Biomedical subjects

Satoshi Takeo

Publications and source records attributed to Satoshi Takeo.

At least 19 recordsLinked to original sources

PubMed2007

Changes in Hsp60 level of the failing heart following acute myocardial infarction and the effect of long-term treatment with trandolapril.

Changes in heat shock protein (Hsp) 60 of the viable left ventricular muscle (viable LV) after myocardial infarction in rats and the effect of the angiotensin I-converting enzyme inhibitor (ACEI) trandolapril were examined. Myocardial infarction was induced in rats by ligation of the left coronary artery. The coronary artery-ligated (CAL) and sham-operated (Sham) rats were orally treated with 3 mg/kg/d trandolapril from the 2nd to 8th week after surgery. Hemodynamic parameters and tissue weights of the left and right ventricles of the animals at the 8th week after CAL (8w-CAL rats) showed signs indicating chronic heart failure. An increase in Hsp60 content, a decrease in mitochondrial oxygen consumption rate (OCR), and an increase in the mitochondrial thiobarbiturate-reacting substance (TRS) of the viable LV were detected. Eight weeks after CAL. Long-term treatment of the CAL rats with trandolapril improved the hemodynamic parameters, attenuated the CAL-induced increase in Hsp60 content, the decrease in mitochondrial OCR, and the increase in the mitochondrial TRS content of the viable LV at the 8th week after myocardial infarction. The increase in Hsp60 content was closely related to the decrease in the mitochondrial OCR and to a rise in the LVEDP of the CAL animal at the 8th week after myocardial infarction. These results suggest that a series of pathophysiological alterations, including a reduction in mitochondrial function, appearance of reactive oxygen stress, and production of Hsp60 is involved in the development of cardiac failure and that trandolapril is beneficial for preventing these alterations.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2006

Vasopressin V1A receptor enhances baroreflex via the central component of the reflex arc.

The neurohypophyseal peptide [Arg(8)]-vasopressin (AVP) exerts its physiological actions via 3 distinct receptor isoforms designated V1A, V1B, and V2. We recently showed that V1A receptor was involved in the baroreflex control of heart rate using V1A receptor knockout mice. The present study was undertaken to further clarify this finding. In conscious mice, resting blood pressure of the knockout group was lower than that of the wild-type group (wild-type, 108+/-2.0 mm Hg; knockout, 98+/-3.8 mm Hg; n=6-7) without notable change in heart rate. Although phenylephrine and nitroprusside-induced changes in blood pressure did not differ in these strains, the subsequent bradycardia and tachycardia were markedly blunted in the knockout mice (mean slopes for baroreflex curve after phenylephrine treatment; wild-type, -5.65+/-0.30 bpm/mm Hg; knockout, -3.97+/-0.52 bpm/mm Hg; those after nitroprusside treatment; wild-type, -0.51+/-0.10 bpm/mm Hg; knockout, -0.18+/-0.05 bpm/mm Hg; n=6-7). Under urethane anesthesia (1.0-1.2 g/kg, i.p.), electrical stimulation of the vagal afferent nerve evoked frequency-dependent hypotension and bradycardia in the wild-type mice. In contrast, in the knockout mice such stimulation induced a pressor, not a depressor, response and diminished bradycardia. Moreover, electrical stimulation-induced hemodynamic changes through the vagal afferent nerve in the wild-type mice were significantly attenuated by pretreatment with intravenously administered V1A receptor antagonist d(CH(2))(5)Tyr(Me)AVP. Electrical stimulation of the vagal efferent nerve-induced hemodynamic changes (depressor and bradycardia) and chronotropic responses to adrenergic and cholinergic stimuli were not different between the 2 strains. These results suggest that the V1A receptor in the central nervous system is involved in the regulation of the heart rate via the baroreflex arc.

Animals↗

PubMed2006

Hepatocyte growth factor attenuates cerebral ischemia-induced increase in permeability of the blood-brain barrier and decreases in expression of tight junctional proteins in cerebral vessels.

