Myocardial High-energy Phosphate Stores Research Articles

Improvement of Cardiac Function and Subcellular Defects Due to Chronic Diabetes upon Treatment with Sarpogrelate.

In order to investigate the subcellular mechanisms underlying the beneficial effects of sarpogrelate-a 5-HT2A receptor antagonist-on diabetic cardiomyopathy, diabetes was induced in rats by injecting streptozotocin (65 mg/kg). Diabetic animals were treated with or without sarpogrelate (5 mg/kg daily) for 6 weeks; diabetic animals were also treated with insulin (10 units/kg daily) for comparison. Elevated plasma levels of glucose and lipids, depressed insulin levels, hemodynamic alterations and cardiac dysfunction in diabetic animals were partially or fully attenuated by sarpogrelate or insulin treatment. Diabetes-induced changes in myocardial high-energy phosphate stores, as well as depressed mitochondrial oxidative phosphorylation and Ca2+-uptake activities, were significantly prevented by these treatments. Reductions in sarcolemma Na+-K+ ATPase, Na+-Ca2+ exchange, Ca2+-channel density and Ca2+-uptake activities were also attenuated by treatments with sarpogrelate and insulin. In addition, decreases in diabetes-induced sarcoplasmic reticulum Ca2+-uptake, Ca2+-release and Ca2+-stimulated ATPase activities, myofibrillar Mg2+-ATPase and Ca2+-stimulated ATPase activities, and myosin Mg2+-ATPase and Ca2+-ATPase activities were fully or partially prevented by sarpogrelate and insulin treatments. Marked alterations in different biomarkers of oxidative stress, such as malondialdehyde, superoxide dismutase and glutathione peroxidase, in diabetic hearts were also attenuated by treating the animals with sarpogrelate or insulin. These observations suggest that therapy with sarpogrelate, like that with insulin, may improve cardiac function by preventing subcellular and metabolic defects as a consequence of a reduction in oxidative stress.

Evaluation of the anti-ischemic effects of D-ribose during dobutamine stress echocardiography: a pilot study

D-Ribose, a pentose sugar, has shown to improve myocardial high-energy phosphate stores depleted by ischemia. This study investigated the ability of D-Ribose with low dose dobutamine to improve the contractile response of viable myocardium to dobutamine and to assess the efficacy of D-ribose in reducing stress-induced ischemia. Twenty-six patients with ischemic cardiomyopathy completed a two-day, randomized, double blind crossover trial comparing the effects of D-Ribose and placebo on regional wall motion. On the first study day, either D-Ribose or placebo was infused for 4.5 hours. Low (5 and 10 μ/kg/min) and subsequently, high (up to 50 μ/kg/min) dose dobutamine echocardiography was then performed. On the second study day, patients crossed over to the alternative article for a similar 4.5 hours infusion time period and underwent a similar evaluation. The wall motion response during low dose dobutamine was the same with D-Ribose and placebo in 77% of segments (203/263, Kappa = 0.37). In segments with discordant responses, more segments improved with D-Ribose than with placebo (41 vs. 19 segments, p = 0.006). With high dose dobutamine infusion, the wall motion response (ischemia vs. no ischemia) was the same with D-Ribose and placebo in 83% of interpretable segments (301/363, kappa = 0.244). In segments with discordant responses, there were more ischemic segments with placebo compared to D-Ribose (36 vs. 26, p = 0.253). Nineteen patients developed ischemia during the dobutamine and placebo infusion and 13 patients had ischemia during dobutamine and D-ribose infusion (p = 0.109). D-Ribose improved contractile responses to dobutamine in viable myocardium with resting dysfunction but had no significant effect in reducing the frequency of stress-induced wall motion abnormalities.

Supranormal Myocardial Creatine and Phosphocreatine Concentrations Lead to Cardiac Hypertrophy and Heart Failure

Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT). We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66+/-6 nmol/mg protein in WT versus 133+/-52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5+/-4.3 microL in WT versus 33.1+/-9.6 microL in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64+/-9% in WT versus 49+/-13% in CrT-OE; range, 22% to 70%; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=-0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dt(max) (r=-0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels. Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.

