Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of intravenous infusion of 10 per cent glycerol on regional cerebral blood flow (using hydrogen bolus and Xenon-133 (133Xe) clearance methods) and metabolism was investigated in 57 patients with recent cerebral infarction. Hemispheric blood flow (HBF) increased, together with increase in regional cerebral blood flow (rCBF) and cerebral blood volume (rCBV), in foci of brain ischemia. Hemispheric oxygen consumption (HMIO2) decreased together with hemispheric respiratory quotient. Systemic blood levels of glucose, lactate, pyruvate, and triglycerides also increased after glycerol while free fatty acids (FFA) and inorganic phosphate (Pi) decreased. Hemispheric glucose consumption was unaltered after glycerol so that hemispheric glucose to oxygen ratio tended to rise. Pyruvate and lactate production by brain was unchanged. Glycerol moved across the blood brain barrier into brain and cerebrospinal fluid (CSF). Release of FFA and Pi from infarcted brain was reversed by glycerol. Total phosphate balance was maintained actoss brain both before and after glycerol infusion. Triglycerides increased in CSF after glycerol, originating either from cerebral blood or as a result of lipogenesis in cerebral tissue. The EEG Recording and neurological status of the patients improved despite decreased brain oxygen consumption. Results of this study suggest that after intravenous infusion of 10 per cent glycerol in patients with recent cerebral infarction, glycerol rapidly enters the CSF and brain compartments and favorably affects the stroke process in two ways: first, by redistribution of cerebral blood flow with increase in rCBF and rCBV in ischemic brain secondary to reduction in focal cerebral edema; and second glycerol may become an alternative source of energy either by being directly metabolized by the brain, or indirectly, by enhancing lipogenesis, or by both processes. Involvement of glycerol in lipogenesis with esterification to accumulated FFA might lead to improved coupling of oxidative phosphorylation, a hypothesis that fits the finding of improved neuronal function despite further decrease in cerebral hemispheric oxygen consumption.
 ...
PMID:Circulatory and metabolic effects of glycerol infusion in patients with recent cerebral infarction. 109 Mar 93

In isolated guinea pig hearts performing a defined stroke work, the influence of heart work and substrate uptake on the interconversion of pyruvate dehydrogenase (PDH) was studied. When hearts from fasted animals are perfused with a salt solution containing 10mM glucose, an increase in cardiac output and aortic pressure effects an increase in active PDH from 50 to 74% of total PDH activity and a decrease in tissue content of energy-rich phosphates. Pyruvate turnover calculated from oxygen consumption corresponds with PDH activity. Under these experimental conditions, PDH activity might either represent the rate limiting step of oxidative glucose breakdown, or it might be adjusted to a flux rate controlled by other factors. In fed animals, PDH activity exceeds the pyruvate turnover. However, an increase of heart work raises the active PDH from 76 to 95%. Addition of 10 mM acetate to the perfusion medium decreases PDH activity and glucose uptake. In fed animals, an increase of heart work raises the active PDH from 43 to 59% only, whereas in fasted animals this effect is abolished. The effect of changes in heart work on PDH interconversion might be explained by changes in energy-rich phosphate concentrations. However, substrate uptake and nutritional state may interfere or even abolish this effect.
 ...
PMID:[Influence of heart work and substrate uptake on the regulation of pyruvate dehydrogenase activity in isolated guinea pig hearts (author's transl)]. 117 27

The concentration of pyruvate in the venous blood of 31 patients with stroke was determined by the enzymatic spectrophotometric method. The pyruvate concentration was raised on the 1st, 3rd and 10th days after stroke and this increase was statistically significant. Pyruvate concentration changes in venous blood were associated with severe clinical condition of the patients.
 ...
PMID:[Venous blood concentration of pyruvates in patients with stroke]. 125 28

