Biomedical subjects

S Takeo

Publications and source records attributed to S Takeo.

At least 55 records · Page 3Linked to original sources

PubMed1998

Microsphere embolism-induced changes in noradrenaline uptake of the cerebral cortex in rats.

The present study was undertaken to elucidate pathophysiological changes in noradrenaline (NA) transporter and Na+/K+-ATPase, key regulators of cation gradient across the plasma membrane, in nerve terminals of the cerebral cortex after microsphere-induced cerebral embolism in rats. The Vmax value of NA uptake, when analyzed by the Eadie-Hofstee plot, tended to decrease on the 1st day and decreased on the 3rd and 7th days after the embolism without any change in the Km value. The NA content in cerebrocortical synaptosomes did not alter on the 1st day, but decreased on the 3rd and 7th days after the embolism. Ouabain (1 mM) inhibited NA uptake on the 1st day, but did not alter the uptake on the 3rd and 7th days after the embolism. The activity of Na+/K+-ATPase of cerebrocortical synaptosomes increased on the 1st day and gradually decreased up to the 7th day after the embolim. These results suggest that NA uptake in nerve terminals of the cerebral cortex decreased after microsphere embolism, which may be due to a reduction in function of NA transporters. The changes in Na+/K+-ATPase following microsphere embolism may represent a compensatory action to maintain ion homeostasis in nerve terminals at an early stage of ischemic injury.

Animals↗

PubMed1998

Microsphere embolism-induced changes in noradrenaline release in the cerebral cortex in rats.

The present study was undertaken to elucidate pathophysiological changes in noradrenaline release, phosphorylation of synapsin I and ultrastructure of the cerebrocortical nerve terminals following microsphere embolism in rats. In the microdialysis study, K+-stimulated noradrenaline release in the cerebral cortex was not altered on the 1st day but markedly decreased on the 3rd and 7th days after the embolism. Synaptosomes were isolated from the cerebral cortex of the operated animals on the 1st, 3rd and 7th days after the embolism. The level of calmodulin and the phosphorylation of synapsin I in the synaptosomes were not altered up to the 7th day, but the levels of calcium/calmodulin-dependent protein kinase II and synapsin I in the synaptosomes were significantly decreased by microsphere embolism. Electron microscopic study showed no appreciable changes in the structure of the synaptosomes on the 1st day, but a large number of clumps of synaptic vesicles were observed on the 3rd and 7th days after the embolism. These results suggest that microsphere embolism-induced changes in noradrenaline release from nerve terminals are due to a failure in the process following phosphorylation of synapsin I. Aggregation of synaptic vesicles in nerve terminals may contribute to the pathogenesis of microsphere embolism.

Animals↗

PubMed1998

Thujaplicin-copper chelates inhibit replication of human influenza viruses.

The effects of alpha-, beta- and gamma-thujaplicins and six of their metal chelates on human influenza virus-induced apoptosis in Madin-Darby canine kidney (MDCK) cells were examined by DNA fragmentation and flow cytometry. Among the compounds tested, thujaplicin copper chelates inhibited apoptosis induced in the infected MDCK cells with influenza A/PR/8/34(H1N1), A/Shingapol/1/57(H2N2), A/Aichi/2/68(H3N2) and B/Lee/40 viruses, at concentrations of more than 5 microM. These results indicate that the copper chelates inhibit influenza virus-induced apoptosis and that the inhibitory effects may be independent of influenza virus subtype or types. Furthermore, the copper chelates also inhibited the release of the viruses from the infected MDCK cells during apoptosis. The anti-apoptotic effects of the copper chelates may occur 2 4 h postinfection, suggesting that the copper chelates affect MDCK cells directly in the early stage of influenza virus-induced apoptosis. In this study, we demonstrated that thujaplicin-copper chelates inhibit influenza virus-induced apoptosis of MDCK cells and also inhibit virus replication and release from the infected cells.

Animals↗

PubMed1998

Effects of long-term treatment with trandolapril on sarcoplasmic reticulum function of cardiac muscle in rats with chronic heart failure following myocardial infarction.