Left ventricular myocardial adenosine triphosphate changes during reperfusion of ventricular fibrillation: the influence of flow and epinephrine.

To determine whether epinephrine in combination with high flow worsens left ventricular (LV) myocardial high-energy phosphate stores during reperfusion of ischemic ventricular fibrillation (VF). Blinded, prospective block randomized, placebo controlled study. University medical center research laboratory. A total of 22 mixed breed swine weighing 22.0+/-3.3 kg (SD). Open-chest swine, anesthetized with alpha-chloralose, underwent 10 mins of nonperfused VF followed by reperfusion with cardiopulmonary bypass for 90 mins and then defibrillation. Animals were block randomized to four groups for reperfusion: Group 1 (n = 5), high flow (100 mL/kg/min) and epinephrine (2.5 microg/kg/min); Group 2 (n = 5), high flow and placebo; Group 3 (n = 6), low flow (30 mL/kg/min) and epinephrine; and Group 4 (n = 6), low flow and placebo. In vivo LV creatine phosphate (CP) and adenosine triphosphate (ATP) were determined using whole wall and spatially localized 31P NMR spectroscopy at 4.7 Tesla. During perfusion of the fibrillating myocardium, epinephrine significantly increased aortic pressure (p < .05) and improved defibrillation rates (p < .01). ATP levels during reperfusion were significantly decreased within all groups compared with baseline. There were no differences in ATP levels between groups. High flow, independent of epinephrine, was associated with increased preservation of ATP (p < .05), increased CP/ATP ratios (p < .02) in all layers of the LV wall, and decreased aortic and cardiac vein lactates (p < .001). Epinephrine, in combination with flow higher than standard cardiopulmonary resuscitation flows, increased perfusion pressure and defibrillation rates, but did not significantly alter myocardial ATP during VF reperfusion in the in vivo heart Reperfusion flow, independent of epinephrine, is a critical determinant of myocardial ATP preservation.

Myocardial High-Energy Phosphates and Hepatic Redox State in Jaundiced Rats

Background.The mechanism underlying the fatal complications in jaundiced states after shock has not been fully clarified. The present study was designed to examine the effect of hemorrhagic shock on myocardial high-energy phosphate stores and the arterial ketone body ratio (AKBR:acetoacetate/β-hydroxybutyrate), which reflects the redox state of the liver mitochondria, in normal and jaundiced rats.Materials and methods.At 1 week after ligation of the common bile duct, hemorrhagic shock was induced by exsanguination (mean arterial blood pressure = 40 mmHg) and maintained for 2 h. Serial changes in AKBR were measured. The myocardial adenine nucleotides phosphocreatine (PCr) and inorganic phosphate (Pi) were determined before and after hemorrhagic shock.Results.Before shock, myocardial ATP in the jaundiced group was lower than that in the sham group. However, the myocardial PCr levels in the two groups did not differ. After reinfusion of the shed blood, ATP and PCr recovered to the preshock levels in the sham group. However, ATP and PCr were further increased in the jaundiced group. At 60 min after reinfusion, AKBR recovered to the normal level in the sham group, but decreased below 0.7 in the jaundiced group. Metabolic acidosis was more severe in the jaundiced group than in the sham group.Conclusions.The decrease in AKBR indicated irreversible metabolic acidosis. As a result, fatal circulatory failure occurred, although the phosphoenergetic level in the myocardium was sufficiently maintained.