1. We have investigated the in vitro cardiac actions of flosequinan and of its major metabolite in man, BTS 53554. 2. Positive inotropic activity was seen with flosequinan in guinea-pig isolated ventricles, the threshold concentration for effect being less than 1 x 10(-5) M. BTS 53554 was approximately half as potent as the parent compound. 3. In guinea-pig working whole hearts flosequinan increased left ventricular dp/dtmax, indicating a positive inotropic action. This effect was accompanied by increases in heart rate, cardiac output and stroke volume. 4. The virtual complete inhibition of inotropic responses to flosequinan and BTS 53554 by carbachol suggests that these responses are adenosine 3':5'-cyclic monophosphate (cyclic AMP)-mediated. 5. Flosequinan was shown to increase calcium inward current in guinea-pig ventricle, an action consistent with a cyclic AMP involvement in the response. 6. The inotropic activity of flosequinan was not potentiated by the selective phosphodiesterase (PDE) III inhibitor SK&F 94120, a result which indicates that flosequinan does not increase cyclic AMP concentrations via stimulation of adenylate cyclase. 7. Flosequinan inotropic responses were potentiated by rolipram, a selective PDE IV inhibitor, a result consistent with flosequinan being itself a PDE III inhibitor. 8. Biochemical studies with purified enzymes confirmed that flosequinan and BTS 53554 are relatively selective inhibitors of PDE III. 9. A comparison of pharmacological and biochemical data for both flosequinan and BTS 53554 indicates that their PDE III inhibitory potency is sufficient to account for their inotropic activity.
 ...
PMID:Studies on the cardiac actions of flosequinan in vitro. 132 61

BTS 49465 (flosequinan), a putative selective, balanced arterial and venous vasodilator, displays positive inotropic effects in doses lower than those producing vasodilation. Thus rather than unloading the myocardium, flosequinan may increase myocardial work and oxygen consumption (MVO2), and may adversely affect the patient with myocardial ischemia or compromised coronary blood flow. This study compared the effects of flosequinan with milrinone, a mixed positive inotropic agent and vasodilator, and with nitroprusside (SNP), a standard direct-acting vasodilator, on myocardial dP/dT, MVO2, and myocardial energetics in the normal pentobartital-anesthetized dog. The effect of flosequinan on myocardial work was also evaluated in the dog with propranolol-induced heart failure (PIHF). Fifteen minutes after intraduodenal (id) administration of flosequinan (0.3, 1.0, and 3.0 mg/kg) to seven dogs, mean myocardial dP/dT was increased by 11%, 27%, and 54%, respectively, whereas stroke MVO2 was increased by 10%, 24%, and 47%, respectively. Doses of flosequinan greater than 0.3 mg/kg decreased left ventricular (LV) work but LV efficiency decreased in a dose-related manner. Milrinone (0.1, 0.3, and 1.0 mg/kg, id) increased LV dp/dt by 34%, 68%, and 104% above basal values, while increasing stroke MVO2 by 24%, 106%, and 249%, respectively (n = 7). LV work and LV efficiency decreased after each dose of milrinone. SNP (0.001, 0.003, and 0.01 mg/kg/min, intravenously) did not increase dP/dT but decreased LV work by 28%, 42%, and 46% (n = 5). In animals with PIHF, flosequinan (1 and 3 mg/kg, id) increased LV dP/dT 58% and 87% and increased LV work by 58% and 76% above control values. It was concluded that (1) flosequinan is a positive inotropic agent as well as a vasodilator; (2) in the normal animal the energy cost of positive inotropic activity is less with flosequinan than with milrinone, despite the lesser vasodilating action of the former; and (3) in the animal with a depressed myocardium, flosequinan may adversely affect myocardial work and wall tension.
 ...
PMID:Effect of flosequinan (BTS 49465) on myocardial oxygen consumption. 235 21

