Patent Abstract:
the present invention provides compositions and methods for using cardioprotective or hemodynamic drugs in combination with dichloroacetate enabling usage of cardioprotective or hemodynamic drugs at concentrations higher than used in normal clinical practice without increasing deleterious side effects normally associated with the cardioprotective or hemodynamic drug , thereby conferring added clinical benefit . the present invention teaches administration of dca with cardioprotective or hemodynamic drugs as an adjunct therapy thereby conferring added clinical benefit to clinically recommended protocols .

Detailed Description:
repetitive contraction of cardiac muscle requires an efficient and ready source of atp production to sustain mechanical activity . there are two main mechanisms to produce this atp in cardiac muscle : 1 ) glycolysis utilizing glucose as a substrate ; and 2 ) oxidative metabolism utilizing lactate , glucose or fatty acids as substrates . glycolysis is an anaerobic process and produces 2 atp per mole of glucose converted to pyruvate . fatty acid , lactate and glucose oxidation are aerobic processes , that is , requiring oxygen , and produce 129 moles of atp , 18 moles of atp and 36 moles of atp per mole of substrate metabolized , respectively . bing et al identified that the adult human heart primarily utilizes glucose , lactate and fatty acids as the major sources of energy ( bing , r . j ., et al . am . j . med . 15 : 284 - 296 ( 1953 )). the type of energy substrate used by the heart can have a profound impact on the ability of the heart to withstand an episode of hypoxia or ischemia ( lopaschuk , g . d ., et al . circ . res . 63 ( 6 ): 1036 - 1043 ( 1988 )). as a result , changes in energy substrate preference during maturation of the heart should influence the outcome of hypoxia or ischemia . under non - ischemic conditions , as noted previously , fatty acids are the primary energy substrate in the adult heart , with glucose oxidation providing only 30 to 40 percent of myocardial atp production . in experimental studies , it has been demonstrated that glucose oxidation provides an even smaller portion of atp production in hearts reperfused following a period of global ischemia ( lopaschuk , g . d et al . circ . res . 66 : 546 - 553 ( 1990 )). one of the primary factors resulting in low glucose oxidation rates post - ischemia is the circulating level of fatty acids : serum fatty acids are potent inhibitors of myocardial glucose oxidation . in patients suffering a myocardial infarction or undergoing heart surgery , serum fatty acids can be markedly elevated ( lopaschuk , g . d ., et al . am . heart j ., 128 : 61 - 67 ( 1994 )). these high levels of fatty acids have been shown to potentiate ischemic injury in several experimental models including pig , dog , rabbit and rat hearts ( saddik , m ., et al . j . biol . chem . 266 : 8162 - 8170 ( 1991 )). in both aerobic and reperfused ischemic rat hearts , high levels of fatty acids markedly inhibit glucose oxidation rates . this is believed to be the result of marked inhibition by fatty acids of the pyruvate dehydrogenase complex ( pdc ), a key enzyme complex regulating carbohydrate oxidation . it is further believed that overcoming fatty acid inhibition of pdc will dramatically increase glucose oxidation and improve functional recovery of ischemic hearts . one of the pharmacological agents that is particularly effective in reversing fatty acid inhibition of pdc is dichloroacetate . dichloroacetate ( dca ) directly stimulates pdc , resulting in a marked stimulation of glucose oxidation ( mcveigh , j . j et al . ( 1990 ) am . j . physiol . 259 : h1079 - 1085 ). in this investigation we studied the metabolic effects of dca in combination with a na + / k + atpase inhibitor ( digoxin ), a β 1 - adrenoreceptor agonist ( dobutamine ), a β 1 - adrenoreceptor antagonist ( metoprolol ) and a calcium channel blocker ( diltiazem ) in the perfused rat heart . we investigated whether the stimulation of glucose metabolism by dca could be maintained in the presence of these agents . by being able to stimulate glucose oxidation using dca in conjunction with the combined effect of the previously mentioned compounds , it is hoped that a new type of therapy for the treatment of heart disease may be found . the studies described in examples 1 - 9 utilized the methods described as follows . dosage of each cardioprotective or hemodynamic drug used is based on the equivalent administration of the maximum dosage allowed for the maximum physiological effect in clinically recommended protocols for the treatment of human patients . rat hearts were cannulated for isolated working heart perfusions as described in “ an imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts .”, ( j pharmacol exp ther . 