Hepatocyte growth factor (HGF) exerts its physiological activities as that of an organotropic factor for regeneration and can prevent ischemia-induced injuries; however, its effect and mechanism of action under in vivo pathophysiological conditions remains to be determined. Recently, we demonstrated that treatment with human recombinant HGF (hrHGF) attenuated the disruption of the blood-brain barrier (BBB) observed after microsphere embolism-induced sustained cerebral ischemia. To see if tight junctional proteins were involved in this attenuation, in the present study, we investigated the effects of HGF on the levels of occludin and zonula occludens (ZO)-1 in cerebrovascular endothelial cells after microsphere embolism. Sustained cerebral ischemia was induced by the injection of 700 microspheres (48 microm diameter) into the right internal carotid artery of rats. hrHGF was injected into the right ventricle of the brain by using an osmotic pump at a dose of 30 microg/7 days per animal. The levels of tight junctional proteins in the endothelial cells were examined by immunohistochemical analysis. Treatment with hrHGF attenuated the decrease in the expression of occludin and ZO-1 proteins in the endothelial cells that occurred after sustained cerebral ischemia. Furthermore, treatment with hrHGF resulted in retention of these tight junctional proteins in fluorescein isothiocyanate (FITC)-albumin-perfused cerebral vessels, which did not leak FITC-albumin in the ipsilateral cortex. These results suggest that HGF-mediated maintenance of the tight junctional proteins in the endothelial cells may be a possible mechanism for the protective effect of HGF against the disruption of the BBB after cerebral ischemia.

Animals↗

PubMed2006

The protective effect of hepatocyte growth factor against cell death in the hippocampus after transient forebrain ischemia is related to the improvement of apurinic/apyrimidinic endonuclease/redox factor-1 level and inhibition of NADPH oxidase activity.

Early oxidative DNA damage is regarded to be an initiator of neuronal apoptotic cell death after cerebral ischemia. Although evidence suggests that HGF has the ability to protect cells from oxidative stress, it remains unclear as to how HGF suppresses oxidative DNA damage after cerebral ischemia. Apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) is a multifunctional protein in the DNA base repair pathway that is responsible for repairing apurinic/apyrimidinic sites in DNA after oxidation. We demonstrated that both the immunoreactivity and the number of APE/Ref-1-positive cells in the hippocampal CA1 region were decreased after transient forebrain ischemia and that treatment with HGF suppressed this reduction. The expression of Cu/ZnSOD and MnSOD in the hippocampal CA1 region did not change after ischemia, regardless of treatment with or not with HGF. The activity of NADPH oxidase was increased mainly in glia-like cells in the hippocampal CA1 region after ischemia, and this increase was attenuated by HGF treatment. These results suggest that the protective effects of HGF against cerebral ischemia-induced cell death in the hippocampal CA1 region are related to the improvement of neuronal APE/Ref-1 expression and the inhibition of NADPH oxidase activity in glia-like cells.

Apoptosis↗

PubMed2006

V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity.

Arginine-vasopressin (AVP) is a hormone that is essential for both osmotic and cardiovascular homeostasis, and exerts important physiological regulation through three distinct receptors, V1a, V1b, and V2. Although AVP is used clinically as a potent vasoconstrictor (V1a receptor-mediated) in patients with circulatory shock, the physiological role of vasopressin V1a receptors in blood pressure (BP) homeostasis is ill-defined. In this study, we investigated the functional roles of the V1a receptor in cardiovascular homeostasis using gene targeting. The basal BP of conscious mutant mice lacking the V1a receptor gene (V1a-/-) was significantly (P < 0.001) lower compared to the wild-type mice (V1a+/+) without a notable change in heart rate. There was no significant alteration in cardiac functions as assessed by echocardiogram in the mutant mice. AVP-induced vasopressor responses were abolished in the mutant mice; rather, AVP caused a decrease in BP, which occurred in part through V2 receptor-mediated release of nitric oxide from the vascular endothelium. Arterial baroreceptor reflexes were markedly impaired in mutant mice, consistent with a loss of V1a receptors in the central area of baroreflex control. Notably, mutant mice showed a significant 9% reduction in circulating blood volume. Furthermore, mutant mice had normal plasma AVP levels and a normal AVP secretory response, but had significantly lower adrenocortical responsiveness to adrenocorticotropic hormone. Taken together, these results indicate that the V1a receptor plays an important role in normal resting arterial BP regulation mainly by its regulation of circulating blood volume and baroreflex sensitivity.

