Biomedical subjects

K Satoh

Publications and source records attributed to K Satoh.

At least 199 records · Page 11Linked to original sources

PubMed2000

Induction of antitumor immunity by combined immunogene therapy using IL-2 and IL-12 in low antigenic Lewis lung carcinoma.

Interleukin-2 (IL-2) and interleukin-12 (IL-12) are crucial cytokines that induce potent antitumor responses in a variety of animal cancer models. Although single gene transfer of either IL-2 or IL-12 exhibits limited antitumor effects, the combination of IL-2 and IL-12 has been shown to induce a stronger antitumor response and to cure tumor-bearing mice. To examine the conditions necessary for tumor rejection, we varied the local concentration of IL-2 and IL-12 by introducing these genes into Lewis lung carcinoma (LLC) cells via retroviral vectors and/or an adenoviral vector and evaluated the growth of inoculated LLC cells (5 x 10(5) cells). In contrast to the result when using a stepwise dose increase of IL-2 either without or with a fixed production of IL-12 (4-5 ng/5 x 10(5) cells/24 hours, insufficient for tumor rejection by itself), rejection of the tumor was achieved in 75% of the mice when the IL-12 secretion was combined with high and transient IL-2 production (42 ng/5 x 10(5) cells/24 hours) using additional adenoviral vector transduction (100 multiplicities of infection). An abundant infiltration of both CD4+ (47.4/mm2) and CD8+ (85.6/mm2) T cells was a characteristic finding in the dual gene-transfected LLC tumors. Importantly, consistent with the rejection of rechallenged parental cells, tumor-specific cytotoxic T lymphocytes were induced only from the splenocytes of mice inoculated with the dual gene-transduced LLC cells, suggesting the existence of protective antitumor memory. In addition, only vaccination of dual gene-transduced LLC cells inhibited the growth of pre-established LLC tumors. These results indicate that generation of a pivotal antitumor response likely depends on the synergistic combination and concentration of IL-2 and IL-12 in the local milieu by which tumor-specific immune memory is established.

Adenoviridae↗

PubMed2000

Rabeprazole, amoxycillin and low- or high-dose clarithromycin for cure of Helicobacter pylori infection.

BACKGROUND: Rabeprazole sodium is a proton pump inhibitor. AIM: To evaluate the efficacy and safety of 1-week triple therapy with rabeprazole, amoxycillin and clarithromycin for the eradication of Helicobacter pylori. METHODS: A total of 100 subjects with H. pylori were randomly divided into two groups of 1-week triple therapy with rabeprazole 10 mg b.d., amoxycillin 750 mg b.d. and either clarithromycin 200 mg b.d. (RAC400, n=50) or clarithromycin 400 mg b. d. (RAC800, n=50). Endoscopic examination with four biopsies (two specimens from the antrum and two from the gastric body) was performed. The status of H. pylori infection was determined using culture and histology (Giemsa stain) of the biopsy specimens. Sensitivity to clarithromycin was determined using the E-test: MIC > 8 g/mL was considered to be resistant, whereas MIC < 2 g/mL was considered to be sensitive. Cure was defined as no evidence of H. pylori infection 1 month after completion of treatment. RESULTS: There were no significant differences in the clinical characteristics of the two groups. Eradication rates (intention-to-treat and per protocol, respectively) were: RAC400: 86% (95% CI: 76-95%) and 89% (95% CI: 80-97%); RAC800: 94% (95% CI: 87-100%) and 97% (95% CI: 94-100%). There was no significant difference between the eradication rates of either regimen. Three subjects with failed eradication in the RAC400 group were all infected with a clarithromycin-resistant strain before beginning the therapy. Haemorrhagic colitis was the only severe adverse event, which was observed in one patient in the RAC800 group. CONCLUSION: One-week triple therapy with rabeprazole, amoxycillin and low-dose clarithromycin is effective for the eradication of H. pylori infection.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2000

Intronic U50 small-nucleolar-RNA (snoRNA) host gene of no protein-coding potential is mapped at the chromosome breakpoint t(3;6)(q27;q15) of human B-cell lymphoma.