1 Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca2+ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The present study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic reticular function in animals with CHF following myocardial infarction. 2 CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic flow and cardiac output index were decreased, and left ventricular end-diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF. 3 The developed force transients of cardiac skinned fibres of the rats with CHF were decreased when the skinned fibre was preloaded for 0.25-1 min with 10(-5) M Ca2+ (48-88%) and when preloaded with 10(-6) M Ca2+ and then exposed to 0.1-1 mM caffeine (45-93%). 4 The [3H]-ryanodine-binding activity in SR-enriched fractions was reduced by 23% in the CHF group. These results suggest that the amount of Ca2+ released from SR is decreased due to a reduced rate of SR Ca2+ uptake and a downregulation of the SR Ca2+-release channel. 5 Rats were treated orally with 3 mg kg(-1) day(-1) trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic flow and cardiac output index and the increase in left ventricular end-diastolic pressure, and improved the developed force transients of the skinned fibre of the animal with CHF without causing a reduction of infarct size. Treatment with trandolapril also attenuated the reduction in ryanodine receptor density in the viable left ventricle of the rat with CHF. 6 It is concluded that long-term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underlying this effect is, at least in part, attributed to prevention of downregulation of Ca2+ release channel.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Effects of the antihypertensive agent, cicletanine, on noradrenaline release and vasoconstriction in perfused mesenteric artery of SHR.

1. The mechanism by which cicletanine (CIC) exerts its antihypertensive effects has not been fully elucidated. The present study was undertaken to examine the effects of in vivo and in vitro treatment with CIC on the pressor response and noradrenaline (NA) overflow during periarterial nerve stimulation (PNS) in perfused mesenteric arterial beds isolated from spontaneously hypertensive rats (SHR). 2. CIC at a dose of 50 mg kg(-1) day(-1) was administered orally to both SHR and normotensive Wistar-Kyoto rats (WKY) from the 6th to 10th week of age. At the 10th week, the isolated mesenteric arterial bed was perfused with Krebs-Henseleit buffer and changes in perfusion pressure and NA overflow during PNS were measured. 3. Chronic treatment with CIC suppressed the age-related elevation of systemic blood pressure in SHR but not in WKY. 4. The PNS (20 Hz)-induced mesenteric vasoconstrictor response and NA overflow were greater in SHR than in WKY. In the vasculature of SHR chronic treatment with CIC resulted in a significant attenuation of the vasoconstriction and the NA overflow during PNS, whereas it did not alter vasoconstrictor responses to bolus injections of KCl and phenylephrine. 5. Treatment with 30 microM CIC in vitro diminished the PNS-induced vasoconstriction and NA overflow but not the NA- and KCl-induced vasoconstriction in the vasculature of untreated SHR. 6. In the vasculature of SHR PNS-induced NA overflow was attenuated by prostaglandin E2 (0.05 microM), whereas it was augmented by the cyclo-oxygenase inhibitor diclofenac-Na (30 microM). In the presence of diclofenac, in vitro treatment with CIC did not attenuate the NA overflow during PNS. 7. The results suggest that the antihypertensive effect of CIC in SHR is partially due to the presynaptic inhibition of NA release during sympathetic nerve activation. Transjunctional inhibition of NA release by prostaglandins may contribute to the inhibitory action of CIC on NA release in the vasculature of SHR.

Animals↗

PubMed1998

The effect of chronic treatment with trandolapril on cyclic AMP-and cyclic GMP-dependent relaxations in aortic segments of rats with chronic heart failure.

