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Cardiomyocytes proliferate during fetal life but lose their ability to proliferate soon after birth and further increases in cardiac mass are achieved through an increase in cell size or hypertrophy. Mammalian target of rapamycin complex 1 (mTORC1) is critical for cell growth and proliferation. Rheb (Ras homologue enriched in brain) is one of the most important upstream regulators of mTORC1. Here, we attempted to clarify the role of Rheb in the heart using cardiac-specific Rheb-deficient mice (Rheb(-/-)). Rheb(-/-) mice died from postnatal day 8 to 10. The heart-to-body weight ratio, an index of cardiomyocyte hypertrophy, in Rheb(-/-) was lower than that in the control (Rheb(+/+)) at postnatal day 8. The cell surface area of cardiomyocytes isolated from the mouse hearts increased from postnatal days 5 to 8 in Rheb(+/+) mice but not in Rheb(-/-) mice. Ultrastructural analysis indicated that sarcomere maturation was impaired in Rheb(-/-) hearts during the neonatal period. Rheb(-/-) hearts exhibited no difference in the phosphorylation level of S6 or 4E-BP1, downstream of mTORC1 at postnatal day 3 but showed attenuation at postnatal day 5 or 8 compared with the control. Polysome analysis revealed that the mRNA translation activity decreased in Rheb(-/-) hearts at postnatal day 8. Furthermore, ablation of eukaryotic initiation factor 4E-binding protein 1 in Rheb(-/-) mice improved mRNA translation, cardiac hypertrophic growth, sarcomere maturation, and survival. Thus, Rheb-dependent mTORC1 activation becomes essential for cardiomyocyte hypertrophic growth after early postnatal period.

We investigated the effects of fasting on gene expression and intracellular signals regulating energy metabolism in adipose tissue. Following fasting for 15h or 39h, epididymal fat pads were isolated from Wistar rats. PPARgamma mRNA levels decreased in the adipose tissues isolated from rats fasted for 39h, whereas adipocyte lipid-binding protein (aP2) and lipoprotein lipase (LPL) mRNA levels increased. Overnight fasting increased the AMP/ATP ratio and AMP-activated protein kinase (AMPK) in adipose tissue, but not in muscle or liver tissue. In addition, the effect of 5-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR) on PPARgamma expression in primary cultured adipocytes was investigated. AICAR reduced PPARgamma mRNA levels but increased aP2 and LPL mRNA levels. Thus, fasting-induced AMPK activation may affect on the regulation of gene expression in adipocytes.

Objectives We aimed to clarify the relation between sarpogrelate (SG), a 5-hydroxytryptamine (5-HT)-2 receptor blocker, and myocardial interstitial serotonin or infarct size during ischemia and reperfusion. Background In cardiac tissues serotonin is rich in vascular platelets, mast cells, sympathetic nerve endings, and the receptors are present in platelets and cardiomyocytes. Methods The myocardial interstitial serotonin levels were measured using a microdialysis technique during 30-min ischemia with and without SG in in vivo as well as isolated rabbit hearts. Other rabbits underwent 30 min of ischemia and 48 h of reperfusion, and the effect of SG on the infarct size was investigated in the absence and presence of a selective protein kinase C (PKC) inhibitor, chelerythrine (5 mg/kg, intravenously), or a mitochondrial adenosine triphosphate sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate (5-HD) (5 mg/kg, intravenously). In another series, the effect of SG on PKC isoforms in cytosol and membrane fraction was assessed after a 20-min global ischemia in isolated rabbit hearts. Results Interstitial serotonin levels were markedly increased during 30-min ischemia in in vivo and isolated hearts, and the increases were inhibited by SG in each. The infarct size was reduced by SG (27 ± 2% vs. 40 ± 3% of control). This effect was blocked by chelerythrine and 5-HD, respectively. Sarpogrelate further enhanced the ischemia-induced translocation of PKC-ϵ to the membrane fraction. Conclusions Sarpogrelate reduces the myocardial infarct size by inhibiting the serotonin release followed by enhancement of PKC-ϵ translocation and opening of the mitochondrial KATP channel in ischemic myocytes.