BACKGROUND: In eukaryotic cells, nucleolar processing of preribosomal RNAs (prerRNAs) is assisted by a large number of small nucleolar RNAs (snoRNAs) that function in the 2'-O-methylation or the pseudouridylation of rRNAs. Most snoRNAs so far characterized are encoded and processed from introns of premRNAs. RESULTS: We found a novel intronic snoRNA gene, named U50HG, located on chromosome 6q15, at the breakpoint of chromosomal translocation t(3;6)(q27;q15). The U50HG gene is composed of six exons, whose spliced transcripts have little potential for coding a protein, and its introns produce both U50 and U50-like (U50') snoRNAs that are localized in nucleoli. It possesses an oligopyrimidine tract that is characteristic of the 5'-terminal oligopyrimidine (5'TOP) class of genes which have been shown to be coordinately regulated in response to cell growth. CONCLUSIONS: U50HG is a member of the nonprotein-coding multiple snoRNA host gene family, as well as of the 5'TOP gene family similar to UHG (U22 host gene), U17HG (U17 host gene), U19HG (U19 host gene) and gas5 (growth arrest-specific transcript 5 gene). It is novel to find that the snoRNA gene is located at the breakpoint of chromosomal translocation t(3;6)(q27;q15) involved in human B-cell lymphoma.

Alternative Splicing↗

PubMed2000

The colorectal tumour suppressor APC is present in the NMDA-receptor-PSD-95 complex in the brain.

BACKGROUND: The synaptic protein PSD-95/SAP90 interacts with ion channels such as the N-methyl-D-aspartate-receptor (NMDA-R) via its PDZ domain, and is involved in their clustering. Moreover, it interacts with signalling molecules and plays an important role in coupling NMDA-R to pathways that control synaptic plasticity and learning. RESULTS: We report that PSD-95 interacts with the adenomatous polyposis coli (APC) tumour suppressor protein via its PDZ domain. Furthermore, we found that PSD-95, NMDA-R and APC are contained in the same complex in vivo. PSD-95-NMDA-R-APC association was found to require two cysteine residues conserved in the amino-terminus of PSD-95 that are known to be critical for its multimerization. CONCLUSION: Our findings suggest that the PSD-95-NMDA-R-APC complex forms due to the multimerization of PSD-95 monomers, each of which can associate with either NMDA-R or APC. It is possible that APC is involved in the regulation of ion channel clustering and/or organization of signalling molecules.

Adenomatous Polyposis Coli Protein↗

PubMed2000

The hDLG-associated protein DAP interacts with dynein light chain and neuronal nitric oxide synthase.

BACKGROUND: Postsynaptic density (PSD)-95 interacts with and mediates clustering of the N-methyl-D-aspartate-receptors (NMDA-R). PSD-95 also interacts with the hDLG-associated protein DAP, which is also called Synapse-associated protein 90-associated protein (SAPAP), and Guanylate kinase-associated protein (GKAP). RESULTS: DAP interacted directly with the dynein light chain (DLC) family of proteins. DLC was contained in the NMDA-R-PSD-95-DAP-neuronal nitric oxide synthase (nNOS) complex. Furthermore, DAP interacted with nNOS and recruited it into the Triton X-100-insoluble fraction of transfected cells. CONCLUSION: DAP interacts directly with DLC and nNOS, and links these proteins to the NMDA-R-PSD-95 complex.

Animals↗

PubMed2000

Activation of adenosine A1-receptor pathway induces edema formation in the pancreas of rats.

BACKGROUND & AIMS: Adenosine has been shown to modulate various pathophysiologic conditions through receptor-mediated mechanisms. However, the role of adenosine in the pathogenesis of acute pancreatitis has not been described. We examined the effect of adenosine-receptor stimulation or inhibition on the pathologic changes of the pancreas. METHODS: Rats received intraperitoneal injections of selective agonists of A1, A2a, and A3 adenosine receptors: 2-chloro-N(6)-cyclopentyladenosine (CCPA), CGS-21680 (CGS), or 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-be ta-D-ribofuranuronamide (IB-MECA), respectively. Serum amylase activity and pathologic changes of the pancreas were evaluated. The effects of a specific A1-receptor antagonist (FK-838) on the pathologic findings of cerulein- and taurocholate-induced pancreatitis were also examined. RESULTS: Administration of a selective A1 agonist induced hyperamylasemia and morphologic changes in the pancreas characterized by interstitial edema and leukocyte infiltration; neither A2a nor A3 agonist produced such changes. Treatment with an A1-receptor antagonist significantly attenuated the outcome induced by A1 agonist stimulation. In addition, the A1-receptor antagonist significantly ameliorated pancreatic edema in both pancreatitis models, although it did not improve the acinar cell damage of the pancreas or the increase of serum amylase. CONCLUSIONS: Activation of the adenosine A1-receptor pathway may have an important role in the pathogenesis of acute pancreatitis.