Regression of a dilated cardiomyopathy after radiofrequency ablation of incessant supraventricular tachycardia

Incessant supraventricular tachycardia has been demonstrated to result in a dilated cardiomyopathy in both animal models and humans. l-3 The phenomenon occurs in the absence of preexisting cardiac abnormalities. Termination of the tachycardia may lead to regression of myocardial dysfunction and normalization of left ventricular volume and systolic function. 1-4 The precise mechanisms responsible for the tachycardia-induced cardiomyopathy have not been elucidated. Hypotheses include depletion of myocardial high-energy phosphate stores, altered myocardial sarcoplasmic reticulum calcium ion transport,?, 6 abnormalities of myocardial blood flo~,~ and alterations in the myocardial capillary vasculature.8 We present a patient with an incessant supraventricular tachycardia and dilated cardiomyopathy who underwent successful radiofrequency catheter ablation of an atrioventricular nodal reentry pathway and regained normal biventricular volume and systolic function within a 3-week period. A 49-year-old woman with a history of chronic obstructive lung disease arrived at the emergency department in respiratory distress. Three weeks before presentation, the patient underwent a presurgical evaluation for an otolaryngologic procedure. At that time examination revealed an elevated pulse, and an electrocardiogram displayed a supraventricular tachycardia at a rate of 150 beats/min. The patient denied palpitations and reportedly was “asymptomatic,” so ther,apy was not initiated. Ten days later she was reevaluated by her primary care physician and, despite persistence of the tachycardia, continued to be “asymptomatic.” Several laboratory studies were ordered, and the patient was instructed to return in 2 weeks. During the interim, she had progressive dyspnea, orthopnea, and fatigue, and sought medical assistance.

Reperfusion of hibernating myocardium: Contractile function, high-energy phosphate content, and myocyte injury after 3 hours of sublethal ischemia and 3 hours of reperfusion in the canine model

Hibernating myocardium has been defined as a persistent impairment of contractile function resulting from reduced coronary blood flow that can be partially or completely resolved once coronary perfusion is restored. In fact, recent clinical reports have documented a dramatic improvement in contractile function after relief of chronic sublethal ischemia. To investigate the phenomenon of sublethal ischemia followed by reperfusion, we assessed myocyte morphology, high-energy phosphate content, and regional contractile function in dogs undergoing (1) 3 hours of subtotal coronary artery occlusion (CO) and 3 hours of reflow or (2) 3 hours of total CO followed by reflow, in which myocyte viability was maintained by extensive collateral perfusion during ischemia (total CO/negligible necrosis). Data were compared with findings in a third group of dogs with total CO and low collateral blood flow during ischemia, in which large confluent infarcts developed. Endocardial blood flow averaged 30 ± 6% ( p < 0.01) and 27 ± 4% ( p < 0.01) of baseline preocclusion values during ischemia in the groups with subtotal CO and total CO/negligible necrosis, versus 3 ± 1% of baseline values in dogs with total CO/confluent necrosis. Both the subtotal CO and total CO/negligible necrosis groups exhibited only mild-to-moderate reversible myocyte injury (assessed by electron microscopy) and had essentially no necrosis: infarct size was 1 ± 1% ( p < 0.01) and 4 ± 2% ( p < 0.01) of the risk region in the subtotal CO and total CO/negligible necrosis groups, versus 55 ± 9% of the risk region in the total CO/confluent necrosis group. Furthermore, myocardial high-energy phosphate stores were in part preserved in all dogs that underwent sublethal ischemia: endocardial adenosine triphosphate (ATP) content was 55 ± 11% ( p < 0.01) and 56 ± 8% ( p < 0.01) versus 11 ± 2% of baseline values in the subtotal CO, total CO/negligible necrosis, and total CO/confluent necrosis groups, respectively. At 3 hours post occlusion, segment shortening averaged +21 ± 10% of baseline values in dogs with subtotal CO, ( p <0.01 versus both total CO groups), −29 ± 9% in dogs with total CO/negligible necrosis, and −36 ± 13% in dogs with total CO/confluent necrosis. Reperfusion after sublethal ischemia produced an acute improvement in contractile function in both the subtotal CO and total CO/negligible necrosis groups. This functional rebound was short lived, however; by 3 hours after reflow, segment shortening had deteriorated to values that did not differ from those measured during ischemia (+20 ± 15% and −24 ± 5% of baseline values in dogs with subtotal CO and total CO/negligible necrosis, respectively). Thus a 3-hour episode of sublethal ischemia in this canine model results in a reduction in contractile function during hypoperfusion associated with preserved myocardial high-energy phosphate stores and prevention of myocyte necrosis. However, in contrast to some clinical reports, reperfusion after sublethal ischemia was not associated with a dramatic improvement in contractile function. Rather the postischemic dysfunction, partial preservation of ATP stores, and creatine phosphate overshoot observed after relief of sublethal ischemia suggest that this previously hypoperfused but viable tissue is stunned during the initial hours after reflow.