1 Characteristics of cyclic GMP- and cyclic AMP-mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation. 2 Cardiac output indices of coronary artery-ligated and sham-operated rats were 125+/-8 and 189+/-10 ml min(-1) kg(-1), respectively (P<0.05), indicating the development of CHF at this period. 3 The maximal relaxant response of aortic segments to 10 microM acetylcholine in rats with CHF and sham-operated rats was 64.0+/-5.7 and 86.9+/-1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham-operated rats. 4 In endothelium-intact segments of rats with CHF, the maximal relaxant response to 10 microM isoprenaline (44.5+/-6.7%) was lower that sham-operated rats (81.3+/-2.5%, P<0.05) and the concentration-response curve for NKH477, a water-soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline-induced relaxation of aortic segments was attenuated by NG-nitro-L-arginine methyl ester (L-NAME) in sham-operated rats, but not in rats with CHF. Relaxation to 30 microM dibutyryl cyclic AMP in rats with CHF (26.8+/-2.7%) was lower than that in sham-operated rats (63.4+/-11.8%, P<0.05). 5 Trandolapril (3 mg kg(-1) day(-1)) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5+/-3.6 ml min(-1)) was lower than that of sham-operated rats (55.0+/-3.0 ml min(-1)), and this reduction was reversed (54.1+/-3.4 ml min(-1)) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril-treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7+/-1.0%; that to isoprenaline, 80.5+/-2.8%; that to dibutyryl cyclic AMP, 54.7+/-6.2%). However, aortic segments of trandolapril-treated rats with CHF, L-NAME did not attenuate isoprenaline-induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged. 6 The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP-mediated signal transduction, was partially restored by long-term treatment with trandolapril. The mechanism underlying the restoration may be attributed in part to prevention of CHF-induced endothelial dysfunction.

Acetylcholine↗

PubMed1998

Modulation of cAMP-mediated vasorelaxation by endothelial nitric oxide and basal cGMP in vascular smooth muscle.

Recent in vitro evidence shows a role of endothelial nitric oxide (NO) in the modulation of isoproterenol-induced vasorelaxation. To elucidate roles of endothelial cells and NO in cyclic adenosine monophosphate (cAMP)-mediated vasodilators we examined the effects of removal of endothelium and a NO synthase (NOS) inhibitor on relaxant responses in vitro of rat aortic strips to beta-adrenoceptor stimulants and colforsin dapropate, a water-soluble forskolin, and changes in cAMP and cyclic guanosine monophosphate (cGMP) contents. Relaxant responses of rat aorta to isoproterenol, denopamine, salbutamol, colforsin, and dibutyryl cAMP (dbcAMP) were blunted by removal of endothelial cells or treatment with NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Relaxant response of endothelium-intact segments to isoproterenol was associated with increases in tissue cAMP and cGMP contents. Removal of endothelium or treatment with L-NAME markedly reduced basal cGMP and abolished the isoproterenol-induced increase in cGMP but not cAMP content. In endothelium-removed segments, pretreatment with sodium nitroprusside (SNP) restored the diminished relaxant response to isoproterenol and increased basal cGMP (from 0.08 +/- 0.01 to 0.16 +/- 0.02 pmol/mg protein), whereas it did not affect the isoproterenol-induced increase in cAMP. The diminished relaxant response of endothelium-removed segments to dbcAMP was not restored by SNP pretreatment. The results suggest that relaxant response of rat aorta to cAMP-mediated vasodilators is mediated, in part, by NO production in endothelium and subsequent increase in cGMP in vascular smooth-muscle cells.

Adrenergic beta-Agonists↗

PubMed1998

Pharmacologic preconditioning induced by beta-adrenergic stimulation is mediated by activation of protein kinase C.

Ischemic preconditioning (I-PC) occurs via activation of protein kinase C (PKC). This study was undertaken to determine whether pharmacologic preconditioning by beta-adrenergic stimulation (beta-PC) is mediated by PKC activation. Isolated rat hearts were subjected to 40-min ischemia and 30-min reperfusion. Beta-PC was induced by 0.25 microM isoproterenol pretreatment for 2 min followed by 10-min normoxic perfusion. Beta-PC enhanced the recovery of rate-pressure product of the ischemic/reperfused heart (79.1 +/- 8.4% vs. 12.4 +/- 1.6% of initial for Non-PC group, n = 6) and attenuated the release of creatine kinase during 30-min reperfusion (30.2 +/- 2.2 vs. 59.8 +/- 6.1 nmol/min/g wet wt for Non-PC group, n = 6), similar to an I-PC stimulus of 5-min ischemia and 5-min reperfusion. Treatment with 50 microM polymyxin B, a PKC inhibitor, abolished the cardioprotection of both beta-PC and I-PC. Furthermore, similar changes in subcellular distribution of PKC were induced by both beta-PC and I-PC. The changes in subcellular distribution of PKC-delta suggested its translocation from cytosol to membrane fraction, a marker of PKC activation. These results suggest that the cardioprotection induced by beta-PC, like I-PC, is mediated by PKC activation.