Acute Disease↗

PubMed2000

Frequent presence of Helicobacter pylori genome in the saliva of patients with hyperemesis gravidarum.

Recently, possible involvement of Helicobacter pylori (H. pylori) in hyperemesis gravidarum have been reported based on serological studies and the therapeutic effects of antibiotics. In this study, we examined for the presence of H. pylori genome [by (PCR) of saliva] in combination with serological techniques. Thirty-four patients with hyperemesis and 29 normal pregnant subjects were examined for serum anti-H. pylori IgG antibodies and PCR of saliva. By serum antibody test, 16 of 34 hyperemesis patients (47.5%) were positive for anti-H. pylori IgG antibody, while 6 of 29 control subjects (20.6%) were positive (chi2 p < 0.0005). PCR revealed positive H. pylori genome in 21 cases out of 34 hyperemesis (61.8%, 14 of 16 patients positive for H. pylori antibody and 7 of H. pylori-antibody-negative 18 patients) and 8 of 29 control subjects (27.6%) (chi2 p < 0.000001). We suggest chronic infection of H. pylori as one of the important factors on the pathogenesis of hyperemesis gravidarum even though it may not be the single cause of the disorder.

Adult↗

PubMed2000

Platelet activation mediated through membrane glycoproteins: involvement of tyrosine kinases.

Fc gamma RII cross-linking and anti-CD9 mAbs included tyrosine phosphorylation of Fc gamma RII, Syk, and Lyn associated with Fc gamma RII in Fc gamma RII cross-linking but not in anti-CD9 mAb-induced platelet activation. We prepared various GST fusion proteins expressing one or two SH2 domains of Syk and evaluated the association between these GST fusion proteins with Fc gamma RII. Based on the results obtained from these experiments, we suggest that only one tyrosine residue in ITAM of Fc gamma RII is phosphorylated with anti-CD9 mAb and that both are phosphorylated with Fc gamma RII cross-linking. Platelet activation mediated by GPIb, the receptor for vWF, is also related with tyrosine phosphorylation. Botrocetin and vWF induced Syk activation. Shc was also rapidly and heavily tyrosine phosphorylated. Sre and Lyn, a 54-kDa tyrosine kinase, was associated with cytoskeletal proteins. When GPIb was immunoprecipitated with nonfunctional anti-GPIb mAbs after platelets were activated with vWF and botrocetin, an in vitro kinase assay revealed the transient association of a kinase activity with GPIb after platelet activation. Phosphoamino acid analysis of phosphorylated proteins in this assay demonstrated that only tyrosine residues but not serine or threonine were phosphorylated, suggesting that the kinase was indeed a tyrosine kinase.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Activation of protein-tyrosine kinase pathways in human platelets stimulated with the A1 domain of von Willebrand factor.

The binding of multimeric von Willebrand Factor (vWF) to its specific receptor on platelets, glycoprotein (GP)Ib, is a critical event, allowing platelet activation and subsequent thrombus formation in the vessels. In this study, the effects of the monomeric A1 domain, which contains the GPIb-binding site of the vWF molecule, on platelet activation were examined. The binding of the A1 domain to GPIb resulted in Syk activation and association with Src, as is the case with intact vWF. However, the A1 domain, in contrast to vWF, did not induce platelet cytoskeletal association of tyrosine kinases, Src and Lyn. When platelet functional responses, such as aggregation and intracellular Ca2+ mobilization, were monitored, the A1 domain failed to induce the responses by itself and blocked the responses induced by the multimeric vWF molecule. These results suggested that the A1 domain triggers at least some of tyrosine kinase-related signals via GPIb and may be a partial agonist as well as a competitive antagonist for the vWF-GPIb interaction.

Blood Platelets↗

PubMed2000

Statistical analysis of geographical features of lung cancer mortality in Japan.