EFFECT OF LIGNOCAINE ON CORONARY BLOOD FLOW, SYSTOLIC MYOCARDIAL FUNCTION AND MYOCARDIAL HIGH ENERGY PHOSPHATE STORES IN SWINE

1. To investigate the effect of lignocaine upon coronary blood flow, myocardial systolic wall function and high energy phosphate stores, lignocaine was administered as a rapid intravenous injection to 14 open chest anaesthetized swine. 2. Before and after injection, measurements were made of coronary blood flow by electromagnetic flow probe, per cent wall thickening by ultrasonic crystals, adenosine triphosphate (ATP) and creatine phosphate (CP) content by myocardial biopsy, and arterial pressure by central aortic catheter. The animals were divided into two groups based on whether or not they received a continuous low-dose infusion of lignocaine prior to the study. Group I received the continuous low-dose infusion of lignocaine and group II did not. 3. With a 2 mg/kg lignocaine injection, peak diastolic coronary flow rose significantly in groups I and II by 27 +/- 7 and 29 +/- 7% respectively. This was followed by a significant decline in per cent wall thickening in groups I and II of -11 +/- 2 and -19 +/- 6% respectively. In group I myocardial CP content decreased after lignocaine injection by 58 +/- 6% and ATP tended to rise even though systolic and diastolic pressure did not change significantly. In group II neither CP nor ATP changed significantly, but systolic and diastolic blood pressure decreased significantly. 4. Repeat lignocaine injections were given over a wider dosage range (0.5-4.0 mg/kg) to determine dose-response for lignocaine versus coronary blood flow. Coronary blood flow increased and per cent wall thickening decreased as doses of lignocaine were increased. 5. It was concluded that rapid intravenous lignocaine injection appeared to cause a dose-dependent coronary dilatation and systolic dysfunction. Pre-treatment with low-dose continuous infusion of lignocaine appeared to result in a decrease in CP and a rise in ATP when compared with no pre-treatment--despite a similar effect on myocardial function and coronary blood flow.

Changes in myocardial high-energy phosphate stores and carbohydrate metabolism during intermittent aortic crossclamping in dogs on cardiopulmonary bypass at 34° and 25° C

The effect of cooling to 25 degrees C on myocardial metabolism was studied during four periods of global ischemia (10 minutes each) followed by 15 minutes of reperfusion in dogs on cardiopulmonary bypass. Systemic and heart temperature at normothermia (group N, 34 degrees C; n = 15) was compared with general hypothermia (group H, 25 degrees C; n = 16). Before and at the end of each aortic crossclamp period in small myocardial biopsy specimens the adenosine triphosphate, creatine phosphate, inorganic phosphate, glycogen, and lactate content was analyzed. Also, lactate and inorganic phosphate were measured in the coronary effluents during the repetitive periods of reperfusion. Hemodynamic function was not different at 60 minutes after cardiopulmonary bypass compared with pre-cardiopulmonary bypass values, and was not different between the groups N and H. The tissue content of adenosine triphosphate and glycogen decreased progressively during the experimental period, resulting in slightly depressed values in both groups at the end of cardiopulmonary bypass. Pronounced effects of ischemia and reperfusion on tissue content of creatine phosphate, inorganic phosphate, and lactate were observed after each period of ischemia. The net decrease in tissue creatine phosphate content was not different between groups N and H (41 +/- 4 versus 38 +/- 4 mumol.gm-1 dry weight; mean +/- standard error of the mean) after 10 minutes of ischemia. However, during ischemia the net inorganic phosphate increase in myocardial tissue was significantly higher in group H (70 +/- 7 mumol.gm-1) than in group N (44 +/- 3 mumol.gm-1). These findings do not support the notion that myocardial protection is improved during hypothermia. Moreover, quantitatively the release of inorganic phosphate and lactate did not correlate with the amount accumulated in the myocardial tissue during the preceding periods of ischemia. The release appeared to be temperature dependent, that is, significantly reduced at 25 degrees C. The present data demonstrate why clinical outcome is satisfactory in both surgical procedures, when in general the periods of aortic crossclamping do not exceed 10 minutes each and the reperfusion periods in between the ischemic episodes last about 15 minutes. Besides, the findings indicate that hypothermia is not strictly necessary under these circumstances.

