Biomedical subjects

T Takasago

Publications and source records attributed to T Takasago.

At least 19 recordsLinked to original sources

PubMed2000

Elective neck clipping for unruptured aneurysms in elderly patients.

BACKGROUND: With the recent advancements of neuroimaging techniques, the number of unruptured aneurysms diagnosed in elderly patients has increased. However, the surgical indications in this special subgroup have not been studied critically. The purposes of this study were to analyze the results of elective neck clipping surgery for unruptured aneurysms in the elderly and to elucidate the surgical indications. METHODS: From 1985 to 1997, 96 patients, aged 70 years or older, with 103 unruptured cerebral aneurysms underwent elective neck clipping. There were 67 females and 29 males. Their ages ranged from 70 to 86, with a mean of 73.3 years. Seventy-five aneurysms were asymptomatic and 28 were symptomatic. The aneurysms were located on the internal carotid artery (46.6%), middle cerebral artery (35.9%), anterior cerebral artery (16.5%), and basilar artery (1.0%). RESULTS: The surgical outcome was a good recovery in 75 patients (78.1%), mild deficits in 12 (12.5%), severe deficits in 4 (4.2%), and death in 5 (5.2%). Recovery from preoperative symptoms with improved quality of life was seen in 22 (78.6%) of the 28 symptomatic cases. Multiple regression analysis showed that increase in the size of aneurysms and location on the middle cerebral artery and internal carotid artery were significantly related to a poor outcome. The causes of the five deaths were hemorrhagic infarction, systemic infection, and myocardial infarction. CONCLUSION: Surgery for elective neck clipping of unruptured aneurysms in the elderly should be considered in symptomatic patients with simple aneurysms that can be clipped without the use of temporary clips.

Aged↗

PubMed2000

Negative inotropism of hyperthermia increases oxygen cost of contractility in canine hearts.

Heart temperature affects left ventricular (LV) function and myocardial metabolism. However, how and whether increasing heart temperature affects LV mechanoenergetics remain unclear. We designed the present study to investigate effects of increased temperature by 5 degrees C from 36 degrees C on LV contractility and energetics. We analyzed the LV contractility index (E(max)) and the relation between the myocardial oxygen consumption (MVO(2)) and the pressure-volume area (PVA; a measure of LV total mechanical energy) in isovolumically contracting isolated canine hearts during normothermia (NT) and hyperthermia (HT). HT reduced E(max) by 38% (P < 0.01) and shortened time to E(max) by 20% (P < 0.05). HT, however, altered neither the slope nor the unloaded MVO(2) of the MVO(2)-PVA relation. HT increased the oxygen cost of contractility (the incremental ratio of unloaded MVO(2) to E(max)) by 49%. When Ca(2+) infusion restored the reduced LV contractility during HT to the NT baseline level, the unloaded MVO(2) in HT exceeded the NT value by 36%. We conclude that HT-induced negative inotropism accompanies an increase in the oxygen cost of contractility.

Animals↗

PubMed2000

Mechanoenergetics characterizing oxygen wasting effect of caffeine in canine left ventricle.

Caffeine causes a considerable O(2) waste for positive inotropism in myocardium by complex pharmacological mechanisms. However, no quantitative study has yet characterized the mechanoenergetics of caffeine, particularly its O(2) cost of contractility in the E(max)-PVA-VO(2) framework. Here, E(max) is an index of ventricular contractility, PVA is a measure of total mechanical energy generated by ventricular contraction, and VO(2) is O(2) consumption of ventricular contraction. The E(max)-PVA-VO(2) framework proved to be powerful in cardiac mechanoenergetics. We therefore studied the effects of intracoronary caffeine at concentrations lower than 1 mmol/l on left ventricular (LV) E(max) and VO(2) for excitation-contraction (E-C) coupling in the excised cross-circulated canine heart. We enhanced LV E(max) by intracoronary infusion of caffeine after beta-blockade with propranolol and compared this effect with that of calcium. We obtained the relation between LV VO(2) and PVA with E(max) as a parameter. We then calculated the VO(2) for the E-C coupling by subtracting VO(2) under KCl arrest from the PVA-independent (or zero-PVA) VO(2) and the O(2) cost of E(max) as the slope of the E-C coupling VO(2)-E(max) relation. We found that this cost was 40% greater on average for caffeine than for calcium. This result, for the first time, characterized integratively cardiac mechanoenergetics of the O(2) wasting effect of the complex inotropic mechanisms of intracoronary caffeine at concentrations lower than 1 mmol/l in a beating whole heart.

