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In order to study the mechanochemical coupling in actomyosin energy transduction, the sliding distance of an actin filament induced by a myosin head during one ATP hydrolysis cycle was obtained using an in vitro movement assay, which permitted quantitative and simultaneous measurements of (1) the movements of single fluorescently-labeled actin filaments on myosin bound to coverslip surfaces and (2) the ATPase rates. The sliding distance was determined as (the working-stroke time in one ATPase cycle, Tws) x (the filament velocity, v). The working-stroke time (Tws) was obtained from the ATPase turnover rate of myosin during the sliding (kT), the ATP hydrolysis time on myosin heads (delta T) and the ON-rate at which myosin heads enter into the working-stroke when they encounter actin (kON); Tws approximately 1/kT-delta T-1/kON. kON was estimated by analyzing the movements of very short (40 nm) filaments. The resulting sliding distance during one ATP hydrolysis cycle near zero load was greater than 100 nm, which is about 10 times longer than that expected for a single attachment-detachment cycle between an actin monomer and a myosin head. This leads to the conclusion that the coupling between the chemical and mechanical reactions is not rigid in a one to one fashion.
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PMID:Loose coupling between chemical and mechanical reactions in actomyosin energy transduction. 208 30

Brain oedema is an important aspect of infarction from cerebrovascular occlusion. In a cat stroke model where the middle cerebral artery (MCA) was reversibly or permanently occluded, we analyzed the incidence of fatal hemispheral oedema in 35 normo- (6 mM) and 35 hyperglycaemic (20 mM for 6 hours) animals, with (N = 45) and without (N = 25) restoration of blood flow with clip release at 4 and 8 hrs of occlusion. Fatal hemispheral oedema occurred in 23% of cats (16/70) while hyperglycaemia, for one, and restoration of blood flow, for another, each quadrupled its occurrence. Further, evidence of remote oedema in the form of posterior cingulate cortical pressure atrophy from transtentorial herniation was found in animals that were allowed to survive for 2 weeks and that exhibited infarcts that affected 12 to 95% of the MCA territory. Thus, hemispheral oedema in association with MCA occlusion developed sufficiently markedly as to cause transtentorial herniation in 47% of all cats (33/70). We carried out biochemical analyses in 14 hyper- and 10 normoglycaemic cats after 4 hrs of MCA occlusion for ATP, phosphocreatine (PCr), lactate, glucose and glycogen. The biochemical findings then were correlated with the occurrence of reperfusion oedema following clip release after 4 hrs of occlusion point-by-point in the brains. Linear regression analyses of the brain metabolic and pathologic data revealed highly significant (p less than 0.001) correlations of acute oedema with brain tissue ATP and PCr reductions less than 1.5 microM/g, with lactic acid accumulation greater than 20 microM/g and with the extents of reduction in brain tissue glucose concentrations in the ischaemic territories.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Determiners of fatal reperfusion brain oedema. 208 2

In order to study the mechanochemical coupling in actomyosin energy transduction, the sliding distance of an actin filament induced by one ATP hydrolysis cycle was obtained by using an in vitro movement assay that permitted quantitative and simultaneous measurements of (1) the movements of single fluorescently labeled actin filaments on myosin bound to coverslip surfaces and (2) the ATPase rates. The sliding distance was determined as (the working stroke time in one ATPase cycle, tws) x (the filament velocity, v). tws was obtained from the ATPase turnover rate of myosin during the sliding (kt), the ATP hydrolysis time (delta t) and the ON-rate at which myosin heads enter into the working stroke state when they encounter actin (kON); tws approximately 1/kt-delta t-1/kON. kt was estimated from the ATPase rates of the myosin-coated surface during the sliding of actin filaments. delta t has been determined as less than 1/100 per second, kON was estimated by analyzing the movements of very short (40 nm) filaments. The resulting sliding distance during one ATP hydrolysis cycle near zero load was greater than 100 nm, which is about ten times longer than that expected for a single attachment-detachment cycle between an actin and a myosin head. This leads to the conclusion that the coupling between the ATPase and attachment-detachment cycles is not determined rigidly in a one-to-one fashion.
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PMID:Mechanochemical coupling in actomyosin energy transduction studied by in vitro movement assay. 214 98