In vivo infusion of oxygen free radical substrates causes myocardial systolic, but not diastolic dysfunction

Contractile dysfunction of viable, previously ischemic stunned myocardium is thought to be due to reactive oxygen species generated during ischemia/reperfusion. Direct in vivo evidence that oxidants cause systolic or diastolic dysfunction of viable myocardium has, however, been lacking. We sought to determine whether in vivo exposure of canine myocardium to exogenously generated reactive oxygen species could--in the absence of myocardial ischemia or necrosis--"mimic" the depressed systolic contractile function, paradoxical contraction during early diastole, and prolonged diastolic relaxation time characteristic of stunned myocardium. Anesthetized open-chest dogs were randomly assigned to receive either (1) the free radical generating substrates xanthine oxidase + purine + iron-saturated transferrin or (2) saline, infused directly into an anterior coronary vein. Infusion of free radical substrates did not cause ischemia: regional myocardial blood flow and myocardial high-energy phosphate stores were normal in both groups. Furthermore, infusion of xanthine oxidase + purine + transferrin was not associated with histologic or electron microscopic evidence of myocyte injury or death in this model. Xanthine oxidase + purine + transferrin did, however, produce marked abnormalities in regional systolic contractile function; at 2 hours after the onset of infusion, segment shortening (assessed by sonomicrometry) in the perfused region of the heart averaged 62 +/- 5% of baseline, preinfusion values in animals infused with free radical substrates versus 113 +/- 8% of baseline values in saline-administered control dogs (p less than 0.004). This systolic dysfunction was effectively reversed by administration of the free radical scavenging agents superoxide dismutase + catalase.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of triiodothyronine (T3) on myocardial high energy phosphates and lactate after ischemia and cardiopulmonary bypass: An experimental study in baboons

Cardiopulmonary bypass is associated with a reduction in plasma free triiodothyronine in patients undergoing cardiac operations. A previous experimental study in pigs demonstrated a marked inotropic effect when triiodothyronine was administered after a period of myocardial ischemia and cardiopulmonary bypass; this was associated with a significant reduction in mortality compared with the mortality in control pigs. To clarify the effect of triiodothyronine on myocardial high energy phosphate stores and lactate, a series of experiments was done in baboons undergoing 3 hours of myocardial ischemia while supported by cardiopulmonary bypass. Seven baboons received no triiodothyronine and six received 6 micrograms of triiodothyronine at the end of the ischemic period. Seventy minutes after cardiopulmonary bypass, the myocardial adenosine triphosphate level was significantly higher (p less than 0.01) in the treated animals. In untreated animals, a steady increase in myocardial lactate occurred after cardiopulmonary bypass; by 120 minutes after ischemia (70 minutes after cardiopulmonary bypass) there was a significant difference in lactate levels between the two groups (p less than 0.01). We postulate that a combination of global ischemia and depletion of triiodothyronine results in reduced mitochondrial function, inhibition of the tricarboxylic acid cycle, and increased anaerobic metabolism and depletion of myocardial phosphates. Triiodothyronine replacement therapy leads to improved mitochondrial function and increased aerobic metabolism, which results in increased synthesis of myocardial phosphates. We suggest that there may be a place for the administration of triiodothyronine in patients undergoing cardiac operations with a prolonged myocardial ischemic period or in whom there is any evidence of low cardiac output after discontinuation of cardiopulmonary bypass.

