction is increased. Isoproterenol increases force production in DCM, but at the expense of reduced economy of contraction. s.110