BACKGROUND: There is concern about the increase in death rates from lung cancer and that it may become the leading cause of death in the near future. Considerable geographical variations exist in lung cancer mortality in Japan. It seems that the difference cannot be explained by smoking rates, although no data are available to prove this. The evidence implies some unknown risk factors in the development of lung cancer. As an alternative approach, we used geographical or demographic information according to municipality. To explore other factors in lung cancer development, the geographical features of trends in lung cancer mortality in Japan were examined using long-term data. METHODS: We summarized the 20-year municipality-specific standardized mortality ratios (SMRs) by fitting a straight line to the scatter plot of the SMR versus calendar year for each municipality, resulting in an average and a rate of change of SMR. Using the average or rate of change in the SMR as the response variable, we carried out a multiple linear regression analysis for all of Japan and a non-parametric regression analysis for the distance from the municipal office to the nearest coastline, using the ACE algorithm. RESULTS: The average SMR decreased with distance from the coastline and increased with increasing population size of the municipality. The average SMR was high at or near the coastline irrespective of the direction of the nearest coastline. CONCLUSIONS: It was considered that something related to coastline other than population size may be associated with the development of lung cancer.

Adult↗

PubMed2000

Rho-mediated phosphorylation of focal adhesion kinase and myosin light chain in human endothelial cells stimulated with sphingosine 1-phosphate, a bioactive lysophospholipid released from activated platelets.

Since sphingosine 1-phosphate (Sph-1-P) is stored in abundant amounts in blood platelets and released extracellularly upon stimulation, it is important to clarify the effects of this bioactive lysophospholipid on vascular endothelial cells from the viewpoint of platelet-endothelial cell interactions. In this study, we investigated the effects of Sph-1-P on the cytoskeletal remodeling of human umbilical vein endothelial cells (HUVECs). Of a focal adhesion kinase (FAK) family of non-receptor protein-tyrosine kinases, HUVECs were found to express FAK, but scarcely proline-rich tyrosine kinase 2. Sph-1-P induced FAK tyrosine phosphorylation, myosin light chain phosphorylation, and the formation of stress fibers in HUVECs. The specific Rho inactivator C3 transferase from Clostridium botulinum abolished all of these cytoskeletal responses induced by Sph-1-P, while pertussis toxin only partly inhibited FAK tyrosine phosphorylation, and hardly affected myosin light chain phosphorylation and stress fiber formation. In contrast, Sph-1-P-induced intracellular Ca(2)(+) mobilization was suppressed by pertussis toxin, but not at all by C3 exoenzyme. Our results suggest that Sph-1-P, a bioactive lipid released from activated platelets, induces endothelial cell cytoskeletal reorganization, mainly through Rho-mediated signaling pathways.

Cytoskeleton↗

PubMed2000

Morphological effects of an anabolic steroid on muscle fibres of the diaphragm in mice.

Until recently, rats have been used for studies on the effects of anabolic steroids (AS) for improving physical performance. However, no consistent results on the changes in muscle fibre volume have ever been obtained. In this study we investigated the morphological effects of nandrolone phenylpropionate, an AS, on the muscle fibres of the diaphragm in adult male mice. AS (5 mg kg(-1) week(-1)) was injected intramuscularly in the experimental group (AS-administration group), and peanut oil (0.08 ml week(-1)) was injected in the control group. The cross-sectional areas of Type I (red) and Type II (white and intermediate) muscle fibres after 4 weeks of AS administration were 135% and 139% larger than those in the control group, respectively. The mean cross-sectional areas of mitochondria in the subsarcolemmal (SS) region and interfibrillar (IF) region in Type I fibres and the SS region of the Type II muscle fibres in the AS-administration group were 139%, 135% and 124% larger than those in the control group, respectively. No significant differences in the cross-sectional area of mitochondria were noted between the group of mice administered with AS for 8 weeks and the control group, showing that the effect of the AS administration attained a peak at 4 weeks, but that the effect of the 8 weeks of AS administration declined. We concluded from these results that the response of Type I muscle fibres to AS is stronger than that of Type II muscle fibres, as is the response of SS mitochondria compared to IF mitochondria. We also suggested that the two types of mitochondria may have different roles and that administration of AS may cause a different response in the two types of mitochondria.

