NRBF2-mediated autophagy contributes to metabolite replenishment and radioresistance in glioblastoma.

Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)-a positive regulator of the autophagy initiation step-was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine-a vasodilator agent discovered through drug repositioning-significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.

Lidoflazine does not improve neurologic outcome when administered after complete cerebral ischemia in primates.

In order to investigate the effects of the calcium entry blocker lidoflazine on neurologic outcome in primates following an episode of global brain ischemia, 12 pigtail monkeys (Macaca nemestrina) were subjected to 17 min of complete cerebral ischemia, followed by 48 h of intensive care treatment and daily neurologic evaluations for 96 h. The monkeys were randomly assigned to receive, in a blind fashion, either lidoflazine 1.0 mg/kg (n = 6) or inactive lidoflazine solvent (n = 6) at 5 min, 8 h, and 16 h postischemia. One monkey in the lidoflazine group did not meet preestablished protocol criteria and was excluded from data analysis. The remaining monkeys were well matched for age, sex, and other physiologic variables. Neurologic outcome was not significantly different between the lidoflazine- and placebo-treated groups (p greater than 0.5). No monkey in either group achieved a normal neurologic exam by 96 h postischemia. Three lidoflazine-treated monkeys and two placebo-treated monkeys died prior to the 96-h neurologic evaluation. These deaths were judged to be neurologic in origin. The authors concluded that lidoflazine does not improve neurologic outcome in primates when administered after 17 min of complete cerebral ischemia.

Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine.

Mitochondrial degradation is implicated in the irreversible cell damage that can occur during cerebral ischemia and reperfusion. In this study, the effects of 10 min of ventricular fibrillation and 100 min of spontaneous circulation on brain mitochondrial function was studied in dogs in the absence and presence of pretreatment with the Ca2+ antagonist lidoflazine. Twenty-three beagles were separated into four experimental groups: (i) nonischemic controls (ii) those undergoing 10-min ventricular fibrillation, (iii) those undergoing 10-min ventricular fibrillation pretreated with 1 mg/kg lidoflazine i.v., and (iv) those undergoing 10-min ventricular fibrillation followed by spontaneous circulation for 100 min. Brain mitochondria were isolated and tested for their ability to respire and accumulate calcium in a physiological test medium. There was a 35% decrease in the rate of phosphorylating respiration (ATP production) following 10 min of complete cerebral ischemia. Those animals pretreated with lidoflazine showed significantly less decline in phosphorylating respiration (16%) when compared with nontreated dogs. Resting and uncoupled respiration also declined following 10 min of fibrillatory arrest. One hundred minutes of spontaneous circulation following 10 min of ventricular fibrillation and 3 min of open-chest cardiac massage provided complete recovery of normal mitochondrial respiration. Energy-dependent Ca2+ accumulation by isolated brain mitochondria was unimpaired by 10 min of complete cerebral ischemia. However, by 100 min after resuscitation, there was a small, but significant rise in the capacity for mitochondrial Ca2+ sequestration when compared to either control or fibrillated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized, placebo-controlled evaluation of lidoflazine in patients receiving beta-blocker therapy with propranolol: improvement in anginal symptoms and exercise tolerance with combined drug therapy.

Twenty-nine patients symptomatic despite beta-blocker therapy were entered into a randomized, double-blind, placebo-controlled, crossover trial of lidoflazine added to propranolol. After clinically documented beta blockade was achieved, patients were randomized to either propranolol plus placebo (P) or propranolol plus lidoflazine (L). Patients initially receiving lidoflazine (group with treatment sequence LP) showed improvement in exercise tolerance from propranolol alone (7.2 to 9.3 minutes, p less than 0.05). Those randomized initially to propranolol plus placebo (group with treatment sequence PL) had unchanged exercise tolerance (7.3 minutes). After 4 months, patients were crossed over to the alternative form of therapy. Patients (group PL) now receiving lidoflazine in addition to propranolol increased their exercise duration (7.8 minutes), but not, significantly. However, patients switched to propranolol plus placebo (group LP) continued to sustain their improved exercise capacity, showing a "carryover" effect. Symptomatic improvement was manifested by a statistically significant reduction in both anginal attack rate and nitroglycerin consumption. The therapeutic efficacy of combined therapy was associated with further blunting of the heart rate response to exercise achieved by beta blockade alone. The combination of agents was well tolerated.