Protection of the immature myocardium: An experimental evaluation of topical cooling, single-dose, and multiple-dose administration of St. Thomas’ Hospital cardioplegic solution

Low cardiac output in infants after cardiac operations continues to be a problem, yet little experimental work has been done to evaluate the various methods of protecting the immature myocardium. In this study, we have used an isolated working heart model to test three methods of myocardial protection in 3- to 4-week-old rabbit hearts: (1) topical cooling, (2) single-dose cardioplegia plus topical cooling, and (3) multiple-dose cardioplegia plus topical cooling. Myocardial temperature was maintained at 10 degrees C during ischemia, and St. Thomas' Hospital solution was used for cardioplegia. Sets of 18 hearts were subjected to 60, 90, or 120 minutes of ischemia, and within each set six hearts were protected by all three methods. After 90 and 120 minutes of ischemia, the percent recovery of aortic flow (expressed as mean +/- standard error of the mean) was lower in hearts protected with multiple-dose cardioplegia plus topical cooling (61.5% +/- 4.8%, 50.7% +/- 14.2%) than in those protected with topical cooling (92.4% +/- 5.7%, 94.3% +/- 12.8%) or single-dose cardioplegia plus topical cooling (86.4% +/- 5.3%, 90.2 +/- 3.6%). However, adenosine triphosphate, creatine phosphate, and glycogen levels were adequately preserved in all groups. Both topical cooling and single-dose cardioplegia provide effective protection for the immature rabbit heart during ischemia, but multiple-dose cardioplegia plus topical cooling results in inadequate preservation of hemodynamic function, despite adequate preservation of myocardial high-energy phosphate stores.

Correlation of contractile dysfunction with oxidative energy production and tissue high energy phosphate stores during partial coronary flow disruption in rabbit heart.

The relationships between contractile function, myocardial oxygen consumption, and tissue high energy phosphate and lactate content were investigated during partial coronary flow disruption. The experimental preparation was an isolated, isovolumic retrograde blood-perfused rabbit heart. Both developed pressure (r = 0.94) and dp/dt (r = 0.95) exhibited strong linear correlations with myocardial oxygen consumption that were stable for up to 45 min after blood flow reduction. In contrast, tissue high energy phosphate content exhibited nonlinear relationships with both developed pressure and oxygen consumption such that systolic mechanical function and oxidative metabolism declined to 20 and 30% of control values, respectively, before significant abnormalities in myocardial high energy phosphate stores were observed. Similarly, developed pressure and oxygen consumption decreased to 36 and 48% of control, respectively, before abnormal tissue lactate content was detected. The results of this study indicate that: (a) mechanical function is closely related to the rate of oxidative energy production during partial coronary flow disruption, and (b) despite the development of significant contractile dysfunction, tissue high energy phosphate content remains at normal levels except under the most severely flow-deprived conditions. The preservation of tissue energy stores can be explained by the apparent coupling of contractile performance to oxidative energy production, which could function to maintain myocardial energy balance during partial coronary flow restriction.

Beneficial effects of verapamil in diabetic cardiomyopathy.

It has been suggested that the occurrence of an intracellular Ca2+ overload may result in the development of diabetic cardiomyopathy, which is associated with depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction. Accordingly, the effects of verapamil, a Ca2+ antagonist, on cardiac function, ultrastructure, and high-energy phosphate stores in the myocardium were evaluated in rats made diabetic by an intravenous injection of streptozocin (65 mg/kg). Four weeks after the induction of diabetes, the animals were treated with three doses (2, 4, or 8 mg.kg-1.day-1) of verapamil for 4 wk until they were used for the measurement of different parameters. Untreated diabetic animals had slower heart rates, depressed rate of contraction and rate of relaxation, lower peak left ventricular systolic pressure, and elevated left ventricular diastolic pressure. All of these changes were significantly improved in diabetic rats receiving verapamil treatment. The beneficial effects of verapamil were more evident with higher doses (8 mg.kg-1.day-1) than with the lower doses (2 mg.kg-1.day-1). The diabetic animals also showed alterations in myocardial high-energy phosphate stores and exhibited evidence of ultrastructural damage; these abnormalities were improved by verapamil treatment without affecting their hyperglycemic status. Our results demonstrate that verapamil is capable of preventing diabetes-induced myocardial changes and support the involvement of Ca2+ in the cardiac pathology during diabetes.