Adrenal Cortex↗

PubMed2006

Effects of hepatocyte growth factor on phosphorylation of extracellular signal-regulated kinase and hippocampal cell death in rats with transient forebrain ischemia.

Hepatocyte growth factor (HGF) has been implicated in protection against several types of cell injuries. We investigated the effects of human recombinant HGF (hrHGF) on the selective neuronal cell death in the hippocampal CA1 region after transient forebrain ischemia in rats and explored the nature of the intracellular signaling pathway for the protection against this neuronal injury. hrHGF was injected continuously into the hippocampal CA1 region directly using an osmotic pump from 10 min to 72 h after the start of reperfusion. The marked increase in the number of TUNEL-positive cells found in the CA1 region after ischemia was almost completely abolished by the hrHGF treatment. Akt phosphorylation as well as IkappaB phosphorylation, which has been implicated in events downstream of the Akt, was not affected by hrHGF treatment. Extracellular signal-regulated kinase (ERK) phosphorylation was decreased in the CA1 region with time after ischemia. hrHGF increased or recovered ERK phosphorylation without changing the total amount of ERK protein. Immunohistochemical analysis demonstrated that phosphorylated ERK was colocalized with a neuronal nucleus marker NeuN in the hippocampal CA1 region of ischemic rats with hrHGF treatment at the early period after reperfusion. These results suggest that the protective effects of hrHGF against neuronal death in the hippocampal CA1 after transient forebrain ischemia could be related to an ERK-dependent pathway.

Animals↗

PubMed2006

Prevention of apoptosis-inducing factor translocation is a possible mechanism for protective effects of hepatocyte growth factor against neuronal cell death in the hippocampus after transient forebrain ischemia.

Hepatocyte growth factor (HGF) is one of the prospective agents for therapy against a variety of neurologic and neurodegenerative disorders, although the precise mechanisms for the effect of HGF remain to be elucidated. We showed that treatment with HGF protected hippocampal cornu ammonis (CA) subregion 1 neurons from apoptotic cell death after transient forebrain ischemia. Accumulating evidence indicates that ischemia-induced neuronal damage occurs via caspase-independent pathways. In the present study, we focused on the localization of apoptosis-inducing factor (AIF), which is an important protein in the signal-transduction system through caspase-independent pathways, to investigate the possible mechanism for the protective effect of HGF after transient forebrain ischemia. Hepatocyte growth factor attenuated the increase in the expression of AIF protein in the nucleus after transient forebrain ischemia. We further explored the upstream components of AIF translocation. Primary DNA damage induced by Ca(2+) influx and subsequent NO formation are thought to be the initial events for AIF translocation, which results in the subsequent DNA damage by AIF. Hepatocyte growth factor prevented the primary oxidative DNA damage, as was estimated by using anti-8-OHdG (8-hydroxy-2'-deoxyguanosine) antibody. Oxidative DNA damage after ischemia is known to lead to the activation of poly(ADP-ribose) polymerase (PARP) and p53, resulting in AIF translocation. Marked increases in the PAR polymer formation and the expression of p53 protein after ischemia were effectively prevented by HGF treatment. In the present study, we first showed that HGF was capable of preventing neuronal cell death by inhibiting the primary oxidative DNA damage and then preventing the activation of the PARP/p53/AIF pathway.

Animals↗

PubMed2006

Possible involvement of calpain activation in pathogenesis of chronic heart failure after acute myocardial infarction.