Anabolic Agents↗

PubMed2000

Effects of high-temperature treatments on a thermophilic cyanobacterium Synechococcus vulcanus.

Effects of high-temperature treatments on a thermophilic cyanobacterium, Synechococcus vulcanus, were studied, and the following results were obtained. (1) Oxygen evolution and the PSII photochemical reaction were the most sensitive sites and started to be inactivated at temperatures slightly higher than the cultivating temperature. (2) The decrease in the fluorescence Fv value reflected the inactivation of the charge separation reaction of PSII as well as that of the oxygen evolution reaction. (3) The dark fluorescence level, Fo, showed an increase at around 70 degrees C, which was partially reversed by further incubation at 50 degrees C. This increase reflected the inactivation of PSII reaction centers and probably dissociation of phycobilisomes from the PSII reaction center complexes. (4) At higher temperatures, phycobiliproteins disassembled and denatured in a pH-dependent manner, causing a large Fo decrease. (5) Cell membranes became leaky to low-molecular-weight substances at around 72 degrees C. (6) Inhibition of growth of the cells was recognized when the cells were pretreated at temperatures higher than 72 degrees C. Reversibility of the high-temperature effects and relationship between viability of the cells and the degradation of the cell membranes are discussed.

Bacterial Proteins↗

PubMed2000

Propofol enhances a d-tubocurarine-induced twitch depression in septic rat diaphragm.

UNLABELLED: We estimated the effect of d-tubocurarine (dTc) on neuromuscular transmission and the action of propofol on dTc-induced twitch depression by using sham control and septic rat nerve-hemidiaphragm preparations in vitro. Isometric twitch tension elicited by indirect (phrenic nerve) or direct (muscle) stimulation at 0.1 Hz was evaluated. Sepsis induced by panperitonitis attenuated the twitch tension elicited by indirect and direct stimulation (P < 0.01 in each group) in the absence of significant morphological inflammatory damage to the diaphragm. dTc (1 microM) decreased the twitch tension elicited by indirect stimulation (P < 0.01) less intensely in the septic group than in the sham group (P < 0.01). Propofol accentuated dTc-induced depressed twitch more intensely in the septic group (P < 0.01 or 0.05). These results demonstrate that sepsis attenuates both muscle contractile force and the effect of a neuromuscular blocker and that propofol more intensely enhances dTc-induced twitch depression during sepsis. IMPLICATIONS: Propofol and nondepolarizing muscle relaxants are widely used for various clinical cases, including sepsis. Interactions between nondepolarizing muscle relaxants and propofol during sepsis are interesting from a clinical point of view. We demonstrated that propofol significantly enhances d-tubocurarine-induced twitch depression in vitro in the septic rat model compared with that in the nonseptic rat model.

Anesthetics, Intravenous↗

PubMed2000

Comparative evaluation of Tc-99m MIBI and Tl-201 chloride SPECT in non-small-cell lung cancer mediastinal lymph node metastases.

PURPOSE: To compare the utility of Tc-99m MIBI SPECT and Tl-201 chloride SPECT for presurgical assessment of lung cancer mediastinal lymph node metastases. METHODS: Forty-one patients with non-small-cell lung cancer underwent dual-isotope imaging with Tl-201 chloride and Tc-99m MIBI and were evaluated for mediastinal lymph node involvement. RESULTS: The sensitivity rates of early and delayed Tc-99m MIBI SPECT and of early and delayed Tl-201 chloride SPECT for detecting mediastinal nodal metastases were 69%, 69%, 92%, and 92%, respectively. The corresponding specificity rates were 96%, 96%, 93%, and 96%. CONCLUSION: Tl-201 chloride SPECT is superior to Tc-99m MIBI SPECT when used to detect mediastinal lymph node metastases in patients with non-small-cell lung cancer.

Adult↗

PubMed2000

Diagnostic value of TI-201 and three-phase bone scintigraphy for bone and soft-tissue tumors.