Animals↗

PubMed1998

Topographical and quantitative assessment of white matter injury following a focal ischaemic lesion in the rat brain.

Axonal injury following cerebral ischaemia has attracted less attention than damage in grey matter. However, it is becoming increasingly recognised that axons are highly vulnerable to focal ischaemia [D. Dewar, D.A. Dawson, Changes of cytoskeletal protein immunostaining in myelinated fibre tracts after focal cerebral ischaemia in the rat, Acta. Neuropathol., 93 (1997) 71-77] [2]; [L. Pantoni, J.H. Garcia, J.A. Gutierrez, Cerebral white matter is highly vulnerable to ischemia, Stroke, 27 (1996) 1641-1647] [10]; [P. S. Yam, T. Takasago, D. Dewar, D.I. Graham, J. McCulloch, Amyloid precursor protein accumulates in white matter at the margin of a focal ischaemic lesion, Brain Res., 760 (1997) 150-157] [15]. Since white matter does not contain neuronal cell bodies or synapses it is likely that the mechanisms of injury and strategies for its protection are different from those in grey matter. In order that the effect of therapeutic intervention on the protection of axons can be assessed, a method by which axonal injury can be mapped and quantified is required. For this purpose, we investigated immunocytochemical methods using amyloid precursor protein (APP) following permanent middle cerebral artery occlusion in the rat. APP is transported by fast anterograde axonal transport [E.H. Koo, S.S. Sisodia, D.R. Archer, L.J. Martin, A. Weidemann, K. Beyreuther, P. Fischer, C.L. Masters, D.L. Price, Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport, Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 1561-1565] [7] and has been shown to accumulate following a variety of insults to axons, indicative of dysfunction of axonal transport [R.N. Kalaria, S.U. Bhatti, E.A. Palatinsky, D.H. Pennington, E.R. Shelton, H.W. Chan, G. Perry, W.D. Lust, Accumulation of the beta amyloid precursor protein at sites of ischemic injury in rat brain, Neuroreport, 4 (1993) 211-214] [4]; [T. Kawarabayashi, M. Shoji, Y. Harigaya, H. Yamaguchi, S. Hirai, Expression of APP in the early stage of brain damage, Brain Res., 563 (1991) 334-338] [5]; [N. Otsuka, M. Tomonaga, K. Ikeda, Rapid appearance of beta-amyloid precursor protein immunoreactivity in damaged axons and reactive glial cells in rat brain following needle stab injury, Brain Res., 568 (1991) 335-338] [9]; [K. Shigematsu, P. L. McGeer, Accumulation of amyloid precursor protein in neurons after intraventricular injection of colchicine, Am. J. Pathol., 140 (1992) 787-794] [12]. We have been able to map the topographical relationship between APP accumulation and region of infarction using immunocytochemistry and image analysis techniques. Additionally, using a semi-quantitative scoring system, we have demonstrated that there is a relationship between the amount of APP accumulation and the volume of infarction following middle cerebral artery occlusion. These methods will be useful in the future for the assessment of therapeutic interventions on the protection of axons following ischaemic injury.

Amyloid beta-Protein Precursor↗

PubMed1997

Amyloid precursor protein accumulates in white matter at the margin of a focal ischaemic lesion.