The aim of this study was to determine the dual role of ATP as an energy substrate and as a major source of oxygen-derived free-radical-mediated reperfusion injury by using adenine nucleoside blocker, p-nitrobenzylthioinosine (NBMPR), and adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). In a randomized study, 16 dogs were instrumented with minor-axis LTZ-piezoelectric crystals and intraventricular pressure transducers to monitor, off bypass, left ventricular performance by using a sensitive and load-independent index of contractility (slope of the stroke work-end-diastolic length relation). Hearts were subjected to 60 minutes of normothermic global ischemia and 120 minutes of reperfusion. Normal saline without (Group 1, n = 8) or with (Group 2, n = 8) NBMPR and EHNA was infused in three boluses into the cardiopulmonary bypass reservoir before ischemia and reperfusion. Transmural serial biopsies were obtained before and during ischemia and reperfusion and analyzed for myocardial adenine nucleotide pool intermediates by using high-performance liquid chromatography. In the control group, three hearts developed ischemic contracture and another three hearts exhibited cardiogenic shock during reperfusion. In the EHNA/NBMPR-treated group, left ventricular performance recovered within 30 minutes of reperfusion (p less than 0.05 vs. control). Myocardial ATP was depleted to 20% of normal in both groups by the end of ischemia (p less than 0.05). Intramyocardial adenosine in the EHNA/NBMPR-treated group was 12-fold greater (15.09 +/- 1.6 nmol/mg protein) than the control group at the end of the ischemic period (p less than 0.05). Inosine was about fourfold higher in the control group (19.07 +/- 1.50 nmol/mg protein) compared with the drug-treated group (p less than 0.05). During reperfusion, myocardial ATP levels increased to approximately 50% of normal in the EHNA/NBMPR group while remaining depressed (20% of normal) in the control group. Thus, despite the dramatic loss of myocardial ATP during ischemia, complete recovery of ventricular performance and significant repletion of ATP during reperfusion were observed when adenosine transport and deamination were modulated during ischemia and reperfusion. These results suggest that 1) the myocardium may have more ATP than is needed for basic cardiac functions and 2) washout of ATP diffusible catabolites is detrimental to ventricular performance during reperfusion. Specific blockade of nucleoside transport resulted in complete functional recovery despite low but critical ATP levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Is adenosine 5'-triphosphate derangement or free-radical-mediated injury the major cause of ventricular dysfunction during reperfusion? Role of adenine nucleoside transport in myocardial reperfusion injury. 193 94

Excessive release of glutamate is thought to play a major role in the susceptibility of neurons to ischemia. In the present study, we evaluated whether differences in the magnitude of glutamate release resulted in some regions being vulnerable to ischemia, but others being spared from irreversible histopathologic damage. Specifically, we compared the temporal profile of ischemia-induced changes in extracellular levels of glutamate in a region selectively vulnerable to 10 minutes of transient ischemia (CA1 sector of the hippocampus) to the changes occurring in regions that, although rendered ischemic, are usually unaffected by a 10-minute insult (i.e., thalamus, cortex, and dorsolateral striatum). In an attempt to correlate the regional changes in glutamate release to the magnitude of the ischemic insult, the degree of ischemia (e.g., ATP depletion, lactate accumulation, and local cerebral blood flow reduction) and the final histopathologic outcome were also evaluated in these regions. Blood flow reduction and energy depletion were severe and uniform in all regions. However, the histopathologic outcome illustrated a different pattern. Although the CA1 sector of the hippocampus was severely damaged, all other brain regions were unaffected by the 10-minute insult. Extracellular glutamate levels, measured by microdialysis, were significantly elevated during ischemia in all four regions. These levels continued to increase during the early recirculation period and gradually returned to baseline by 30 minutes of reperfusion, with a similar temporal changes in all four brain structures. These results, taken with our previous findings, demonstrate that elevated intraischemic glutamate levels are insufficient to independently engender ischemic damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Stroke 1990 Nov
PMID:Ischemia induces release of glutamate in regions spared from histopathologic damage in the rat. 223 84