Angina pectoris: effects of lidoflazine on exercise tolerance and chest pain.

In a double-blind study involving 24 patients, treatment with lidoflazine in comparison with placebo was associated with a significant improvement in exercise tolerance; the median increase in work performed was 62 percent. This increase was significant at the 6th week of assessment. Ten patients were followed up for a further 2 years. Lidoflazine therapy was associated with a significant improvement in work done over that period. Lidoflazine was well tolerated and apparent adverse effects were minor.

Beneficial and detrimental effects of lidoflazine in microvascular angina.

Lidoflazine, a piperazine derivative calcium antagonist, was investigated as therapy in 22 patients with microvascular angina (chest pain, angiographically normal coronary arteries and left ventricle, microvascular constrictor response to pacing after ergonovine administration and limited coronary flow response to dipyridamole). Eighteen of 22 patients reported symptom benefit while taking lidoflazine 360 mg daily. Compared to baseline exercise treadmill testing, lidoflazine resulted in significant improvement in exercise duration (812 +/- 337 vs 628 +/- 357 seconds, p less than 0.01) and time to onset of chest pain (530 +/- 343 vs 348 +/- 246 seconds, p less than 0.01). The 5 patients with ischemic ST-segment changes during baseline testing demonstrated an almost 4-minute delay in ST-segment depression (3 patients) or no ST-segment depression (2 patients) while taking lidoflazine. Repeat invasive study of coronary flow in 11 patients taking lidoflazine demonstrated significantly greater coronary vasodilation at rest, during pacing, during pacing after ergonovine and after dipyridamole administration (all p less than 0.03), compared to the initial drug-free study. During the randomized, placebo-controlled phase of the study with 7-week treatment periods, 9 of 11 patients who completed this phase of the study preferred lidoflazine and all demonstrated improved exercise capacity with lidoflazine compared to placebo. However, 3 patients developed malignant ventricular arrhythmias, and 1 died while taking lidoflazine, resulting in termination of the study. Limited coronary vasodilator response in microvascular angina has a reversible vasoconstrictor component and may be due to elevated systolic calcium levels. Despite the hemodynamic, symptom and exercise benefit, lidoflazine may be unsafe for clinical use because of its propensity to cause potentially fatal ventricular arrhythmias.

Lidoflazine in the early stages of acute myocardial ischaemia.

1 Pretreatment of anaesthetized rats with intravenously administered lidoflazine (an antianginal agent) reduced the incidence and severity of ventricular arrhythmias which resulted from acute coronary artery ligation. Ventricular fibrillation was completely prevented by doses of 50 micrograms/kg and 2 mg/kg and no animal so treated died ( contrast 50% incidence of fibrillation in the controls and 30% mortality). 2 In anaesthetized greyhound dogs, lidoflazine (2 mg/kg) administration resulted in transient reductions in systemic arterial pressure, LV dP/dt max and cardiac output. Coronary sinus Po2 was markedly increased, indicating pronounced coronary vasodilatation. 3 Lidoflazine pretreatment inhibited the increase in epicardial ST-segment elevation which resulted, in dogs, from short (3 min) occlusions of the left anterior descending coronary artery. This effect was especially marked at sites where, in control occlusions, ST-segment elevation was most pronounced. 4 Lidoflazine greatly reduced the number of ventricular ectopic beats which usually resulted from more prolonged (30 min) periods of acute coronary artery occlusion. There was no ventricular fibrillation in these dogs (contrast 25% incidence in the controls). 5 Lidoflazine did not modify the ventricular fibrillation which results from reperfusion of a previously ischaemic area of the left ventricular wall.

The effect of lidoflazine on exercise tolerance in patients with angina pectoris.