Amyloid precursor protein (APP) is transported by fast anterograde axonal transport. Since disruption of this transport results in APP accumulation, APP has been proposed as a sensitive marker of axonal injury. In the present study, axonal injury in subcortical white matter and myelinated fibre tracts permeating the striatum, 24 h after permanent middle cerebral artery occlusion in the rat, has been examined by assessing the location and extent of APP immunoreactivity. Increased APP immunoreactivity was present in both areas. This was localised to a circumscribed zone immediately adjacent to the boundary of the ischaemic lesion in grey matter. The amount of APP immunoreactivity was associated with the volume of the ischaemic lesion in individual animals. Increased APP immunoreactivity in subcortical white matter and myelinated fibre tracts at the margin of the ischaemic zone may prove to be a valuable marker for assessing strategies to protect axons after an ischaemic insult.

Amyloid beta-Protein Precursor↗

PubMed1997

Revascularization with split duro-encephalo-synangiosis in the pediatric moyamoya disease--surgical result and clinical outcome.

Dural arteries are potential donor arteries for cortical revascularization. In this report, a technique of indirect anastomosis using a split dura is presented. At surgery, the dura near the branches of the middle meningeal artery was split into outer and inner layers, and the split surface of the outer layer was attached to the cortical surface (split duro-encephalo-synangiosis; split DES). This procedure, combined with standard encephalo-duro-arterio-synangiosis, was applied to 25 hemispheres in 18 patients with pediatric Moyamoya disease (mean age, 6 years). Postoperative superselective angiograms demonstrated effective cortical revascularization through the dural arteries in addition to the supply from the scalp arteries. All the patients were symptom free by 1.5 years after surgery. Postoperative reversible ischemic neurological deficit and infarction were seen in three (12%) and one (4%), respectively. The follow-up period ranged from 1 to 12 years (mean, 6.5 years). Thirteen of 16 (81%) patients led normal lives and three were mildly handicapped due to mental retardation that existed preoperatively. The split DES is a useful technique to extend the area of revascularization of ischemic hemispheres in Moyamoya disease.

Adolescent↗

PubMed1997

Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion.

1. The aim of this study was to investigate whether delayed treatment with the anti-oxidant and anti-inflammatory agent ebselen reduces the volume of infarction in a rodent model of permanent focal cerebral ischaemia. 2. Ebselen (10 or 30 mg kg-1) or vehicle was administered by gavage 30 min and 12 h after the induction of cerebral ischaemia by permanent occlusion of the left middle cerebral artery (MCA). Animals were killed 24 h following MCA occlusion, and the volumes of ischaemic damage in the ebselen and control groups were evaluated by quantitative histopathology. 3. Ebselen was quickly absorbed following oral (gavage) administration and reached peak levels in the plasma by 1 h post-administration (plasma selenium level of 0.68 +/- 0.04 and 0.84 +/- 0.1 microgram ml-1 for 10 and 30 mg kg-1, respectively, compared to control level of 0.51 +/- 0.02 microgram kg-1). 4. Treatment with the lower dose of ebselen (10 mg kg-1) significantly (P < 0.01) reduced the volume of infarction in the cerebral hemisphere and cerebral cortex (by 31.8% and 36.7%, respectively compared with the placebo group). 5. The neuroprotective efficacy of the higher dose ebselen (30 mg kg-1) was less than that of the lower dose ebselen (10 mg kg-1). The volume of ischaemic damage in the cerebral hemisphere was reduced by 23.7% (P < 0.02), and cerebral cortex by 27.5% (P < 0.01). 6. Both doses of ebselen (10, 30 mg kg-1) had no therapeutic efficacy on the caudate nucleus, where ischaemia was most severe, in this model. 7. Free radical-mediated injury is normally associated with reperfusion of ischaemic tissue. The present results suggest that oxidative injury is also a significant contributor to brain damage in models of maintained (permanent) ischaemia and that ebselen is effective in attenuating this free radical-induced damage.

Animals↗

PubMed1997

Cerebral aneurysms in the elderly in Yamaguchi, Japan. Analysis of the Yamaguchi Data Bank of Cerebral Aneurysm from 1985 to 1995.