Adrenergic beta-Agonists↗

PubMed1998

Long-term supplementation with eicosapentaenoic acid salvages cardiomyocytes from hypoxia/reoxygenation-induced injury in rats fed with fish-oil-deprived diet.

Dietary supplementation of fish oil containing eicosapentaenoic acid (C20:5 n-3, EPA) and docosahexaenoic acid (C22:6 n-3, DHA) has been shown to exert protective effects on ischemic/reperfused hearts. We determined whether deprivation of fish oil from the diet paradoxically enhances susceptibility of cardiomyocytes to hypoxia/reoxygenation-induced injury and whether supplementation with either EPA or DHA overcomes such alterations. Rats were fed with fish-oil-rich (FOR) diet, fish-oil-deprived (FOD) diet alone, FOD diet with EPA (1 g/kg/day), or FOD diet with DHA (1 g/kg/day) for 4 weeks. The FOD diet reduced n-3 polyunsaturated fatty acids (PUFAs) and increased n-6 PUFAs such as linoleic (C18:2) and arachidonic acids (C20:4) in myocardial phospholipids. EPA or DHA supplementation increased its incorporation into phospholipid pools. Cardiomyocytes isolated by treatment with collagenase were subjected to 150 min of hypoxia and subsequent reoxygenation for 15 min. In the FOD diet group, the number of surviving rod-shaped cells after hypoxia and reoxygenation was smaller than that of the FOR group. Supplementation with EPA did not affect the number of rod-shaped cells, but attenuated reoxygenation-induced reduction in the number of square-shaped cells. In contrast, DHA supplementation did not afford any protection. The results suggest that deprivation of fish oil from dietary intake enhances the susceptibility of cardiomyocytes to hypoxic injury, and EPA, but not DHA, is capable of salvaging cardiomyocytes from hypoxia/reoxygenation-induced damage.

Animals↗

PubMed1998

Effects of long-term treatment with eicosapentaenoic acid on the heart subjected to ischemia/reperfusion and hypoxia/reoxygenation in rats.

The effects of eicosapentaenoic acid (EPA) and long-term treatment with EPA-ethylester (EPA-E) were examined in perfused rat hearts subjected to ischemia/reperfusion and adult rat cardiomyocytes subjected to hypoxia/reoxygenation. EPA (0.1 microM) improved postischemic contractile dysfunction of the ischemic/reperfused heart. EPA (10 microM) attenuated hypoxia/reoxygenation-induced morphological deterioration of cardiomyocytes. The results suggest the presence of direct cardioprotective effects of EPA. Rats were orally treated for 4 weeks with 1 g/kg/day of EPA-E to elucidate ex vivo effects of EPA, and the fatty acid composition of cardiac phospholipids was determined. The percent ratio of EPA in total fatty acids of cardiac phospholipids increased whereas that of arachidonic acid decreased. The percent ratio of n-3/n-6 fatty acid did not increase. Treatment with EPA-E did not improve the post-ischemic contractile function, but attenuated the ischemia/reperfusion-induced release of prostaglandins during reperfusion. Treatment with EPA-E preserved a better morphological appearance of the cardiomyocytes subjected to hypoxia/reoxygenation. The results suggest that the mechanisms responsible for cytoprotective effects of hypoxic/reoxygenated cardiomyocytes or inhibition of metabolic alterations of the ischemic/reperfused heart by long-term EPA-E treatment did not contribute substantially to recovery of post-ischemic contractile dysfunction. The direct in vitro effects of EPA may play a role in the protection of the heart from ischemia/reperfusion or hypoxia/reoxygenation injury.