264 : 135 ( 1993 ); herein incorporated by reference . in brief , male sprague - dawley rats ( 0 . 3 - 0 . 35 kg ) were anesthetized with pentobarbital sodium ( 60 mg / kg ip ) and hearts were quickly excised , the aorta was cannulated and a retrograde perfusion at 37 ° c . was initiated at a hydrostatic pressure of 60 mm hg . hearts were trimmed of excess tissue , and the pulmonary artery and the opening to the left atrium were then cannulated . after 15 min of langendorff perfusion , hearts were switched to the working mode by clamping the aortic inflow line from the langendorff reservoir and opening the left atrial inflow line . the perfusate was delivered from an oxygenator into the left atrium at a constant preload pressure of 11 mm hg . perfusate was ejected from spontaneously beating hearts into a compliance chamber ( containing 1 ml of air ) and into the aortic outflow line . the afterload was set at a hydrostatic pressure of 80 mm hg . all working hearts were perfused with krebs &# 39 ;- henseleit solution containing calcium 2 . 5 mmol / l , glucose 5 . 5 mmol / l , 3 % bovine serum albumin ( fraction v , boehringer mannheim ), and with 1 . 2 mmol / l palmitate . palmitate was bound to the albumin as described previously ( saddik m ., et al . j biol . chem . 267 : 3825 - 3831 ( 1992 )). the perfusate was recirculated , and ph was adjusted to 7 . 4 by bubbling with a mixture containing 95 % o 2 and 5 % co 2 . for the aerobic model hearts , all tested compounds were introduced into the heart 5 minutes into the working mode following langendorff perfusion . spontaneously beating hearts were used in all perfusions . heart rate and aortic pressure were measured with a biopac systems inc . blood pressure transducer connected to the aortic outflow line . cardiac output and aortic flow were measured with transonic t206 ultrasonic flow probes in the preload and afterload lines , respectively . coronary flow was calculated as the difference between cardiac output and aortic flow . the o 2 contents of the perfusate entering and leaving the heart were measured using ysi ™ micro oxygen electrodes placed in the preload and pulmonary arterial lines , respectively . myocardial o 2 consumption ( mvo 2 ) was calculated according to the fick principle , using coronary flow rates and the arteriovenous difference in perfusate o 2 concentration . cardiac work was calculated as the product of systolic pressure and cardiac output . cardiac efficiency was defined as a ratio of cardiac work to mvo 2 . hearts that were subjected to global ischemia were initially aerobically perfused for 30 minutes , and then subjected to 30 minutes of global no flow ischemia by clamping the left atrial inflow line and the aortic outflow line . this was followed by 60 minutes of reperfusion , which was produced by removing the clamps from the left atrial inflow line and the aortic outflow line . all tested compounds were introduced into the perfusate five minutes prior to reperfusion . hearts that were subjected to a low flow demand ischemia were first perfused aerobically for 30 minutes then a low flow demand ischemia was induced by attenuating coronary flow with a diastolic backflow controller located in the aortic outflow line . using our low flow working rat heart model we are able to achieve a drop of approximately 50 % in coronary flow while still subjecting the hearts to the same afterload ( i . e . maintaining cardiac work ). all tested compounds were introduced into the perfusate five minutes into initiation of aerobic perfusion . glycolysis and glucose oxidation were measured simultaneously by perfusing hearts with [ 5 - 3 h / u - 14 c ] glucose ( liu h ., et al . am j physiol . 270 : h72 - h80 ( 1996 ); taegtmeyer het al . am j cardiol . 80 : 3a - 10a ( 1997 )). the total myocardial 3 h 2 o production and 14 co 2 production were determined at 10 minute intervals for the entirety of the aerobic period , 60 minutes for normal hearts and 30 minutes for the global ischemia and low flow demand ischemia models . in the global ischemia model , the total myocardial 3 h 2 o and 14 co 2 production were determined at 20 minute intervals for the 60 minute reperfusion period . in the low flow demand ischemia model , the total myocardial 3 h 2 o and 14 co 2 production were determined at 10 minute intervals for the 30 minute reperfusion period . glucose oxidation rates were determined by quantitative measurement of 14 co 2 production as described previously ( barbour r . l ., et al . biochemistr . 