BACKGROUND AND PURPOSE: The number of elderly people is markedly increasing in Japan. We have investigated the epidemiology and management outcome of cerebral aneurysms in elderly patients aged > or = 70 years. METHODS: A total of 3100 patients were enrolled in the Yamaguchi Data Bank of Cerebral Aneurysm between 1985 and 1995. Of these, 598 with ruptured cerebral aneurysms and 120 with unruptured cerebral aneurysms were elderly (ie, aged > or = 70 years). RESULTS: The number of elderly patients with cerebral aneurysms has markedly increased since 1991, and in 1995 approximately 30% of all patients with cerebral aneurysms were elderly. In cases of ruptured cerebral aneurysms, the proportion of patients with severe neurological grade did not change and that with an unfavourable outcome did not decrease throughout the 11 years. The proportion of patients with severe neurological grade in the elderly group was higher than in the younger group (< 70 years), and the management outcome of elderly patients for each neurological grade on admission was worse than that of younger patients (P < .01). However, the incidence rate of symptomatic cerebral vasospasm and rebleeding was the same for the two age groups. Eventually, 60.4% of all elderly patients with ruptured cerebral aneurysms had an unfavorable outcome. In cases of unruptured cerebral aneurysms, 63.3% of the selected elderly patients were surgically treated, and the surgical morbidity and mortality rates were 26.3% and 4.0%, respectively. These rates were nonsignificantly higher than those for younger patients. CONCLUSIONS: The number of elderly patients with cerebral aneurysms has markedly increased in Yamaguchi. Because of the unsatisfactory management outcome of ruptured cerebral aneurysms and surgical outcome of unruptured cerebral aneurysms in elderly patients during the 11-year period, we propose the treatment of unruptured cerebral aneurysms at a younger age and the use of a screening system to detect these subjects.

Age Distribution↗

PubMed1997

2,3-Butanedione monoxime suppresses excitation-contraction coupling in the canine blood-perfused left ventricle.

The negative inotropism of 2,3-butanedione monoxime (BDM) < or = 5 mmol/l has been attributed primarily to directly suppressed crossbridge force development without much suppressed intracellular Ca2+ handling. However, there is evidence that BDM simultaneously or even primarily suppresses myocardial excitation-contraction (E-C) coupling. We therefore studied the mechanoenergetic effects of intracoronary BDM in the left ventricle (LV) of 11 canine excised cross-circulated hearts. We fully utilized the VO2-PVA-Emax framework that we have developed, where VO2 is myocardial O2 consumption, PVA is the systolic pressure-volume area as a measure of the total mechanical energy, and Emax is a contractility index. We gradually depressed Emax from 5.9 to 3.4 mmHg/(ml/100 g) on average by increasing intracoronary BDM to 2.6 +/- 2.1 mmol/l, and then gradually restored Emax to the pre-BDM level by increasing intracoronary CaCl2. We compared the O2 cost of Emax between BDM and Ca2+. We found that BDM and Ca2+ had a similar O2 cost of Emax. BDM did not affect the concentrations of blood-borne catecholamines. We therefore conclude that the negative inotropism of BDM is primarily due to suppressed E-C coupling in canine blood-perfused hearts.

Analysis of Variance↗

PubMed1997

Ryanodine decreases internal Ca2+ recirculation fraction of the canine heart as studied by postextrasystolic transient alternans.

We tested our hypothesis that the O2 wasting of Ca2+ handling in the excitation-contraction (E-C) coupling in ryanodine-treated failing hearts could be reflected by a decrease in the internal Ca2+ recirculation fraction (RF). We have reported, using canine excised cross-circulated hearts, that intracoronary ryanodine (40 nmol/l blood) halved left ventricular contractility without decreasing myocardial O2 consumption for the E-C coupling. We previously suspected this mechanoenergetic state to manifest energy wasting of Ca2+ handling due to ryanodine causing leakage of Ca2+ from the sarcoplasmic reticulum. To test this hypothesis, we analyzed all the sporadic spontaneous cases of postextrasystolic potentiation (PESP) obtained during the ryanodine experiments. We calculated RF from the beat constant of the exponential decay component of not only the monotonic type but also the transient alternans type of PESP. Results showed that ryanodine significantly decreased the beat constant in both types of PESP from about 2 to 1.5 beats and hence RF from 0.6 to 0.5 on the average, supporting the hypothesis. This organ-level systems approach to Ca2+ handling using transient alternans PESP as well as monotonic PESP may help obtain better insights into the mechanoenergetics of failing hearts.