Changes in proteolytic activity of the myocardium during the development of heart failure after left coronary artery ligation (CAL) of rats were examined. Hemodynamics of the rats at the eighth week (8w-CAL rat), but not at the second week (2w-CAL rat), after CAL showed the symptoms of chronic heart failure. Contents of mu-calpin and m-calpain, but not an intrinsic calpain inhibitor calpastatin, in the viable left ventricular muscle (viable LV) and the right ventricular muscle (RV) of the 2w-CAL and 8w-CAL rats were increased, which was associated with an elevation of intrinsic activities of leupeptin-sensitive, Ca(2+)-activated proteolysis in the cytosolic fractions of the viable LV and RV. Oral administration of 3 mg/kg/d trandolapril or 1 mg/kg/d candesartan from the second to eighth week after CAL improved the hemodynamics of 8w-CAL rats. The drug treatment attenuated the increases in mu-calpain and m-calpain contents and the elevation of the proteolytic activity of the viable LV and RV in the 8w-CAL rat. The drug treatment increased calpastatin content of the RV in the 8w-CAL rat. These results suggest that sustained activation of calpain is involved in the development of chronic heart failure and that trandolapril and candesartan prevent the activation of calpains after CAL.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Amelioration of ischemia/reperfusion-induced myocardial infarction by the 2-alkynyladenosine derivative 2-octynyladenosine (YT-146).

The present study was aimed at determining whether the novel adenosine A2-agonist YT-146 may have cardioprotective effects against ischemia-reperfusion injury. Anesthetized open-chest dogs underwent 90-min occlusion of the left anterior descending artery and subsequent 300-min reperfusion. The animals were randomly assigned to receive vehicle, 3, or 10 microg/kg YT-146 or ischemic preconditioning (4 episodes of 5 min occlusion followed by 5 min of reperfusion). Blood pressure, heart rate, and regional myocardial blood flow throughout the experiment were measured, as was the myocardial infarct size after reperfusion. The infarct size of the vehicle-treated dog was 56.2% +/- 2.7% (n = 5), whereas that of 3 or 10 microg/kg YT-146-treated dog was smaller (ie, 29.5% +/- 8.7% or 20.2% +/- 7.0%, respectively; n = 5). The infarct size of the dog treated with 10 microg/kg YT-146 was reduced to a degree similar to that of the ischemic preconditioning (19.2% +/- 6.3%, n = 5). YT-146 at both doses elicited a dose-dependent increase in acute hyperemic coronary flow immediately after reperfusion. The cardioprotective effect may be attributed to the limitation of the infarct size, probably via A2-receptor-mediated coronary artery dilatation during the early period of reperfusion.

Adenosine↗

PubMed2006

Cardiac effects of ST-6, a novel cyclohexane dicarboximide derivative.

Na(+) channel blockade is thought to be involved in the cardioprotection against ischemia/reperfusion injury. We synthesized various cyclohexane dicarboximides and examined their cardioprotective actions. Some of these derivatives had local anesthetic action and were capable of enhancing post-hypoxic contractile recovery of the isolated perfused rat heart. Among them, 2-[4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]hexahydro-1H-isoindol-1,3(2H)-dione hydrochloride (ST-6) was most effective in the enhancement of post-hypoxic contractile recovery of isolated perfused rat hearts subjected to 20-min hypoxia and 45-min reoxygenation. This enhanced recovery by 30 mg/min of ST-6 was associated with attenuation of Na(+), but not of Ca(2+), accumulation during ischemia and prevention of creatine kinase release from the heart during reperfusion. When hearts subjected to 30-min ischemia followed by 60-min reperfusion were pretreated with 30 muM ST-6, the post-ischemic contractile recovery was enhanced and ischemia-induced accumulation of Na(+), as well as reperfusion-induced accumulation of Na(+) and Ca(2+), was attenuated. Also the reperfusion-induced release of creatine kinase was reduced, while restoration of myocardial high-energy phosphates was enhanced during reperfusion. Na(+) channel blockade by ST-6, as assessed by the depression of the Vmax of the action potential, was similar to that produced by flecainide but more pronounced than with either lidocaine or disopyramide. ST-6, 1, or 2 mg/kg i.v. or 10 mg/kg i.p., abolished ventricular fibrillation induced by 4 min of ischemia and subsequent 4 min of reperfusion in rats. The prevention of ventricular fibrillation by the continuous injection of 0.2 mg/kg per min ST-6 from the first min after ischemia to the end of reperfusion was similar in degree to that produced by 0.1 mg/kg/min lidocaine or 0.5 mg/kg/min diltiazem. The former treatment elicited a transient decrease in the systemic blood pressure in anesthetized rats during ischemia, whereas treatment with the latter did not reduce systemic blood pressure. These findings suggest that ST-6 may have cardioprotective effects in ischemia/reperfusion injury.