1923 : 6503 - 6062 ( 1984 )). effects of dca ( 2 mm ) on cardiac function and efficiency in normal hearts . as can be seen in table 1 treatment with dca had no significant effect on heart rate , peak systolic pressure or heart rate × peak systolic pressure ( hr × psp ). in table 2 , treatment with dca shows that there was no effect on any functional parameters , nor were there any differences in o 2 consumption or cardiac efficiency . as shown in fig1 , the na + / k + atpase inhibitor digoxin , when compared to control , did not show a significant increase in glucose oxidation rates ( 361 ± 43 vs 469 ± 111 respectively ). in addition , when compared to dca treated hearts , digoxin appears to attenuate the stimulatory effects of dca on glucose oxidation ( 1697 ± 179 vs 1314 ± 62 , respectively : fig1 ). in fig2 dca showed an increase in glycolysis when compared to control , but this increase was not significant ( 8 . 917 ± 3 . 060 vs . 3 . 430 ± 0 . 604 , respectively ). digoxin alone increased glycolytic rates when compared to control ( 5 . 651 ± 1 . 298 vs . 3 . 430 ± 0 . 604 , respectively ; fig2 ). digoxin with dca increased glycolytic rates when compared to control rates ( 9 . 028 , vs . 3 . 430 ± 0 . 604 , respectively ; fig2 ) and dca alone ( 9 . 028 vs . 8 . 917 ± 3 . 060 ; fig2 ). digoxin had no significant effect on any of the functional parameters shown in table 1 . when combined with dca , digoxin had a negative effect on peak systolic pressure when compared to control ( 121 ± 1 vs . 137 ± 5 , respectively ). table 2 shows that digoxin has a small but significant effect on aortic outflow when compared to control ( 31 ± 1 vs . 27 ± 1 , respectively ). treatment with digoxin and dca together returned the aortic out flow to control levels . however , when digoxin is used in conjunction with dca , cardiac work is significantly reduced when compared to control ( 53 ± 1 vs . 72 ± 10 , respectively ). as well , when compared to digoxin treatment alone , digoxin and dca together cause a significant decrease in cardiac work ( 67 ± 3 vs . 53 ± 1 , respectively ). although digoxin has no effect on cardiac metabolism , decreases in overall workload lead to a decrease in cardiac efficiency when digoxin is used along with dca in normal hearts . as will be seen in later examples contained herein , this decrease in efficiency is clearly absent in hearts subjected to global ischemic , with clear benefit to overall workload observed in hearts treated with dca and digoxin regardless of the decreased efficiency observed in aerobic models effects of diltiazem ( 0 . 8 μm ) and diltiazem ( 0 . 8 μm ) with dca ( 2 mm ) on glucose oxidation , glycolysis , cardiac function and efficiency in normal hearts . diltiazem is a ca 2 + channel blocker . fig3 shows that when compared to control hearts , diltiazem caused a significant decrease in the rates of glucose oxidation ( 361 ± 43 vs 175 : 1 ± 24 respectively ). when hearts were treated with diltiazem and dca together , the effect of diltiazem alone on glucose oxidation was blocked and a significant increase in glucose oxidation was seen when compared to control ( 1737 ± 237 vs . 361 ± 63 ; fig3 ). though , this increase in glucose oxidation was no different than treating the hearts with dca alone ( 1737 ± 264 vs . 1526 ± 79 ; fig3 ). diltiazem alone also had an effect on glycolytic rates when compared to control ( 0 . 727 ± 0 . 160 vs . 3 . 430 ± 0 . 604 , respectively ; fig4 ). diltiazem and dca together result in an attenuation of the effect of dca alone ( 6 . 865 ± 0 . 887 vs . 8 . 917 ± 3 . 060 , respectively ; fig4 ). as well . dca was able to overcome the attenuating effects of diltiazem . treatment with diltiazem caused a significant decrease in heart rate when compared to control ( 202 ± 3 vs . 239 ± 12 , respectively ; table 1 ). as well , a significant decrease in hr × psp was observed ( 25 ± 1 vs . 32 ± 1 , respectively ; table 1 ). when treated with diltiazem and dca , these functional parameters are returned to control levels ( table 1 ). as shown in table 2 , diltiazem caused a significant decrease in aortic outflow when compared to controls ( 21 ± 1 vs 27 ± 1 , respectively ). though significant , a decrease in cardiac work was observed when comparing diltiazem treated hearts to control hearts ( 51 ± 1 vs . 72 ± 10 ). the calcium channel blocker diltiazem , has the ability to block the influx of ca 2 + into muscle cell and therefore prevents contraction . diltiazem causes a reduced heart rate as well as a decrease in cardiac work . the overall effect of diltiazem is a reduction in the functional performance of the heart , resulting in a concommitment drop in metabolism . when hearts are treated with dca and diltiazem together the inhibitory effects of diltiazem on metabolism are prevented and functional decreases seen with diltiazem are reversed . effects of dobutamine ( 1 μm ) and dobutamine ( 1 μm ) with dca ( 2 mm ) on glucose oxidation , glycolysis , cardiac function and efficiency in normal hearts . dobutamine is a β 1 - adrenoreceptor agonist ( catecholamine ). when compared to control , there is a large and significant increase in glucose oxidation ( 361 ± 43 vs 1707 ± 435 , respectively ; fig5 ). the effects of dobutamine on glucose oxidation mirrored that of dca , but no significant additive effect was seen when the hearts were treated with dca and dobutamine ( 1697 ± 179 vs . 