High concentrations of adrenergic agonists are known to cause significant structural damage to the heart, accompanied by depressed cardiac performance. These studies were undertaken to further elucidate mechanisms that contribute to this process. Rabbits were infused with either norepinephrine (NE, 3 micrograms.min-1.kg-1 iv) for 90 min or with an equivalent volume of normal saline (controls). The heart was immediately extracted and studied as an isolated working heart preparation perfused with erythrocyte-enhanced buffer. Stroke work, coronary flow, and O2 metabolism were determined, and substrate oxidation was measured by [14C]glucose or palmitate. Stroke work performed by hearts exposed to NE was only 31% of controls (2.6 +/- 0.4 vs. 8.4 +/- 0.9 g.cm-1.g-1). This was matched by reductions in coronary flow and O2 metabolism. Glucose oxidation was reduced from 54.6 +/- 3.9 to 16.0 +/- 5.3 nmol.min-1.g-1, and palmitate oxidation from 49.8 +/- 5.3 to 21.0 +/- 4.1 nmol.min-1.g-1 in the NE group. However, ATP, creatine phosphate, glycogen, and triacylglycerol concentrations were identical with the control group. O2 delivery per unit substrate oxidation was not lower in the NE group, and O2 extraction did not differ significantly. These findings indicate that the markedly lower contractile performance of the hearts exposed to NE cannot be attributed to a deficiency of metabolic capacity or limitation of O2 or substrate availability because of vasospasm. In view of the brief time (90 min), it is unlikely that leukocyte accumulation was a major factor. The observations are consistent with NE-derived oxidant injury, possibly causing disordered excitation-contraction coupling.
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PMID:Preservation of cardiac metabolic capacity after acute catecholamine injury. 230

Myocardial infarction was induced in rats by ligation of the descending branch of the left coronary artery. The time course of changes in heart function was recorded within the first nine days. There was a progressive decline in LVSP, in LV dP/dtmax and in the pressure-rate-product. LVEDP was elevated. Cardiac output and stroke volume index were depressed after two days. The ATP content in the nonischemic region was lower than control, but recovered spontaneously toward the normal value within the first four days. Three metabolic and pharmacologic interventions known to affect cardiac adenine nucleotide metabolism were applied. Continuous i.v. administration of ribose which stimulates further adenine nucleotide biosynthesis attenuated the fall and promoted the restoration of ATP in the nonischemic myocardium within four days after coronary artery ligation. The elevation of LVEDP was attenuated with ribose after two and four days. The calcium antagonist gallopamil administered as i.v. infusion for two days led to a further reduction of all parameters of left heart function, but did not influence the increase in adenine nucleotide and protein synthesis that occurred in the nonischemic heart. Coenzyme Q10 had only slight effects on LVSP, LVEDP, and LV dP/dtmax, but attenuated significantly the fall in cardiac output and stroke volume index after two days following coronary artery ligation. Thus, all interventions affected differently the infarct-induced changes in heart and circulatory function. An improvement was observed with ribose and with coenzyme Q10.
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PMID:Myocardial infarction in rats: effects of metabolic and pharmacologic interventions. 250 41