Animals↗

PubMed2005

Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries.

Cerebral ischemia induces disruption of the blood-brain barrier (BBB), and this disruption can initiate the development of brain injuries. Although the molecular structure of tight junctional complexes in the BBB has been identified, little is known about alterations of tight junctional proteins after cerebral ischemia. Therefore, we investigated alterations of tight junctional proteins, i.e., occludin and zonula occludens (ZO)-1, in isolated rat brain capillaries after microsphere-induced cerebral embolism. We demonstrated that the levels of occludin and ZO-1 had decreased after the embolism. The embolism also resulted in a marked increase in tyrosine phosphorylation of occludin, which was coincident with an increase in the activity of c-Src. These results suggest that a decrease in the levels of occludin and ZO-1, and an increase in tyrosine phosphorylation of occludin may play an important role in the disruption of tight junctions, which may lead to dysfunction of the BBB after cerebral ischemia.

Animals↗

PubMed2005

Effects of angiotensin I-converting enzyme inhibitor and angiotensin II type 1 receptor blocker on the right ventricular sarcoglycans and dystrophin after left coronary artery ligation.

We examined the effects of trandolapril and candesartan on changes in the levels of sarcoglycans and dystrophin in the right ventricle of rats with the left coronary artery ligation. Hemodynamic and morphological alterations suggested the development of hypertrophy of the right ventricle and chronic heart failure by the 8th week. By the end of the 8th week, alpha- and beta-sarcoglycans and dystrophin were decreased. Increases in mu- and m-calpains in the hypertrophied right ventricle were associated with an elevation of casein-proteolytic activity in the cytosolic fraction. Oral administration of 3 mg/kg/day trandolapril or 1 mg/kg/day candesartan from the 2nd to 8th week after the left coronary artery ligation attenuated decreases in alpha-sarcoglycan and dystrophin and reduced the increased proteolytic activity. The results suggest that attenuation of decreases in sarcoglycans and dystrophin is a possible mechanism underlying trandolapril- and candesartan-mediated improvement of structural and functional alterations of the right ventricle in the coronary artery-ligated rat.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2005

Inhibition of apoptosis-inducing factor translocation is involved in protective effects of hepatocyte growth factor against excitotoxic cell death in cultured hippocampal neurons.

Although hepatocyte growth factor (HGF) and its receptor are expressed in various regions of the brain, their effects and mechanism of action under pathological conditions remain to be determined. Over-activation of the N-methyl-d-aspartate (NMDA) receptor, an ionotropic glutamate receptor, has been implicated in a variety of neurological and neurodegenerative disorders. We investigated the effects of HGF on the NMDA-induced cell death in cultured hippocampal neurons and sought to explore their mechanisms. NMDA-induced cell death and increase in the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells were prevented by HGF treatment. Although neither the total amounts nor the mitochondrial localization of Bax, Bcl-2 and Bcl-xL were affected, caspase 3 activity was increased after NMDA exposure. Treatment with HGF partially prevented this NMDA-induced activation of caspase 3. Although the amount of apoptosis-inducing factor (AIF) was not altered, translocation of AIF into the nucleus was detected after NMDA exposure. This NMDA-induced AIF translocation was reduced by treatment with HGF. In addition, increased poly(ADP-ribose) polymer formation after NMDA exposure was attenuated by treatment with HGF. These results suggest that the protective effects of HGF against NMDA-induced neurotoxicity are mediated via the partial prevention of caspase 3 activity and the inhibition of AIF translocation to the nucleus.