The hemodynamic effects of BTS 49465, a new oral, direct-acting systemic vasodilator drug, were investigated in 10 patients with severe chronic congestive heart failure. One to 2 hours after the administration of 1.5 mg/kg orally, BTS 49465 produced significant increases in cardiac index, stroke volume index, and stroke work index (26%, 27%, and 23%, respectively, p less than 0.01 to 0.001) and marked decreases in left ventricular filling pressure (-12.6 mm Hg, 44%), mean pulmonary artery pressure (-13.2 mm Hg, 31%), and mean right atrial pressure (-7.7 mm Hg, 63%), all p less than 0.001, without significant changes in heart rate. These hemodynamic responses were accompanied by notable declines in systemic vascular resistance (-28%, p less than 0.001) and pulmonary arteriolar resistance (-24%, p less than 0.05). These effects persisted throughout the 24-hour period of observation. The decline in left ventricular filling pressure in our patients ranged in magnitude from 8 to 21 mm Hg, and varied linearly and directly with pretreatment values for left ventricular filling pressure (r = 0.69). The decrease in systemic vascular resistance ranged in magnitude from 3% to 40% and varied linearly and directly with pretreatment values for systemic vascular resistance (r = 0.85). These data indicate that BTS 49465, a new oral, direct-acting vasodilator agent, exerts balanced cardiocirculatory effects in patients with severe chronic heart failure, which may be sustained with once-daily oral administration.
 ...
PMID:Hemodynamic effects of BTS 49465, a new long-acting systemic vasodilator drug, in patients with severe congestive heart failure. 379 27

Myocardial contractile performance is a function of sarcoplasmic reticular Ca2+ uptake and release. Ca2+ handling is ATP-dependent and can account for up to 40% of total myocardial energy expenditure. We tested the hypothesis that the thermodynamics of the cytosolic adenylate system can modulate sarcoplasmic reticular Ca2+ handling and hence function in intact heart. Cellular energy level was experimentally manipulated by perfusing isolated working guinea-pig hearts with substrate-free medium or media fortified with lactate and/or pyruvate as the main energy substrate. Left ventricular contractile function was judged by stroke work and intraventricular dP/dt. Cytosolic energy level was indexed by measured creatinine kinase reactants. Relative to 5 mM lactate, 5 mM pyruvate increased left ventricular stroke work, dP/dtmax, and dP/dtmin, while lowering left ventricular end-diastolic pressure at physiological left atrial and aortic pressures. Pyruvate also doubled cytosolic phosphorylation potentials and increased [ATP]/[ADP] ratio; this energetic enhancement distinguishes pyruvate from inotropic stimulation by catecholamines, which are known to decrease cytosolic energy level in perfused heart. Sarcoplasmic reticular Ca2+ handling was assessed in hearts prelabeled with 45Ca, subjected to 45Ca washout in the presence of different cytosolic energy levels, then stimulated with 10 mM caffeine to release residual sarcoplasmic reticular 45Ca. When ryanodine (1 microM) was applied to open Ca2+ channels and thereby released 45Ca from the sarcoplasmic reticulum during washout, caffeine-stimulated 45Ca release was decreased 96%, demonstrating that virtually the entire caffeine-sensitive 45Ca pool was located in the sarcoplasmic reticulum. In detailed comparisons of pyruvate-energized vs. substrate-free deenergized hearts, an inverse relationship between cytosolic energy level and caffeine-mobilized 45Ca pool size was observed. Thus, caffeine-induced 45Ca release was decreased 60% by pyruvate energization and increased 2.5-fold by substrate-free deenergization. Taken together, these results support the hypothesis that enhancement of myocardial inotropism by energy-yielding substrate is mediated by increased sarcoplasmic reticular Ca2+ loading/release. Thus we propose that the known control of sarcoplasmic reticular Ca2+ turnover by the protein kinase/phospholamban system can be modulated by cytosolic energy level.
 ...
PMID:Energetic modulation of cardiac inotropism and sarcoplasmic reticular Ca2+ uptake. 794 40