Ribose has been shown to greatly enhance ATP recovery in situations such as postischemia when total adenine nucleotides have been depleted by catabolism. In addition, metabolic studies have reported that both five carbon sugars and alcohols (ribose and xylitol) can support energy metabolism presumably after conversion to substrates for glycolysis. Because of the importance of these two aspects of energy metabolism to myocardial function, we compared the ability of ribose and xylitol with glucose and pyruvate as exclusive substrates for the isolated working rat heart. Our studies revealed, however, that the utilization of ribose or xylitol as substrates by the myocardium is not sufficiently rapid to rely on these as exclusive oxidizable substrates. In fact, ribose or xylitol are no more effective than substrate-free medium in this regard. Myocardial glycogen was depleted in these groups and after a lag period consumption of oxygen also decreased. In contrast to the postischemic situation the total adenine nucleotide levels were preserved during ribose, xylitol or substrate-free perfusion. Consequently, the energy charge in these hearts fell significantly. In hearts perfused with ribose, xylitol or no substrate, the rate pressure product and the stroke volume rapidly declined after an initial brief stable period corresponding to glycogen depletion. Glycogen levels were 6% of the average control value in ribose- and xylitol-perfused hearts and were undetectable in substrate-free perfused hearts. In contrast, either glucose or pyruvate supported steady levels of ATP and myocardial oxygen consumption; maintained the energy charge; and supported the stroke volume, rate pressure product, and cardiac work. In glucose-perfused hearts the glycogen was reduced to 21% of control values, while in pyruvate-perfused hearts the average glycogen levels were 76% of control. Thus, although the heart is able to metabolize ribose and xylitol through the hexose monophosphate pathway, the rate of utilization through glycolysis and presumably the TCA cycle is not sufficient for these compounds to serve as exclusive substrates for the isolated working heart.
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PMID:A comparison of different carbohydrates as substrates for the isolated working heart. 251 81

In the presence of specific inhibitors of beat. 20 microM VO4(3-) or pCa 4, mussel gill lateral (L) cilia can be arrested in two positions--"hands down" or "hands up"--at opposite ends of the stroke cycle. Cilia move to these positions by doublet microtubule sliding. Axonemes of arrested cilia, still tethered to the cell, are intact after demembranation and protease treatment. When reactivated by 4 mM ATP with inhibitors present, about 40% split apart. Splits are not random but occur preferentially between different specific doublets in the two opposite arrest positions. Several different related patterns of splitting are observed; for every pattern in "hands down" axonemes, there is a corresponding complementary split pattern in "hands up" axonemes. In some split patterns two doublets remain firmly attached to the central pair; these also differ depending on axonemal position. Although some of the patterns seen may be artifactual or difficult to explain, the complementary splitting patterns are predictable with simple assumptions by a "switch point" hypothesis of ciliary activity where, during each recovery stroke, doublets 6-8 have active dynein arms, while during each effective stroke, arms on doublets 1-4 become active, and arms 6-8 are turned off. Because of a difference between the patterns seen and the predictions, the status of the arms on doublet 9 is unresolved. The patterns also suggest that a spoke-central sheath attachment cycle may correlate with switching of arm activity during the generation of an asymmetric beat.
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PMID:Splitting the ciliary axoneme: implications for a "switch-point" model of dynein arm activity in ciliary motion. 253 Oct 43

The effects of acute volume and/or pressure loading on myocardial metabolic and mechanical function were studied in 13 dogs. Volume loads were applied by shunting the abdominal aorta to the vena cava using polyethylene tubing (5 mm inner diameter). A plastic regulator allowed shunts to be opened or closed. Dogs were heparinized (100 units/kg) to prevent shunts from clotting. To study the effects of pressure loading, a norepinephrine infusion (1 microgram/kg/min) was administered. Mechanical function of the heart was evaluated using heart rate X systolic blood pressure (HR X SBP), cardiac output (CO), pressure X volume work (systolic blood pressure X stroke volume); (P X V), and oxygen consumption (MVO2) to estimate external myocardial work. Metabolic function was evaluated by 31P NMR. Phosphocreatine/adenosine triphosphate (PCr/ATP) ratios were used to estimate the bioenergetic regulation of oxidative phosphorylation during increased work load. HR X SBP, CO, P X V, and MVO2 were correlated with PCr/ATP. Although there was some variability, generally volume loading was associated with an increase in HR X SBP, CO, P X V, and MVO2 accompanied by no change, or small increases or small decreases in PCr/ATP throughout the loading period. These data indicate that the heart bioenergetics are quite stable during volume and/or pressure loading and that 31P spectroscopy methods can document this stability and tight metabolic regulation during in vivo loading conditions.
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PMID:In vivo myocardial bioenergetics during acute volume and/or pressure loading in a canine model: a 31P NMR study. 261 95


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