Animals↗

PubMed2005

Effects of ACE inhibitor and AT1 blocker on dystrophin-related proteins and calpain in failing heart.

OBJECTIVES: Genetic depletion of dystrophin-related protein (DRP) complex causes cardiomyopathy in animals and humans. We found in a previous study that some types of DRP were degraded and that calpain content was increased in rats with non-genetically induced heart failure. The present study was aimed at examining the effects of an angiotensin-I-converting enzyme inhibitor (ACEI) trandolapril (Tra) or an angiotensin II type 1 receptor blocker (ARB) candesartan (Can), both of which are known to improve the pathophysiology of chronic heart failure (CHF) on degradation of DRP in failing hearts. METHODS: Coronary artery-ligated (CAL) and sham-operated rats (Sham rats) were treated orally with 3 mg/kg/day trandolapril (Tra) or 1 mg/kg/day candesartan (Can) from the 2nd to 8th week after surgery. RESULTS: Hemodynamic parameters of CAL rats at the 8th week after CAL (8w-CAL) indicated heart failure. alpha-Sarcoglycan (SG) and dystrophin in the surviving left ventricle (surviving LV) of 8w-CAL rats decreased, whereas beta-, gamma-, and delta-SGs remained unchanged. Calcium-activated neutral proteases mu-calpain and m-calpain increased in the surviving LV at the 8th week of postmyocardial infarction. Proteolytic activity in the presence of 5 mM Ca2+ markedly increased at the 2nd and 8th weeks, whereas 50 microM Ca2+ slightly but significantly increased proteolysis of casein. Tra or Can treatment improved the hemodynamic parameters, attenuated changes in alpha-SG and dystrophin, and reversed both calpain contents and activities of the failing heart back to sham levels. CONCLUSION: These results suggest that attenuation in calpain-induced degradation of DRP complex is a possible mechanism for the Tra- or Can-mediated improvement of the pathogenesis of CHF following myocardial infarction.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

Changes in the expression of Hes5 and Mash1 mRNA in the adult rat dentate gyrus after transient forebrain ischemia.

Accumulating evidence indicates that neurogenesis in the adult brain occurs in restricted brain regions, including the hippocampal dentate gyrus and is promoted by ischemia. The mechanism responsible for ischemia-induced neurogenesis in the adult brain, however, remains unclear. Notch pathway plays a pivotal role in the regulation of the timing for differentiation and determination of the fate of neural progenitor cells in the developing nervous system. To elucidate the mechanism underlying ischemia-induced neurogenesis, we investigated changes in the expression of mRNAs of Hes5, which is a downstream target of Notch, and Mash1, a neurogenic basic helix-loop-helix factor, which is negatively regulated by Hes5, in the adult hippocampal dentate gyrus after transient forebrain ischemia. Transient forebrain ischemia was produced by four-vessel occlusion procedure in rats. The levels of Hes5 mRNA decreased on days 1 and 3 after the start of reperfusion and the decreased levels of the mRNA returned to the basal level by 5 days after ischemia. In contrast, the level of Mash1 mRNA increased on day 1 and then returned to the basal level by 3 days after ischemia. These results suggest that an inhibition of Notch activity and subsequent expression of neurogenic basic helix-loop-helix factors, including Mash1, may, at least in part, contribute to ischemia-induced neurogenesis in the adult dentate gyrus.

Animals↗

PubMed2005

Production and autocrine/paracrine effects of endogenous insulin-like growth factor-1 in rat cardiac fibroblasts.