Animals↗

PubMed1996

Effects of milrinone and sulmazole on left ventricular mechanoenergetics in canine hearts.

BACKGROUND: The effect of cardiotonic drugs with calcium-sensitizing effect (Ca2+ sensitizers) on cardiac mechanoenergetics is not fully understood. Accordingly, the effects of milrinone (a phosphodiesterase inhibitor) and sulmazole (a calcium sensitizer with a phosphodiesterase-inhibiting effect) on left ventricular mechanics and energetics were studied. METHODS AND RESULTS: In excised, cross-circulated canine hearts, myocardial oxygen consumption (Vo2), left ventricular contractility index (Emax), and systolic pressure-volume area (a measure of ventricular total mechanical energy) were measured before and during administration of either drug. Milrinone significantly increased Emax by 108.7 +/- 45.9% (mean +/- SD), from 6.3 +/- 3.5 to 13.1 +/- 6.8 mmHg.mL-1.100 g (P < .05), and sulmazole, by 73.6 +/- 54.2%, from 6.3 +/- 2.6 to 10.3 +/- 2.9 mmHg.mL-1.100 g (P < .05). Milrinone significantly abbreviated the contraction duration (Tmax) from 171 +/- 19 ms to 153 +/- 20 ms (P < .05), whereas sulmazole did not (164 +/- 36 ms to 161 +/- 31 ms, not significant), suggesting that the inotropic mechanisms of these two drugs differed. However, both drugs significantly increased the Vo2 intercept of the Vo2/pressure-volume area relation (milrinone: 0.027 +/- 0.004 to 0.036 +/- 0.003 mL O2/beat/100 g, P < .05; sulmazole: 0.025 +/- 0.005 to 0.032 +/- 0.006 mL O2/beat/100 g, P < .05) without significantly changing the slope (reciprocal of contractile efficiency). This parallel upward shift of the Vo2/pressure-volume area relation was similar to that observed with epinephrine and ouabain in our previous studies. CONCLUSIONS: These results suggest that the two positive inotropic drugs exhibit similar mechanoenergetic effects in the normal canine heart despite the different mechanisms of action.

Animals↗

PubMed1996

Surgical modulation of the natural course of collateral circulation in chronic ischemic patients.

The purpose of this study was to evaluate hemodynamic compromise in terms of baseline CBF and CRC in patients with chronic cerebral occlusive lesions and its modulation by a superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. The study subjects were 10 healthy volunteers and 49 chronic ischemic patients with stenosis or occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA). The hemodynamics were measured using stable xenon enhanced computed tomographic CBF measurement with the acetazolamide challenge. The compromised hemodynamics in patients with chronic steno-occlusive lesions did not improve during their natural course after two months. STA-MCA bypass modulated hemodynamic compromise in the ischemic patients. We recommend STA-MCA bypass for patients with reduced CRC, regardless of whether baseline CBF is reduced or normal. Hemodynamic classification using a combination of baseline CBF values and CRC values is useful for evaluating cerebral hemodynamics and for choosing the best treatment for cerebral ischemia with occlusive lesions.

Adult↗

PubMed1996

Effects of acute percutaneous transluminal recanalization on cerebral embolism.

The effects of percutaneous transluminal recanalization (PTR) on critical hemodynamics of cerebral embolism were studied using stable xenon-enhanced computed tomography in patients within 6 hours after onset. PTR was conducted in 10 cases (PTR group) and not conducted 8 cases (non-PTR group). The development of infarction was followed by CT scan. In the cortical arterial regions, the lowest cerebral blood flow (CBF) value in regions of interests (ROIs) without development of infarction was 12.9 ml/100 g/min in the PTR group and 17.0 ml/100 g/min in the non-PTR group. In ROIs with a cerebrovascular reserve capacity (CRC) less than 0 ml/100 g/min, even with a CBF greater than 12.9 ml/100 g/min, 3 of 4 ROIs underwent cerebral infarction. PTR conducted within 6 hours after onset of cerebral embolism would prevent the cortical regions with a CBF greater than 12.9 ml/100 g/min and with a CRC greater than 0 ml/100 g/min from undergoing cerebral infarction.