The effect of therapy with lidoflazine on maximal exercise in the upright position was evaluated in 21 patients with angina pectoris. The study consisted of the following three consecutive periods: (1) a three-month period of receving placebo; (2) six months of therapy with lidoflazine; and (3) a six-month period in which patients were randomized to either therapy with lidoflazine or placebo. Functional status was monitored by multistage tests of exercise capacity and the amount of nitroglycerin consumed. From period 1 to period 2, the mean maxial exercise time increased from 4.4 to 6.5 minutes (48 percent; P less than 0.001), and the external workload increased by 68 percent (P less than 0.001). the mean heart rate at two minutes of exercise decreased from 114 to 101 beats per minute (P less than 0.001) but was unchanged at symptom-tolerated maximal exercise. During period 3, the patients receiving therapy with liodflazine maintained their improved exercise tolerance, and the reduction in mean heart rate at two minutes of exercise persisted. Patients receiving placebo during period 3 had a decrease in exercise tolerance, and the mean heart rate at two minutes of exercise increased to control values. Lidoflazine in effective as an antianginal medication, in part due to suppression of the heart rate during exercise.

Cardioprotective effects of lidoflazine in extensive aorta-coronary bypass grafting.

The cardioprotective effects of lidoflazine, a calcium entry blocker, were tested in patients undergoing multiple aorta-coronary bypass grafting (at least four grafts). Intermittent aortic cross-clamping at 25 degrees to 28 degrees C was used. Mean cross-clamp time was 11 minutes for one distal anastomosis. Patients were randomized into three groups: a control group (I), a group (II) pretreated with 0.5 mg . kg-1 lidoflazine intravenously before cardiopulmonary bypass (CPB), and a group (III) pretreated with 1 mg . kg-1 lidoflazine intravenously. The following markers of ischemia are used: (1) adenosine triphosphate (ATP), creatine phosphate (CP) and glycogen determined in transmural left ventricular biopsy specimens taken at the beginning and end of CPB; (2) ultrastructure in a similar pair of specimens; and (3) hemodynamic recovery 15 minutes after cessation of CPB. At the end of the intervention, ATP decreased to 73% in Group I but remained unchanged in Groups II (98%) and III (88%). CP decreased to 82% in Group I and remained unaltered in Groups II (100%) and III (110%). Glycogen decreased in Group I (to 44%) and in Group II (78%) but remained unchanged in Group II (138%). Ultrastructural study showed better preservation of the glycocalyx and sarcolemma in Group III than in Group I. Left ventricular stroke work index remained unaltered after CPB in Group III but decreased in Groups I and II to about 60% of its initial value. Thus lidoflazine pretreatment protects the myocardium in a dose-dependent manner against deterioration of myocardial function and structure.

Pretreatment with lidoflazine, a calcium-channel blocker. Useful adjunct to heterogeneous cold potassium cardioplegia.

Ten mongrel dogs were studied to determine if pretreatment with lidoflazine would protect the canine myocardium during aortic cross-clamping when circumflex coronary artery occlusion limits the distribution of cold potassium cardioplegia. A canine right heart bypass preparation was used. Regional function was determined with a sonomicrometer. Twenty minutes before aortic cross-clamping, lidoflazine or solvent was administered in a random, blind fashion. A circumflex artery snare prevented the cardioplegic solution from entering the circumflex artery. A 100 minute arrest period with cardioplegic infusion every 20 minutes was followed by 45 minutes of reperfusion before global and regional function were reevaluated. In the group receiving solvent, postarrest function in the circumflex region recovered to only 30% of prearrest values (p less than 0.05), a marked functional deterioration. In the group protected by lidoflazine, function in the circumflex region returned to 90% of prearrest values (NS). Function in the left anterior descending (LAD) regions of both groups demonstrated full recovery after arrest. Global left ventricular function was well preserved in both groups and failed to reflect the damaged, malfunctioning region in the group receiving solvent. These findings suggest that pretreatment with lidoflazine can improve myocardial protection when delivery of cardioplegia is not homogeneous.

Nucleoside transport inhibition mediates lidoflazine-induced cardioprotection during intermittent aortic crossclamping.