OBJECTIVES This study focused on 1) the determination of the optimal preconditioning (PC) duration, and 2) the protective effect of nicorandil (NC), a hybrid nitrate with a K atp channel opening effect, during a percutaneous transluminal coronary angioplasty (PTCA) model in humans. BACKGROUND The ischemic PC effect is induced in 180 s ischemia, but not in 120 s ischemia in rabbit hearts. However, the duration of ischemia that induces PC effect and the role of the K atp channel in the PC effect in humans are still unclear. METHODS Forty-six patients with stable angina were randomly allocated to four groups: the duration of the first inflation as PC ischemia was 60 s in the PC60 group (n = 12), and 180 s in the PC180 group (n = 12). In the other groups, NC (80 μg/kg) was intravenously given for 1 min in the NC group (n = 12), and isosorbide dinitrate (ISDN) (40 μg/kg) was given in the ISDN group (n = 10). Five minutes after first inflation or drug administration, a second inflation was conducted for 120 s in each group. In the ECG, the lead with the largest shift in ST segment (deltaST max), and the sum of elevated ST levels in all leads (sigmaST) were determined. RESULTS In the PC60 group, no significant difference was observed in either deltaST max or sigmaST between the first and second inflation. However, the second inflation in the PC180 group showed significantly lower levels of deltaST max and sigmaST compared with those of the first inflation. In the NC group, both deltaST max and sigmaST measured at 30 s and 60 s after balloon inflation were significantly lower than those of the first inflation in the PC60 and PC180 control groups. In the ISDN group, no significant difference was observed in deltaST max or sigmaST. CONCLUSION In human PTCA models, a PC effect is observed in 180 s ischemia, but not in 60 s ischemia. A pharmacological PC effect is induced by NC, a K atp channel opener with a nitrate-like effect but not ISDN. This suggests that the opening of K atp channels plays an important role in the protecting effect of NC.

We examined whether nicorandil reduces myocardial infarct size (1) when administered before ischemia, and (2) when administered before reperfusion, and whether (3) infarct size is influenced by the plasma nicorandil concentration and the opening of the K(ATP) channel. Anesthetized open-chest Japanese white male rabbits were subjected to a 30 min coronary occlusion (ischemia) and a 48 h reperfusion in the following six groups; Group 1 (n=9): control group, Group 2 (n=9): pre-ischemia to post-reperfusion group (nicorandil 10 microg/kg/min, i.v.), Group 3 (n=7): pre-ischemia to post-reperfusion+glibenclamide group (glibenclamide 0.3 microg/kg, i.v.+nicorandil 10 microg/kg/min, i.v.), Group 4 (n=8): pre-reperfusion to post-reperfusion group (nicorandil 10 microg/kg/min, i.v.), Group 5 (n=8): pre-ischemia low-dose group (nicorandil 10 microg/kg/min for 5 min i.v.), Group 6 (n=7): pre-ischemia high-dose group (nicorandil 100 microg/kg/min for 5 min i.v.). The plasma nicorandil concentrations were measured from blood samples taken immediately before the ischemia. After the 48 h reperfusion, the size of the infarct was measured histologically with immunohistochemical actin staining and expressed as a percentage of the area at risk.Infarct sizes were as follows; Group 1 (control): 41.0+/-3.5%, Group 2: 31.3+/-2.0% (P0.05 vs. control), Group 3: 40.9+/-3.4%, Group 4: 45.2+/-4.4%, Group 5: 35.8+/-3.3%, Group 6: 25.2+/-3.9% (P0.05 vs. control). Infarct size was inversely correlated with the plasma nicorandil concentrations (y=-0.031x+41.0, r=0.65, P0.05).The pre-ischemic but not post-ischemic administration of nicorandil reduced the size of myocardial infarct by opening the K(ATP) channels, and this effect was dependent on the plasma nicorandil concentrations immediately before the ischemia induced in rabbits.

Thirteen children (1.8–15.8 years of age) with brain tumors were studied with [11C] l -methionine positron emission tomography (METPET). Patients were injected intravenously with tracer before a baseline PET scan was obtained. To assess the sensitivity of [11C] l -methionine uptake to competitive inhibition, 10 patients received oral l -phenylalanine (100 mg/kg); 1 hour later, a second METPET was obtained. Subjective assessment of [11C] l -methionine uptake closely paralleled results of quantitative examination (r = 0.81). [11C] l -methionine uptake in tumor-containing brain was increased in 11 patients (mean ratio of [11C] radioactivity in tumor to normal brain: 1.5 ± 0.57; range: 1.13–2.98). Increased tracer uptake occurred in ependymomas (3), medulloblastoma (1), and astrocytomas (5), but was less intense in low-grade tumors. l -phenylalanine reduced l -methionine uptake (25–69%) in 70% of studies. l -methionine uptake was not sensitive to competitive inhibition in brain radiation injury. Two-phase METPET is of potential value in difficult clinical situations evident in children with brain tumors, including the differential diagnosis of tumor recurrence and cerebral radiation injury.