Acute Disease↗

PubMed1996

Mechanoenergetics of negative inotropism of ventricular wall vibration in dog heart.

Mechanical vibration depresses cardiac contractility. We studied the mechanoenergetic effects of this negative inotropism in the left ventricle (LV) of an isolated, cross-circulated dog heart preparation. We took full advantage of the mechanoenergetic relationship among the LV end-systolic elastance (Emax, contractility index), systolic pressure-volume area (PVA), and myocardial oxygen consumption (VO2). PVA is a measure of the total mechanical energy that cardiac contraction generates. PVA correlates closely with VO2. The VO2 intercept of the VO2-PVA relation reflects the VO2 component for excitation-contraction (E-C) coupling plus basal metabolism (PVA-independent VO2). VO2 above the PVA-independent VO2 reflects the VO2 component for mechanical contraction (PVA-dependent VO2). When we applied 70-Hz vibration of 2-mm amplitude to a LV wall region, it instantly decreased Emax and PVA by 20%, followed by a 10% decrease in VO2 at a fixed volume. However, the vibration neither lowered the VO2-PVA relation obtained at different LV volumes, unlike ordinary negative inotropism, nor changed its slope (1.88 +/- 0.23 vs. 1.86 +/- 0.23 x 10(-5) ml O2.mmHg-1.ml-1). The virtually zero delta PVA-independent VO2/delta Emax with vibration indicates a much smaller O2 cost of Emax than that seen with calcium and propranolol inotropism. These mechanoenergetics support the hypothesis that mechanical vibration primarily suppresses cardiac contractility without suppressing E-C coupling.

Animals↗

PubMed1995

Cardiac quick-release contraction mechanoenergetics analysis using a cardiac muscle cross-bridge model.

Huxley's sliding filament cross-bridge muscle model coupled with parallel and series elastic components was simulated to examine the conflicting reports on the amount of energy saved by quick release at the peak contraction time. Cross-bridge energy utilization was determined by considering the ATP hydrolysis for the cross-bridge cycling. The quick-release cases were simulated by letting the muscle fiber suddenly shorten to the resting fiber length at peak systole, and then the contraction was allowed to continue at the resting length. Simulation results demonstrated that, using realistic parameter values, typically approximately 15% of the muscle fiber energy is used after peak systole (and approximately 30% of the cross-bridge energy), but this is also a function of the muscle fiber properties characterized by cross-bridge association and dissociation rate constants. Increasing the kinetic rate constants, the series elasticity, the initial fiber length, or the time of peak intracellular calcium will increase the amount of energy left, which may explain some of the discrepancies in the literature. Cardiac muscle hypertrophy will increase the fraction of muscle fiber energy left after peak systole to approximately 30%. The strongest indicator of the percent energy left at peak systole was the time the fiber reached peak systole, and as the fiber reached peak systole faster, the amount of energy saved by quick release increased.

Animals↗

PubMed1994

Hypercapnic acidosis increases oxygen cost of contractility in the dog left ventricle.

The effect of acidosis on left ventricular (LV) mechanoenergetics was assessed in seven excised, cross-circulated dog hearts with the use of the frameworks of the contractility index (Emax) and the relationship between myocardial oxygen consumption (VO2) and pressure-volume area (PVA; a measure of the LV total mechanical energy). Acidosis was stably maintained without hypoxia by appropriately mixing CO2 and air in a membrane oxygenator in the coronary arterial perfusion circuit. Acidosis [pH: 6.98 +/- 0.09 (SD), PCO2: 91 +/- 25 mmHg in the coronary arterial blood] decreased Emax by 45 +/- 12% (P < 0.01) and PVA by 47 +/- 12% (P < 0.01) at a fixed LV volume. When the preacidosis Emax level was restored by Ca2+ infusion during acidosis, unloaded VO2 (the VO2 intercept of the VO2-PVA relation) exceeded the control value by 19 +/- 17% (P < 0.05), indicating that acidosis required higher VO2 for nonmechanical activities at a matched Emax. Moreover, the oxygen cost of enhanced contractility (the incremental ratio of unloaded VO2 to Emax) was 1.53 +/- 0.40 times higher (P < 0.01) during acidosis than preacidosis. We conclude that acidosis results in LV contractile dysfunction accompanied by an increased oxygen cost of contractility. This increased energy cost of the excitation-contraction coupling can be accounted for by a decreased Ca2+ sensitivity of the contractile proteins during acidosis.