Animals↗

PubMed1997

Cardiac sarcoplasmic reticular function in rats with chronic heart failure following myocardial infarction.

Sarcoplasmic reticular function of rats with chronic heart failure (CHF) following coronary artery ligation was examined. The coronary artery ligation produced 43% infarction of the left ventricle and increased left ventricular end-diastolic pressure 8 weeks after the operation, suggesting the development of CHF by this period. The developed force transients of the skinned fiber of coronary artery-ligated rats were decreased when the skinned fiber was preloaded for 0.25-0.5 min with 10(-5)M Ca2+ (53-70%) and when preloaded with 10(-6)M Ca2+ and then exposed to 0.1-1 mM caffeine (39-87%). The results suggest that the rate of Ca2+ uptake by the sarcoplasmic reticulum (SR) and its ability to release Ca2+ were reduced in the failing heart. [3H]Ryanodine binding activities in homogenates and SR-enriched fractions were significantly reduced in the coronary artery-ligated group (32% and 21%, respectively). The results suggest that the amount of Ca2+ released from SR decreased due to decreased Ca2+ uptake rate of SR and down-regulation of the SR Ca(2+)-release channel, which contributes to cardiac dysfunction in failing hearts following acute myocardial infarction.

Animals↗

PubMed1997

Acetylcholine-induced vasoconstrictor response of coronary vessels in rats: a possible contribution of M2 muscarinic receptor activation.

A mechanism by which acetylcholine (ACh) may elicit vasoconstrictor response in coronary vessels was studied in rat hearts perfused at a constant flow rate. In spontaneously beating hearts, bolus injections of ACh and carbachol (CCh) produced biphasic changes in coronary perfusion pressure (CPP): a transient increase at the initial period followed by a sustained decrease. In KCl-arrested hearts, ACh and CCh produced a monophasic increase in CPP, which was attenuated by either removal of endothelial cells by saponin or cyclooxygenase inhibition by diclofenac sodium. In the spontaneously beating heart, ACh-induced vasoconstriction was almost abolished by atropine (0.1 microM) and was markedly attenuated by an M2 antagonist, methoctramine (0.1 microM), but not by an M1 antagonist, pirenzepine (1 microM). Arecaidine propargyl ester (APE), an M2 agonist, produced coronary artery constriction which was attenuated by methoctramine (0.1 microM) but not by pirenzepine (0.1 microM) in both spontaneously beating and KCl-arrested hearts. McN-A-343, an M1 agonist, increased CPP in both beating and KCl-arrested hearts, but to a lesser degree than APE. These results suggest that the release of vasoconstrictor prostaglandins from endothelial cells contributes to the vasoconstrictor response to ACh in perfused rat coronary vessels, and the response to ACh appears to be mediated, in part, via the M2 subtype of muscarinic receptors.

Acetylcholine↗

PubMed1997

Does glycogen depletion play an important role in ischemic preconditioning?

The present study was undertaken to determine whether or not tissue glycogen depletion prior to ischemia, and subsequent attenuation of tissue lactate accumulation during ischemia, correlates with postischemic functional recovery of the preconditioned heart. Isolated rat hearts were subjected to 40-min ischemia and 30-min reperfusion. Preconditioning with 5-min ischemia and 5-min reperfusion reduced the preischemic glycogen and postischemic lactate levels of the heart to 60.5 +/- 5.6% and 66.9 +/- 7.7% respectively, of values in non-preconditioned hearts (n = 6), and improved the recovery of the rate-pressure product (RPP) of the ischemic/reperfused heart (87.0 +/- 5.8% versus 25.2 +/- 4.5% of the initial value for the non-preconditioned group, n = 8). Treatment with polymyxin B (50 microM) abolished the preconditioning-induced postischemic recovery of the RPP. Treatment of the non-preconditioned heart with phorbol 12-myristate 13-acetate (15 pmol/5 min) resulted in an improvement in the postischemic recovery of RPP. Neither of these treatments affected the preischemic glycogen and postischemic lactate levels. The results suggest that preischemic glycogen depletion and subsequent attenuation of ischemic lactate accumulation do not play a major role in the preconditioning-induced protection against postischemic contractile dysfunction in perfused rat hearts.