The effects of pretreatment with the nucleoside transport inhibitor lidoflazine on repeated ischemia-reperfusion injury induced by normothermic intermittent aortic crossclamping were studied in canine hearts. Eighteen mongrel dogs were allocated to three groups: placebo (n = 6), lidoflazine (1 mg/kg) (n = 6), and lidoflazine (1 mg/kg) plus the adenosine receptor blocker aminophylline (7 mg/kg) (n = 6). Pretreatment was performed intravenously during 15 minutes before extracorporeal circulation. All hearts were subjected to four intervals of 15 minutes of global ischemia each followed by 10 minutes of reperfusion. After weaning from extracorporeal circulation, functional recovery was followed for 1 hour. In the lidoflazine group, myocardial adenosine content (0.25 +/- 0.06 mumol/gm dry weight) was 3.5 times higher than that in the control group (0.07 +/- 0.03 mumol/gm dry weight; p < 0.05) at the end of the last aortic crossclamping. The release of adenosine from the myocardium during each reperfusion period was significantly higher than that in the control group (p < 0.05). Myocardial extraction of lactate was normalized at every reperfusion interval in the lidoflazine group but not in the control group (p < 0.05). In the lidoflazine group functional recovery was significantly better than that in the control group. Positive rate of rise of pressure, negative rate of rise of pressure, and cardiac output recovered to, respectively, 150% +/- 19%, 82% +/- 8%, and 131% +/- 15% in the lidoflazine group versus, respectively, 37% +/- 9%, 23% +/- 7%, and 29% +/- 8% in the control group (p < 0.001) at 1 hour after extracorporeal circulation. When the adenosine receptor blocker aminophylline was administered in association with lidoflazine, protection dropped significantly: positive and negative rate of rise of pressure and cardiac output were, respectively, 58% +/- 8%, 46% +/- 9%, and 67% +/- 16% at 1 hour after extracorporeal circulation (p < 0.05 versus lidoflazine alone). These results suggest that the cardioprotective effects of lidoflazine are at least in part mediated by adenosine receptor stimulation via nucleoside transport inhibition-induced accumulation of endogenous adenosine in the myocardium.

A clinical trial design avoiding undue placebo treatment.

A design is descirbed of a modified placebo-controlled double-blind clinical trial procedure. The design was evolved in attempt to overcome certain problems inherent in the conventional double-blind procedure, in particular the ethical problem of prolonged exposure of the patient to placebo treatment. The modified designs consist of two phases. In the first (open) phase, patients selected according to the normal protocol requirements are given the medication under study for a predetermined time. Patients responding favorably to such treatment then enter a second (double blind) phase during which is tested the null hypothesis that all the favorable effects observed during the open phase are placebo effects. Experience with this clinical trial design in the evaluation of an antianginal agent is briefly described. In this case, the null hypothesis was disproved, and a potent therapeutic action was evidenced.

Determinants of early and late results of combined valve operations and coronary artery bypass grafting.

BACKGROUND: Factors determining the outcome of operative correction of valvular abnormalities combined with coronary artery bypass grafting are still incompletely defined. METHODS: Determinants of early and late (more than 90 days) deaths and event-free survival were studied for combined valve operations and coronary artery bypass grafting in 741 patients using multivariate analysis. RESULTS: Ninety-day survival probability was 89% (95% confidence interval, 87% to 92%). Preoperative risk factors for early death were age, female sex, renal failure, New York Heart Association class IV or V, and mitral insufficiency. The operative risk factor was the duration of aortic cross-clamping. Five- and 10-year survival probabilities were 74% (95% confidence interval, 71% to 78%) and 43% (95% confidence interval, 36% to 50%), respectively. Preoperative risk factors for late death were age, preoperative renal failure, New York Heart Association class IV or V, vessel disease, and nonsinus rhythm. Five- and 10-year event-free survival probabilities were 57% (95% confidence interval, 53% to 61%) and 23% (95% confidence interval, 17% to 28%), respectively. Preoperative risk factors for non-event-free survival were age, female sex, reduced left ventricular function, mitral regurgitation, and pacemaker rhythm. CONCLUSION: The demographic factors of age and female sex; the comorbid condition of renal failure; the cardiac conditions of advanced New York Heart Association class, left ventricular function, mitral regurgitation, vessel disease, and cardiac rhythm; and the operative condition of ischemia time are the most important predictors of clinical outcome after combined valve operations and coronary artery bypass grafting.

The effect of carbon dioxide, lidoflazine and deferoxamine upon long term survival following cardiorespiratory arrest in rats.