Acidosis↗

PubMed1994

Stunned myocardium after rapid correction of acidosis. Increased oxygen cost of contractility and the role of the Na(+)-H+ exchange system.

Left ventricular (LV) contractile dysfunction during acidosis has been reported to be almost reversible in crystalloid-perfused hearts after correction of acidosis. In contrast, we have found that, in blood-perfused hearts, contractile function is paradoxically depressed after correction of acidosis with a transient overshoot of contractility during the recovery of pH. To clarify the mechanism of this phenomenon, we measured the LV contractility index (Emax) and the relation between myocardial oxygen consumption (VO2) and systolic pressure-volume area (PVA, a measure of the LV total mechanical energy) before and after induction and rapid correction of acidosis by CO2 loading (pH 7.00) and unloading in 13 excised cross-circulated canine hearts. During the rapid correction of acidosis in six control hearts, a severe transient overshoot of Emax (404% of acidosis) occurred. However, after correction of acidosis, Emax and PVA were lower than the preacidosis values by 46% (P < .01) and 44% (P < .01) at the same LV volume. When the preacidosis Emax level was restored by Ca2+ infusion, the VO2 intercept (PVA-independent VO2) of the linear VO2-PVA relation exceeded the control value by 18% (P < .05) with an unchanged slope. In addition, the oxygen cost of contractility, defined as the slope of the relation between PVA-independent VO2 and Emax, increased by 83% (P < .01) after correction of acidosis, indicating that postacidosis myocardium requires higher VO2 for nonmechanical activities for a unit increase in Emax. Then, we hypothesized that these mechanoenergetic disorders after rapid correction of acidosis would result from Ca2+ overload via accelerated Na(+)-Ca2+ exchange due to the heavily operating Na(+)-H+ exchange system at the time of rapid pH recovery. To examine this hypothesis, dimethylamiloride, a selective Na(+)-H+ exchange inhibitor, was administered just before the correction of acidosis in the other seven hearts. The administration of dimethylamiloride completely prevented both the mechanical and energetic disorders after correction of acidosis. We conclude that rapid recovery of pH paradoxically depresses myocardial contractility and increases the oxygen cost of contractility through an activation of the Na(+)-H+ exchange system.

Acidosis↗

PubMed1993

Comparison of the cardiac force-time integral with energetics using a cardiac muscle model.

Several investigators have found experimentally that the force-time integral varies non-linearly with energy expenditure over the course of a cardiac contraction. Also, recent research findings have indicated that the crossbridge cycle to ATP hydrolysis ratio in muscle fiber systems may not be coupled with a one-to-one ratio. In order to investigate these findings, Huxley's sliding filament crossbridge muscle model coupled with parallel and series elastic components was simulated to examine the behavior of the crossbridge energy utilization and force-time integral vs time. Crossbridge (CB) energy utilization was determined by considering the ATP hydrolysis for the crossbridge cycling, and this CB energy was compared with the force-length energy in a contraction. This CB energy was calculated in both isometric and isotonic contractions as a function of contraction time and compared to the force-time integral. Simulation results demonstrated that the ratio of the force-time integral to CB energy varies strongly throughout the cardiac cycle for both isometric and isotonic cases, as has been observed experimentally. Simulations also showed that using the force-length energy component of energy vs the CB energy gave a better correlation between the total energetic predictions and the force-time integral, agreeing with recent finding that the crossbridge cycle to ATP hydrolysis ratio may not be coupled one-to-one, especially at lower force levels.

Actins↗