Cardiac and renal responses to cross-clamping of the descending thoracic aorta

The present study was performed to document the relative efficacy of commonly applied techniques used adjunctively during 1 hour of descending thoracic aortic cross-clamping. Renal and cardiac responses were determined by standard laboratory methods. There were four experimental groups: (1) heparin-bonded shunt; (2) partial femoral-femoral bypass; (3) sodium nitroprusside; (4) control. Each of the experimental groups showed abnormal hemodynamic responses during cross-clamping. Elevations in left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure were common events during clamping, and cardiac output often decreased. Nevertheless, left ventricular performance curves after cross-clamping showed similar increases in left ventricular stroke work (LVSW) with increasing preload. In addition, left ventricular biopsy specimens showed preservation of myocardial high-energy phosphate stores and essentially normal ultrastructural integrity. Radioactive microspheres generally showed increased myocardial blood flow during and after cross-clamping, but no evidence of preferential subendocardial ischemia. Examination of renal function showed a marked decrease in urine output, glomerular filtration rate, and renal plasma flow during cross-clamping. Following the release of the cross-clamp, renal function returned to 50% to 85% of baseline status. Since we could find no major advantage of any of the techniques employed under the present experimental conditions, we suggest that all of the techniques should be part of the surgical armamentarium and the particular preoperative and/or intraoperative findings in a specific case should determine which technique is most appropriate for a given patient.

Depressed high-energy phosphate content in hypertrophied ventricles of animal and man: the biologic basis for increased sensitivity to ischemic injury.

It is frequently stated that hypertrophied ventricles tolerate ischemia less well than nonhypertrophied ventricles. The authors' earlier studies in a rat supravalvular aortic stenosis model and canine valvular aortic stenosis model, both with concentric left ventricular hypertrophy, disclosed accelerated rates of ischemic contracture and diminished basal myocardial high energy phosphate stores. These studies have been extended to ten patients with severe left ventricular hypertrophy caused by valvular aortic stenosis and normal coronary arteries. ATP (endocardial and epicardial) from transmural left ventricular biopsies taken at operation before aorta cross-clamping, and frozen immediately in liquid nitrogen, were compared with similar biopsies from patients with nonhypertrophied myocardium supplied by normal coronary arteries. The subendocardial high energy phosphate levels in the nonhypertrophied myocardium was greater than high energy phosphate levels in the subepicardium of nonhypertrophied ventricles (ATP-micromoles/gram-protein, epi = 36.8 +/- 3.3, endo = 37.7 +/- 3.3) (p = NS). However, in the hypertrophied myocardium the subendocardium consistently showed significantly depressed high-energy phosphate levels when compared with subepicardial levels (ATP-hypertrophied myocardium, epi = 31.5 +/- 1.6, endo = 25.9 +/- 1.7) (p less than 0.05). This uniform depression of ATP stores, greatest in the subendocardium, in left ventricular hypertrophy suggests a common biologic mechanism for the enhanced sensitivity to ischemia. Of importance for patients may be the prior observation in rats that repletion of ATP( stores before ischemia eliminates the accelerated rate to ischemic contracture. Diminished subendocardial ATP stores appear to be an intrinsic property of severely hypertrophied myocardium and probably contribute to its enhanced sensitivity to ischemia.