2105 ± 232 , respectively ; fig5 ). when compared to control , dobutamine treated hearts resulted in a large and significant increase in glycolysis ( 3 . 430 ± 0 . 604 vs . 13 . 365 ± 1 . 981 , respectively fig6 ). the effects of dobutamine on glycolysis mirrored those of dca , but no additive effect was seen when the hearts were treated with dca and dobutamine ( 8 . 917 ± 3 . 060 vs . 7 . 187 ± 2 . 163 , respectively ; fig6 ). in table 1 , dobutamine is shown to increase heart rate when compared to controls . ( 333 ± 7 vs . 239 ± 12 , respectively ). as well , hr × psp increased significantly in the dobutamine treated group versus control ( 40 ± 2 vs . 32 ± 2 , respectively ). treatment with dca and dobutamine together , show no different effect on the functional parameters shown in table 1 , than treatment with dobutamine alone . table 2 shows that treatment with dobutamine alone has no significant effect on the functional parameters shown . though , when dobutamine is used in conjunction with dca , a significant increase in o 2 consumption is observed and a decrease in cardiac efficiency is observed as well . while dobutamine was able to stimulate glucose oxidation it also increased glycolysis that would result in an increase in overall workload . in the presence of dca and dobutamine , this uncoupling of glycolysis from glucose metabolism was attenuated and could lead to a decrease of h + production and beneficial effect to the patient . increased oxygen consumption results in a decrease in cardiac efficiency , though this is balanced with the observed increase in cardiac work . effects of metoprolol ( 1 μm ) and metoprolol ( 1 μm ) with dca ( 2 mm ) on glucose oxidation , glycolysis , cardiac function and efficiency in normal hearts . metoprolol is a β 1 - adrenoreceptor antagonist . its effect on glucose oxidation , when compared to control , was insignificant ( 361 ± 43 vs . 651 ± 222 respectively ; fig7 ). when combined with dca , a trend was seen towards the attenuation of the effects of dca on glucose oxidation , but this trend was not significant ( 1297 ± 40 vs . 1697 ± 179 , respectively ; fig7 ). the effect of metoprolol on glycolysis when compared to control was insignificant ( 3 . 430 ± 0 . 604 vs . 4 . 530 ± 0 . 876 respectively ; fig8 ). when combined with dca , there was also no change when comparing dca treatment and dca with metoprolol ( 8 . 917 ± 3 . 060 vs . 8 . 022 + 1 . 132 respectively ; fig8 ) table 1 and table 2 show that metoprolol had no significant effect on any of the functional parameters shown . however , when metoprolol is used in combination with dca , coronary flow and cardiac work significantly reduced . effects of digoxin ( 3 nm ) and digoxin ( 3 nm ) with dca ( 2 mm ) on glucose oxidation , glycolysis , cardiac function and efficiency in hearts subjected to global ischemia . the effects of the na +/ k + atpase inhibitor digoxin in combination with dca on post - ischemic hearts was determined . as shown in table 1 and table 2 , all functional attributes measured are depressed during the reperfusion period when compared to the pre - ischemic aerobic values . however when compared to the control values during , the reperfusion period , the addition of dca , digoxin , or digoxin with dca appear to significantly improve both cardiac function and cardiac efficiency . when compared to the control values during the reperfusion period , the addition of dca , digoxin , or digoxin with dca appears to significantly improve cardiac function and cardiac efficiency . as shown in fig9 , dca appears to have significantly higher glucose oxidation rates when compared to either the aerobic control , reperfused control , or digoxin alone . the combination of digoxin and dca appears to enhance the ability of dca to improve glucose oxidation rates and is significantly higher than dca alone . as shown in fig1 , neither dca , digoxin , nor digoxin with dca altered glycolytic rates as compared to control . as shown in fig1 , dca , digoxin , or digoxin with dca significantly improves the recovery of cardiac function of previously ischemic hearts , when compared to the recovery of control hearts during the reperfusion period . as shown in fig1 , dca , digoxin , or digoxin with dca appear to significantly improve the recovery of cardiac work of previously ischemic hearts when compared to the recovery of control hearts during the reperfusion period . as shown in fig1 , dca , digoxin , or digoxin with dca significantly improve the recovery of oxygen consumption of previously ischemic hearts when compared to the recovery of control hearts during the reperfusion period . as shown in fig1 , dca , digoxin , or digoxin with dca significantly