The aim of the study was the assessment of concentrations of pyruvic acid in the blood of patients with mild course and severe course of ischaemic stroke in the earliest stage of the disease. The subject of the study were 20 patients with a mild ischaemic stroke and 20 patients with a severe one on its 1st, 3rd and 7th day. Enzymatic method for determining pyruvic acid content in the blood was used (ready made reagents Test-Combination Pyruvate by Boerhinger Mannheim). In the group of patients with mild ischaemic stroke the concentrations of pyruvic acid were increased on all days of the disease, compared with controls, but the differences were statistically insignificant. In the group of patients with severe ischaemic stroke the concentrations of pyruvic acid were higher than the ones in control group, but only on the 1st and 3rd day of the disease the differences were statistically significant. The results of determinations indicate that there is a positive correlation between levels of pyruvic acid and severity of the clinical course of the disease.
 ...
PMID:[Evaluation of pyruvic acid concentration in blood of patients with ischemic stroke in the earliest stage of the disease]. 1110 73

BTS 72664, (R)-7-[1-(4-chlorophenoxy)]ethyl]-1,2,4-triazolo(1,5-alpha)pyrimidine, was identified as a drug development candidate from a research program designed to discover novel, broad-spectrum, non-sedative anticonvulsant drugs. BTS 72664 antagonized bicuculline (BIC)- and maximal electroshock (MES)-induced convulsions with ED(50) values of 1.9 and 47.5 mg/kg p.o., respectively. In rodents, it has a wide spectrum of activity preventing seizures induced by picrotoxin, pentylenetetrazol, i.c.v. 4-aminopyridine or NMDA, and audiogenic seizures in DBA-2 mice and GEPR-9 rats. BTS 72664 was also effective in preventing convulsions in amygdala-kindled rats The lack of sedative potential was predicted on the basis of wide separation between ED(50) in anticonvulsant models and TD(50) for motor impairment in mice in rotating rod and inverted horizontal grid tests. BTS 72664 is likely to produce its anticonvulsant effect by enhancing chloride currents through picrotoxin-sensitive chloride channels, and by weak inhibition of Na(+) and NMDA channels. It does not act, however, at the benzodiazepine binding site. In addition to its potential use in the treatment of epilepsy BTS 72664 may be useful in the treatment of stroke. At 50 mg/kg p.o. x 4, given to rats at 12 hourly intervals, starting at 15 min after permanent occlusion of middle cerebral artery (MCA), it reduced cerebral infarct size by 31% (measured at 2 days after insult) and accelerated recovery in a functional behavioral model. BTS 72664 prevented increases in extraneuronal concentrations of glutamate, glycine and serine brain levels induced by a cortical insult to rats (cf. cortical spreading depression). It may, therefore, have also antimigraine activity.
 ...
PMID:BTS 72664-- a novel CNS drug with potential anticonvulsant, neuroprotective, and antimigraine properties. 1147 22

Pyruvate has a remarkable protective effect against zinc neurotoxicity. Because zinc neurotoxicity is likely one of the key mechanisms of ischemic brain injury, the neuroprotective effect of pyruvate was tested in a rat model of transient forebrain ischemia. Control experiments in mouse cortical culture showed that pyruvate almost completely blocked zinc toxicity but did not attenuate calcium-overload neuronal death. Adult rats subjected to 12 min forebrain ischemia exhibited widespread zinc accumulation and neuronal death throughout hippocampus and cortex 72 hr after reperfusion. However, rats injected intraperitoneally with sodium pyruvate (500-1000 mg/kg) within 1 hr after 12 min forebrain ischemia showed almost no neuronal death. In addition, the mortality was markedly decreased in the pyruvate-protected groups (3.8%) compared with the NaCl-injected control group (58.1%). The neuroprotective effect persisted even at 30 d after the insult. The spectacular protection without noticeable side effects makes pyruvate a promising neuroprotectant in human ischemic stroke.
 ...
PMID:Protection by pyruvate against transient forebrain ischemia in rats. 1158 1


1 2 3 Next >>