Animals↗

PubMed1997

Activation of cardiac muscarinic receptor and ischemic preconditioning effects in in situ rat heart.

Activation of cardiac muscarinic receptors by vagal stimulation decreases cardiac work, which may have a protective effect against ischemic injury. To determine whether cardiac muscarinic receptors contribute to the mechanisms of preconditioning effects, we examined the effect of carbachol on ischemia/reperfusion damage and the effect of vagotomy on cardioprotection induced by ischemic preconditioning. Rats were subjected to 30 min of left coronary artery occlusion followed by 30-min reperfusion in situ. Pre-conditioning was induced by three cycles of 2-min coronary artery occlusion and, subsequently by 5 min of reperfusion. The incidence of ischemic arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), and the development of myocardial infarction were markedly reduced by the preconditioning. Carbachol infusion (4 micrograms/kg per min) delayed the occurrence of VT and VF during ischemia and reduced the infarct size. Compared with non-ischemic left ventricle, the cyclic guanosine monophosphate (GMP) content in the ischemic region of the left ventricle was decreased by ischemia/reperfusion, whereas the cyclic adenosine monophosphate (AMP) content of this region was increased. These changes were reversed by preconditioning. Similar changes in cyclic GMP and AMP content in the ischemic region were seen in rats undergoing carbachol treatment. These results suggest the possible contribution of muscarinic receptor stimulation to preconditioning. Vagotomy prior to preconditioning diminished the antiarrhythmic effects, whereas it did not block the anti-infarct effect afforded by pre-conditioning. Vagotomy abolished the preconditioning effect on the tissue cyclic GMP, but it did not attenuate the decrease in tissue cyclic AMP. The results suggest that muscarinic stimulation exerts preconditioning-mimetic protective effects in ischemic/reperfused hearts, but that a contribution of reflective vagal activity to the mechanism for preconditioning is unlikely.

Animals↗

PubMed1997

Failure in learning task and loss of cortical cholingergic fibers in microsphere-embolized rats.

The present study was undertaken to elucidate the pathological changes in learning and memory functions and in the metabolism of cortical cholinergic neurons following microsphere embolism in the rat. Microspheres (48 microm) were injected into the right internal carotid artery of rats. Learning and memory functions were measured 7 or more days after the embolism by active and passive avoidance, and water maze tasks. In the biochemical study, cortical acetylcholine and choline contents, and choline acetyltransferase activity were measured. Cortical acetylcholinesterase-containing fibers were quantitatively estimated in the embolized rat. The active and passive avoidance, and water maze tasks were impaired in the microsphere-embolized rat. In the histochemical study, the density of cortical acetylcholinesterase-containing fibers of the ipsilateral hemisphere of the microsphere-embolized rat was decreased, but cell density was unchanged. Furthermore, microsphere embolism decreased the cortical acetylcholine concentration and choline acetyltransferase activity and increased the choline concentration. The results suggest that microsphere embolism causes severe damage to cortical cholinergic neurons, which may be, at least in part, related to the impairment of learning and memory functions in the sustained brain ischemia.

Acetylcholine↗

PubMed1997

Preconditioning preserves mitochondrial function and glycolytic flux during an early period of reperfusion in perfused rat hearts.