improve the recovery of cardiac efficiency of previously ischemic hearts , when compared to the recovery of control hearts during the reperfusion period . effects of metoprolol ( 1 μm ) and metoprolol ( 1 μm ) with dca ( 2 mm ) on glucose oxidation , glycolysis , cardiac function and efficiency in hearts subjected to global ischemia . the β 1 - adrenoreceptor antagonist metoprolol and metoprolol with dca significantly improved functional parameters of the hearts during the reperfusion period , compared to control ( table 1 , table 2 ). as shown in fig1 , the metoprolol had no effect on glucose oxidation rates during the reperfusion period . dca or the combination of metoprolol with dca appeared to have significantly increased glucose oxidation rates when compared to either metoprolol or control during both the aerobic and reperfusion periods . as can be seen in fig1 , neither dca , metoprolol or metoprolol with dca altered glycolytic rates as compared to control as shown in fig1 , dca appears to significantly improve the recovery of cardiac function of previously ischemic hearts when compared to the recovery of control hearts during the reperfusion period . however , metoprolol or the combination of metoprolol with dca does not change cardiac function as compared to control . as shown in fig1 , dca , metoprolol , or metoprolol with dca appear to significantly improve the recovery of cardiac work of previously ischemic hearts when compared to the recovery of control hearts during the reperfusion period . however the combination of dca with metoprolol did not show an additive effect when compared to dca alone . there does not appear to be significant differences with respect to recovery of oxygen consumption of previously ischemic hearts between dca , metoprolol , or metoprolol with dca ( fig1 ). as shown in fig2 , dca or metoprolol with dca appear to significantly improve the recovery of cardiac efficiency of previously ischemic hearts when compared to the recovery of control hearts during the reperfusion period . however , metoprolol alone does not . as well the combination of dca with metoprolol did not show an additive effect when compared to dca alone . effects of diltiazem ( 0 . 8 μm ) and diltiazem ( 0 . 8 μm ) with dca ( 2 mm ) on glucose oxidation , glycolysis , cardiac function and efficiency in hearts subjected to low flow demand ischemia . as shown in table 1 , the presence of diltiazem decreased peak systolic pressure as compared to control . dca with diltiazem increased peak systolic pressure as compared to dca , diltiazem , or dca with diltiazem ( table 1 ). similar increases were observed for dca with diltiazem in cardiac output , aortic outflow and coronary flow as compared to control and dca or diltiazem alone ( table 2 ). as shown in fig2 , diltiazem did not appear to interfere with the ability of dca to increase glucose oxidation in either the aerobic or low - flow ischemic perfusions . there did appear to be some attenuation of glycolysis by diltiazem alone , or with dca in both aerobic and low - flow ischemic perfusions ( fig2 ). neither diltiazem , dca , nor dca with diltiazem significantly affected cardiac function in the low - flow ischemic period ( fig2 ). dca with diltiazem significantly increased cardiac work ( fig2 ) and decreased oxygen consumption ( fig2 ); thereby significantly increasing cardiac efficiency ( fig2 ) compared to control , dca and diltiazem alone . effects of metoprolol ( 1 μm ) and metoprolol ( 1 μm ) with dca ( 2 mm ) on glucose oxidation , glycolysis , cardiac function and efficiency in hearts subjected to low flow demand ischemia . as shown in table 2 , the addition of metoprolol with dca caused a significant increase in aortic outflow and cardiac output as compared to control , metoprolol , or dca alone . compared to control there was no significant increase observed in coronary outflow ( table 2 ), heart rate ( table 1 ) or peak systolic pressure ( table 1 ) following the addition of dca , metoprolol , or dca with metoprolol . the decrease observed in peak systolic pressure observed in dca and metoprolol was not compounded by simultaneous addition of the compounds together ( table 1 ). the presence of metoprolol does not appear to attenuate the increase in glucose oxidation observed with dca alone ( fig2 ) either in low - flow ischemic or aerobic conditions , nor are there significant changes observed to glycolysis in low - flow ischemic conditions ( fig2 ). there are no significant changes to cardiac function ( fig2 ), cardiac work ( fig3 ), or oxygen consumption observed with addition of dca , metoprolol , or dca with metoprolol ; as compared to control ( fig3 ); though there is an observed increase in cardiac efficiency for dca with metoprolol during low - flow ischemic conditions as compared to control ( fig3 ). metabolic modulators , such as dca , can be used to shift the metabolism of the heart away from fatty acids oxidation and towards glucose oxidation . this shift has been shown to be beneficial during periods of cardiac stress such as angina , myocardial infarction or post - cardiac surgery . we sought to determine if the metabolic effects of using dca are maintained in the presence of other cardioprotective or hemodynamic classes of drugs such as inotropic drugs ( including digoxin and dobutamine ), beta - blockers and calcium channel blockers . isolated perfused working rat hearts were perfused in the presence of 5 . 