This study examined the effect of carbon dioxide, lidoflazine and deferoxamine therapy upon the 10-day survival incidence and subsequent neurologic function of rats subjected to 7 min of cardiorespiratory arrest with resuscitation. Cardiac arrest (asystole) was induced at time zero by injection of cold, 1% KCl into the left ventricle of ketamine-anesthetized rats pretreated with succinylcholine. Positive pressure ventilation was discontinued at time zero. Cardiopulmonary resuscitation (CPR) was begun at 7 min, and animals with return of spontaneous circulation were entered into the study. Twenty treated rats were ventilated for 1 h with 7% carbon dioxide-93% oxygen and given lidoflazine (2.0 mg/kg, i.v.) and deferoxamine (50 mg/kg, i.v.) 5 min after CPR. Twenty control rats were ventilated for 1 h with 100% oxygen and given lidoflazine vehicle and deferoxamine vehicle. Lidoflazine treatment (1.0 mg/kg) for the treated group, or lidoflazine vehicle for the control group, was repeated at 8 h postresuscitation. At 2 days postresuscitation, 75% of treated rats vs. 25% of control rats were alive (CHI2 = 10.0, d.f. = 1, P less than 0.01), and at 10 days, 60% of treated rats vs. 25% of control rats were alive (CHI2 = 5.01, d.f. = 1, P less than 0.05). There was no detectable neurologic deficit among survivors in either group at 15 days. The combination of carbon dioxide, lidoflazine and deferoxamine, administered after return of spontaneous circulation, is a simple and easily administered treatment regimen that improves the survival incidence without neurologic deficits in this animal model of cardiorespiratory arrest and CPR.

Asphyxiation versus ventricular fibrillation cardiac arrest in dogs. Differences in cerebral resuscitation effects--a preliminary study.

UNLABELLED: We explored the hypothesis that brain damage after cardiac arrest caused by ventricular fibrillation (VF) needs different therapies than that after asphyxiation, which has been studied less thoroughly. In 67 healthy mongrel dogs of both sexes cardiac arrest (at normothermia) by ventricular fibrillation (no blood flow lasting 10 min) or asphyxiation (no blood flow lasting 7 min) was reversed by normothermic external cardiopulmonary resuscitation, followed by intermittent positive-pressure ventilation for 20 h, and intensive care to 96 h. To ameliorate ischemic brain damage, the calcium entry blocker lidoflazine or a solution of free radical scavengers (mannitol and L-methionine in dextran 40) plus magnesium sulphate, was given intravenously immediately upon restoration of spontaneous circulation. Outcome was evaluated as functional deficit, brain creatine kinase (CK) leakage into the cerebrospinal fluid (CSF) and brain morphologic changes. Lidoflazine seemed to improve cerebral outcome after VF but not after asphyxiation. Free radical scavengers plus magnesium sulphate seemed to improve cerebral outcome after asphyxiation, but not after VF. After VF, scattered ischemic neuronal changes in multiple brain regions dominated, and total brain histopathologic damage scores correlated with final neurologic deficit scores at 96 h (r = 0.66) and with peak CK levels in CSF (r = 0.81). After asphyxiation, in addition to the same ischemic neuronal changes, microinfarcts occurred, and there was no correlation between total brain histopathologic damage scores and neurologic deficit scores or CK levels in CSF. CONCLUSIONS: Different mechanisms of cardiac arrest, which cause different morphologic patterns of brain damage, may need different cerebral resuscitation treatments.

A quantitative morphological assessment of the effect of lidoflazine and deferoxamine therapy on global brain ischaemia.

The effect of the combination of two drugs, i.e. lidoflazine (a calcium antagonist), and deferoxamine (an iron chelator) was evaluated following 15 min global brain ischaemia (GBI) and reperfusion in dogs in a randomized blind study. GBI was produced by complete cardiac arrest of 15 min duration. Histopathological analysis performed on in situ fixed brains 40 h post-resuscitation revealed diffuse microhaemorrhages in the control group. These were noted rarely in the treatment group, the mean value of foci of microhaemorrhages/20 low power fields (LPF) being 5.2 in the treatment group versus 28 in the control group (p less than 0.001). Diffuse coagulative necrosis of neurons (ischaemic cell change) in the cerebral cortex, especially lamina 3, hippocampus, striatum, brain stem and cerebellum was present in all cases. Quantitation of the degree of cellular damage obtained by counting the number of anoxic neurons (in consistent regions of the brain) with the use of an image analysis system, revealed no significant difference between the 2 groups. The mean percentages of the ischaemic neurons in the control group in the various areas studied were: parietal cortex, 22.25; hippocampus, 50.37 and cerebellum (Purkinje cells), 66.75; and in the treatment group 25.3, 55.04 and 70.6 respectively. Thus, the lidoflazine-deferoxamine regimen significantly reduced the incidence of microhaemorrhages in the brain, but it did not have any protective effect against anoxic neuronal injury 40 h post-ischaemia in this experimental model of GBI of 15 min duration.