OBJECTIVE: The purpose of the present study was to examine the effects of preconditioning on glycolysis and oxidative phosphorylation during reperfusion in perfused rat hearts. METHODS: Preconditioning was induced by 5 min of ischemia and 5 min of reperfusion before 40 min of sustained ischemia and subsequent 30 min of reperfusion. Tissue energy metabolite levels, mitochondrial oxygen consumption capacity and adenine nucleotide translocator content of the perfused hearts were assessed at 40 min of ischemia, 5 and 30 min of reperfusion. RESULTS: Preconditioning improved the postischemic recovery of rate x pressure product (92.5 +/- 8.7 vs. 24.9 +/- 1.2% for non-preconditioned group) and high-energy phosphate content (ATP and CrP; 39.5 +/- 2.0 and 96.2 +/- 4.9% of initial vs. 24.1 +/- 0.9 and 56.1 +/- 4.3% of initial for the non-preconditioned group). The mitochondrial oxygen consumption capacity and the adenine nucleotide translocator content of the non-preconditioned heart were decreased by sustained ischemia and remained decreased throughout reperfusion. Preconditioning prevented these decreases. The tissue lactate level of the non-preconditioned heart was high throughout reperfusion (16.5-fold vs. basal), whereas in the preconditioned heart it returned to the basal level within a few minutes of reperfusion. Furthermore, the ratios of [fructose 1,6-bisphosphate]/([glucose 6-phosphate] + [fructose 6-phosphate]) at 5-min reperfusion were higher (2.2-fold) than those of the non-preconditioned heart. CONCLUSIONS: The results suggest that preconditioning preserves the capacity for normal mitochondrial function and the facilitation of glycolysis during reperfusion, which may play an important role in the improvement of postischemic contractile function and high-energy phosphate content.

Adenosine Triphosphate↗

PubMed1997

Changes in cholinergic neurons and failure in learning function after microsphere embolism-induced cerebral ischemia.

Central cholinergic neurons play an important role in learning and memory functions. The present study was undertaken to elucidate the pathological changes in learning function and acetylcholine metabolism of the cerebral cortex and hippocampus, following microsphere embolism in rats. Microspheres (48 microns) were injected into the right internal carotid artery of the rats. Learning function was determined using a passive avoidance task on the seventh day after the embolism. In the biochemical study, acetylcholine and choline contents, and choline acetyltransferase activity were measured in the cerebral cortex and hippocampus. Cortical acetylcholinesterase-containing fibers were quantitatively estimated in the embolized rat. Passive avoidance was impaired in the microsphere-embolized rat. Microsphere embolism decreased the acetylcholine concentration and choline acetyltransferase activity in the cerebral cortex and hippocampus. In the histochemical study, the length of cortical acetylcholinesterase-containing fibers was decreased, but cell density was unchanged in the ipsilateral hemisphere of the microsphere-embolized rat. The results suggest that microsphere embolism induces severe damage to cholinergic neurons, which may be related to the impairment of learning function in the ischemic brain.

Acetylcholine↗

PubMed1997

Effects of delayed treatment with nebracetam on neurotransmitters in brain regions after microsphere embolism in rats.

1. The effects of delayed treatment with nebracetam, a novel nootropic drug, on neurotransmitters of brain regions were examined in rats with microsphere embolism-induced cerebral ischaemia. 2. Cerebral ischaemia was induced by administration of 900 microspheres (48 microns) into the internal carotid artery. The rats with stroke-like symptoms were treated p.o. with 30 mg kg-1 nebracetam twice daily. The levels of acetylcholine, dopamine, noradrenaline, 5-hydroxytryptamine (5-HT) and their metabolites in the cerebral cortex, striatum and hippocampus of animals with microsphere embolism were determined by high performance liquid chromatography (h.p.l.c.) on the 3rd and 7th days after the operation. 3. Although the microsphere embolism induced significant changes in most of the neurotransmitters and some of their metabolites in the brain regions, the delayed treatment with nebracetam partially restored only the hippocampal 5-HT and the striatal dopamine metabolite contents on the 3rd day. 4. The hippocampal in vivo 5-HT synthesis, but not the striatal dopamine synthesis, was attenuated in rats with microsphere embolism on the 3rd day, but was restored by treatment with nebracetam. In vivo striatal dopamine turnover rate of the rats with microsphere embolism was inhibited on the 3rd day irrespective of treatment with nebracetam. 5. The present study provides evidence for a possible action of nebracetam on 5-HT metabolism in the ischaemic brain.

Acetylcholine↗