5 mm glucose and 1 . 2 mm palmitate . glucose oxidation and glycolysis were measured using { 5 - 3 h / u - 14 - 14 c ] glucose . in the aerobic model , the addition of dca resulted in an increase in glucose oxidation of over 400 %, while glycolysis increased over 300 %. digoxin and metoprolol showed no additive metabolic effect when used with dca , nor did they have any metabolic effect when used alone . diltiazem caused glucose metabolism to decrease when compared to control . dca was able to overcome this effect when used with diltiazem . dobutamine was able to increase glucose metabolism by almost 400 %, but had no synergistic effect when combined with dca . when used in conjunction with dca neither digoxin , dobutamine , metoprolol , nor diltiazem were able to increase the effect that dca alone had on metabolism . in addition , digoxin , metoprolol , diltiazem and dobutamine did not have any adverse effects on dca &# 39 ; s ability to increase glucose oxidation or glycolysis . in aerobic perfusions , digoxin in combination with dca has been - shown to lower overall cardiac work with concomitant drop in cardiac efficiency . however , in our ischemia / reperfusion model , which mimics an ischemic event such as myocardial infarction and reperfusion , the combination of digoxin and dca proved to be significantly beneficial as a synergistic combination to the recovery of cardiac work , cardiac efficiency and glucose oxidation . this suggests that digoxin in combination with dca could be beneficial in post myocardial infarction followed by reperfusion or percutaneous coronary intervention ( angioplasty ) or during cardiac bypass surgery and open heart surgical procedures . in aerobically perfused hearts , diltiazem causes an overall decrease in cardiac work and glucose metabolism . in our low flow ischemia model ( which mimics angina ), diltiazem has the same effect . this decrease in cardiac work with a maintenance of oxygen consumption led to a decrease in overall cardiac efficiency , both during the aerobic period and during low flow ischemia . however , the combination of diltiazem and dca led to a reversal of these functional and metabolic decreases with a significant improvement in cardiac work , cardiac efficiency and glucose oxidation . as well , the combination of dca and diltiazem is synergistic in combination and is more efficacious than dca alone , with respect to maintenance of cardiac efficiency during low flow ischemia events such as angina . as seen in the aerobic model , metoprolol alone has no effect on glucose oxidation , nor does it alter any functional parameters in aerobically perfused hearts . while metoprolol alone has a beneficial effect on recovery of previously ischemic hearts , the combination of metoprolol and dca significantly improves recovery beyond that of the control hearts and beyond that of metoprolol alone , with respect to cardiac function . using our low flow ischemia model . dca and metoprolol appear to show a marked improvement in cardiac efficiency when compared to control during the low flow ischemic period . in addition , the combination of metoprolol and dca significantly improve cardiac efficiency above that of control and dca or metoprolol alone during the low flow ischemic period . this suggests that metoprolol with dca is synergistic with respect to improving cardiac efficiency in treating ischemic conditions such as post myocardial infarction and heart failure . taken together , this data shows that dca is able to significantly increase glucose metabolism and maintain function the presence of dobutamine , digoxin , diltiazem and metoprolol , thereby ameliorating the negative side effects of these drugs and drug classes . furthermore the data indicates that dca is synergistic with metoprolol , diltiazem and digoxin with respect to improving cardiac efficiency . 1 lopaschuk g . d ., wambolt r . b ., harr r . l . an imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts . 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( 1997 ) am j cardiol . 80 : 3a - 10a . 22 barbour r . l ., sotak c . h ., levy g . c ., chan s . h . use of gated perfusion to study early effects of anoxia on cardiac energy metabolism : a new 31 pnmr method . ( 1984 ) biochemistr . 1923 : 6503 - 6062 .