Metabolic and functional consequences of chronic alcoholism on the rat heart

Conflicting data concerning cardiac function and energy metabolism in chronic alcoholism have been reported. Previous studies have shown preferential metabolism of ketone bodies and acetate, a primary metabolite of ethanol, leading to diminished myocardial high energy phosphate stores. We evaluated the following parameters in chronically, severely alcoholic rats: cardiac function utilizing working heart preparations with variable afterload; high energy phosphate stores; and mitochondrial respiratory activity. At low work load no differences existed in hemodynamic measurements between hearts from alcoholic and control animals; however, immediately after the imposition of an increased afterload, hearts from alcoholic animals exhibited a subnormal increment in pressure development. This decrement normalized during the following 30 min of perfusion. ATP and creatinine phosphate levels in hearts from alcoholic animals which were excised and immediately frozen and in those which had been perfused as working heart preparations for 120 min were not different from those found in controls. Studies on mitochondrial respiration revealed a diminished activity of the myocardium from alcoholic rats to utilize glutamate as a substrate; however, the utilization of other substrates was unaffected by alcohol consumption. It is concluded that in chronically alcoholic rats minor changes occur in cardiac function; the heart maintains normal high energy stores; however, alternative substrates are utilized for the production of energy.

Effects of physical training and detraining on intrinsic cardiac control mechanisms.

The effects of a moderate physical training program on the hearts of rats have been studied. The mechanical responses of these hearts are improved. Possible contributing factors in this improvement are increased coronary reserve and capacity to deliver oxygen to the myocardium, increased myocardial glycogen stores and increased turnover of fatty acids through the endogenous triglyceride pool. Myocardial oxidative compounds and high energy phosphate stores are not altered. Major changes are found in the energy utilization pathways. Actomyosin, myosin, and heavy meromyosin ATPase activity and binding activity of isolated sarcoplasmic reticulum are all enhanced. Sulfhydryl control of the active site of myosin ATPase is altered. The biochemical effects of conditioning are short lived when training is decreased or discontinued.

Influence of the thyroid state on the intrinsic contractile properties and energy stores of the myocardium.

The intrinsic contractile properties of isolated cat papillary muscles and myocardial high energy phosphate stores were examined at three levels of thyroid activity and correlated with hemodynamic measurements in the intact animal. In addition, the relationship of thyroid state to endogenous norepinephrine stores and myocardial responsiveness to certain inotropic interventions were studied. In muscles from hyperthyroid cats, the velocity of shortening and the rate of tension development were markedly augmented, while duration of active state was decreased, compared to euthyroid muscles. These findings occurred in the presence and absence of intact norepinephrine stores and over a wide range of temperature and contraction frequency. The opposite changes occurred in muscles from hypothyroid cats. Isometric tension was slightly higher in muscles from hyperthyroid and lower in muscles from hypothyroid cats. The inotropic response to both norepinephrine and strophanthidin varied inversely with the level of thyroid state and allowed all three groups of muscles to reach a common ceiling of isometric tension regardless of thyroid state. Creatine phosphate and adenosine triphosphate stores were intact at all three levels of thyroid state. Thus, the level of thyroid activity profoundly affects the intrinsic contractile state of cardiac muscle, independent of both norepinephrine stores and alterations in high energy phosphate stores, and, in addition, modifies the responsiveness of cardiac muscle to inotropic agents.

Effects of acutely induced ischemic heart failure on myocardial high energy phosphate stores.

The effects of acutely induced ischemic heart failure on myocardial high energy phosphate stores were studied in dogs following an abrupt reduction (avg. 40%) of left main coronary arterial flow. Left ventricular biopsies were obtained before and during the onset of heart failure. Myocardial ATP stores were unchanged (control, 6.65 μmoles/g; ischemia, 6.66 μmoles/g) at a time when left ventricular end-diastolic pressure had risen from 3.9 to 11.3 mm Hg and left ventricular stroke work had fallen from 7.9 to 4.9 g-m. The average myocardial creatine phosphate (CP) stores fell from 13.2 μmoles/g to 7.9 μmoles/g. These results indicate that acute ischemic heart failure is not initiated by a detectable depression in total myocardial ATP stores.