Lidoflazine in the management of angina pectoris.

The effect of lidoflazine administration (120 mg t.i.d. for 9 weeks) on work tolerance (bicycle ergometer), frequency of anginal attacks, and nitroglycerin consumption was investigated in 28 male patients with stable angina pectoris in a combined single-blind/double-bline study. Lidoflazine increased work tolerance and reduced the frequency of anginal attacks and nitroglycerin consumption. The higher work tolerance level was reached at maximal heart rate and heart rate--systolic blood pressure product values similar to those before treatment. The values of these variables after 3 min of exercise at 60 W, however, were significantly lower after treatment with lidoflazine. These findings indicate that the heart is performing more economically during lidoflazine treatment. The improved work tolerance can probably be ascribed to lidoflazine and not to a training effect because of the significant reduction of this variable in the patients allocated to placebo as compared to those remaining on lidoflazine treatment. The side effects were generally slight. In one patient the prolongation of the QT interval due to lidoflazine resulted in rhythm disturbances.

Lidoflazine and physical training in the treatment of stable angina pectoris.

An additive effect in the treatment of angina pectoris by combining lidoflazine and physical training was postulated. Twenty-four patients were randomly divided into placebo and drug groups and subsequently underwent a 6-month physical training program. The drug group had a significantly greater reduction in submaximal heart rate than the placebo group. Similar improvements in symptom-limited exercise capacity were observed in both groups. Resting and maximal exercise coronary sinus blood flow and left ventricular oxygen consumption were not significantly changed with training in either group. Physical training and lidoflazine appear to influence exercise tolerance in the same manner.

The effect of intravenous lidoflazine on whole blood-induced basilar artery contraction. An in vivo study.

Lidoflazine, a piperazine derivative of known selectivity for vascular smooth muscle, was evaluated as a possible agent for prophylaxis of cerebral vascular contraction induced by subarachnoid perfusion with whole blood. Previous studies from this laboratory have indicated its efficacy in preventing basilar artery contraction induced by serotonin. The animals treated with a subarachnoid perfusion of whole blood had a mean 30% reduction in vessel diameter over the control value. Groups that were treated with 0.5 mg/kg of lidoflazine and 1.0 mg/kg of lidoflazine and then perfused with whole blood in the subarachnoid space had reductions in control diameter of 2.8% and 6.8%, respectively. One group treated with 2.0 mg/kg of lidoflazine and then perfused with whole blood actually had an increase in diameter of 6.8% over the control value. Lidoflazine, when administered intravenously at a slow rate, will not adversely lower systemic blood pressure and can prevent the contraction of cerebral vessels when the stimulus for contraction is whole blood within the subarachnoid space.

Myocardial protection by lidoflazine during one-hour normothermic global ischemia.

The cardioprotective effects of lidoflazine, a drug with calcium homeostatic properties, were studied in 12 dogs (6 drug-treated and 6 controls) subjected to 1-hour normothermic global ischemia. None of the control dogs could be weaned from the extracorporeal bypass after 30 minutes of reperfusion. In contrast, all acutely pre-treated animals were able to support their own circulation. Recovery of pre-ischemic values in this group was 97 +/- 3% for systolic aortic pressure, 69 +/- 7% for diastolic aortic pressure, 97 +/- 10% for left ventricular pressure, and 84 +/- 11% for cardiac output. Electron microscopy and calcium cytochemistry were done on left ventricular biopsies taken before, during, and after ischemic arrest. In the control group, severe damage to the sarcolemma and the mitochondria was found at the end of the ischemic period and became more prominent after 5 and 30 minutes of reperfusion. There was great accumulation of calcium in the damaged mitochondria. In the lidoflazine-treated dogs, these lesions were largely prevented. These findings suggest a strong cardioprotective effect of lidoflazine during severe myocardial ischemia.