Insulin-like growth factor (IGF)-1 appears to play an important role in cardiac hypertrophy or remodeling. However, the role of endogenous IGF-1 in the growth of cardiac myocytes and fibroblasts remains unclear. This study investigated the major site of the production of cardiac IGF-1 and the local effects of endogenous IGF-1 secreted from cardiac cells. A significant expression of IGF-1 mRNA was found in cultured neonatal and adult rat cardiac fibroblasts, but not in myocytes. In addition, an in vivo examination by in situ hybridization histochemical analyses demonstrated the IGF-1 transcripts in the interstitial fibrotic tissue of the ventricle. Time-dependent secretion of IGF-1 protein was also observed in cultured cardiac fibroblasts. An antibody against IGF-1 decreased collagen synthesis in cardiac fibroblasts under basal conditions. Fibroblast-conditioned medium, as well as exogenous IGF-1, increased protein synthesis in cardiac myocytes, and this increase was inhibited by antibodies against IGF-1 and IGF-1 receptor, IGF binding protein-3, and IGF-1 receptor antagonist. These observations suggest that IGF-1 is produced and released mainly from cardiac fibroblasts and that endogenous IGF-1 promotes collagen synthesis by cardiac fibroblasts and hypertrophy of myocytes as an autocrine and a paracrine factor. Cardiac IGF-1 may function as an endogenous modulator of cardiac hypertrophy or remodeling.

Animals↗

PubMed2005

Time course and sequence of pathological changes in the cerebellum of microsphere-embolized rats.

Ischemia is a major cause of damage to the central nervous system as a consequence of stroke or trauma. Here, we analyzed with high temporal resolution the time course of pathological changes in the neurons (granule and Purkinje cells) and glia (Bergmann and astroglia cells) in the cerebellar cortex and white matter. The period studied ranged from 30 min to 7 days after a microsphere-induced embolism used as a model of stroke and multi-infarct dementia. Some pathological changes in the neurons in the cerebellar cortex were identified early, that is, beginning at 3 h after the microsphere-induced embolism, and glial pathology appeared only later. The pathological changes in the white matter also appeared slightly later, that is, 6 h after embolism and were less pronounced than those in the cerebellar cortex. This suggests that neuronal pathology is induced more rapidly and/or more easily than the glial pathology. In addition, BrdU staining shows that cell proliferation is limited to a 1-day period beginning about 1 day after the embolism. These data demonstrate that changes after an ischemic lesion of the cerebellum proceeds from upper cerebellar cortex to deeper cerebellar cortex or white matter and also that microsphere-induced changes proceed from neuronal to glial pathology.

Animals↗

PubMed2005

Effects of a novel cyclohexane dicarboximide derivative, ST-6, on reperfusion-induced arrhythmia in rats.

The present study was designed to determine whether a novel cyclohexane dicarboximide derivative, ST-6, 2-[4-[4-(chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]hexahydro-1H-isoindol-1,3(2H)-dione, prevents reperfusion-induced ventricular arrhythmias. Pentobarbital-anesthetized rats were subjected to left coronary artery occlusion for 4 min followed by 4-min reperfusion, and the incidence of their ventricular arrhythmias was examined. The coronary occlusion of control rats induced ventricular tachycardia and fibrillation, eventually leading to sudden death. The intravenous injection of 0.1 to 2 mg/kg ST-6 prior to the occlusion resulted in a dose-dependent suppression of the ventricular arrhythmias. The suppression of ventricular fibrillation was also observed on the intraperitoneal and intradoudenal administration of 2 to 10 mg/kg ST-6 15 min prior to coronary occlusion. Antiarrhythmic effects of this agent (0.5 mg/kg per min) were compared with those of other antiarrhythmic agents including lidocaine (0.1 mg/kg per min), sematilide (0.3 mg/kg per min), and diltiazem (0.5 mg/kg per min) by administrating the agents from 1 min after the coronary occlusion to the end of 4-min reperfusion. Antiarrhythmic effects of ST-6 were similar in degree to those of lidocaine and diltiazem, whereas no significant prevention by sematilide was seen. The results suggest that ST-6 may be capable of suppressing reperfusion-induced arrhythmias following oral or intravenous administration.

Animals↗