PURPOSE: Although TI-201 is highly sensitive for detecting bone and soft-tissue tumors, its uptake is not specific for malignant lesions. This study assessed the differentiation of malignant and benign lesions and evaluated the sensitivity, specificity, and accuracy of TI-201 imaging and three-phase bone scans. MATERIALS AND METHODS: Forty bone and soft-tissue tumors (16 malignant and 24 benign) were evaluated. TI-201 static images were acquired 10 minutes (early) and 2 hours (delayed) after injection of the radionuclide. Within 14 days, three-phase bone scintigraphy was performed using Tc-99m HMDP with the patient in the same position. The count ratio of the lesion compared with the normal contralateral or adjacent site (L:N ratio) was measured. RESULTS: With TI-201 scintigraphy, mean (+/- SD) values of early and delayed L:N ratios were 3.36 +/- 1.25 and 2.88 +/- 1.20, respectively, in malignant lesions; and 1.88 +/- 1.14 and 1.48 +/- 0.76, respectively, in benign lesions. TI-201 accumulation in benign lesions was significantly less than that of malignancies on early and delayed images. However, an overlap of both ratios between malignant and benign lesions was seen. No such significance was detected on three-phase bone scintigraphy (L:N ratios of malignant and benign tumors were 2.57 +/- 1.22 and 2.24 +/- 2.11, respectively, for blood flow imaging; 2.41 +/- 0.78 and 2.26 +/- 1.54, respectively, for blood pool imaging; and 2.80 +/- 2.10 and 2.89 +/- 4.55, respectively, for bone imaging). When we assumed that the tumor was malignant when the delayed TI-201 L:N ratio exceeded the blood pool phase L:N ratio with bone scintigraphy, the sensitivity rate was 81%, specificity rate was 100%, and accuracy rate was 93%. CONCLUSIONS: TI-201 imaging for bone and soft-tissue tumors was better than three-phase bone scintigraphy alone but was not good enough to clearly differentiate malignant lesions from benign ones. TI-201 scintigraphy, performed in combination with three-phase bone scintigraphy, may be superior to either one of the two imaging procedures alone for bone and soft-tissue tumor diagnosis.

Adolescent↗

PubMed2000

Comparative study of Tc-99m MIBI and TI-201 SPECT in predicting chemotherapeutic response in non-small-cell lung cancer.

PURPOSE: Tc-99m MIBI can be excluded from cytosol against its concentration gradient as a suitable transport substrate by P-glycoprotein. Tc-99m MIBI has also been shown to be more effective than TI-201 chloride for evaluating the response to chemotherapy in patients with small-cell lung cancer. The relation between Tc-99m MIBI accumulation by the tumor and its response to chemotherapy were evaluated in patients with non-small-cell lung cancer (NSCLC) and compared with the same parameters achieved using TI-201 chloride. METHODS: Thirty-eight patients with NSCLC were examined before chemotherapy was begun. They were classified according to the results of a follow-up computed tomogram into two groups: responders were patients in whom there was a > or =50% decrease and nonresponders were patients in whom there was a <50% decrease in the sum of the product of the maximum perpendicular diameters of all measurable lesions. All patients underwent dual-isotope imaging with TI-201 chloride and Tc-99m MIBI just before chemotherapy. Regions of interest were placed over the tumor uptake (T) and contralateral normal lung tissue (N) areas on one coronal view with a clearly defined lesion, and the T:N ratio and retention index were calculated. RESULTS: The delayed T:N ratio and retention index for Tc-99m MIBI in the responder group were significantly greater (P<0.05) than those in the nonresponder group. There was no significant correlation between the T:N ratio and retention index and tumor response using TI-201 chloride. CONCLUSION: Tc-99m MIBI SPECT may be more effective than TI-201 chloride SPECT for evaluating the response to chemotherapy in patients with NSCLC.

Adult↗

PubMed2000

Lipophilic HMG-CoA reductase inhibitors increase myocardial stunning in dogs.

Pretreatment of dogs with simvastatin, a lipophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, increases myocardial contractile dysfunction during reperfusion after ischemia (stunning), with reduction of tissue adenosine triphosphate (ATP). This was thought to be a consequence of prevention of ubiquinone biosynthesis by the lipophilic inhibitor in the myocardial cell. We examined whether other lipophilic HMG-CoA reductase inhibitors also influence myocardial stunning in dogs. Vehicle, atorvastatin (2 mg/ kg/day), fluvastatin (4 mg/kg/day), or cerivastatin (40 microg/kg/ day) was orally administered for 3 weeks. Hydrophilic pravastatin (4 mg/kg/day) also was given. After 3 weeks, pentobarbital-anesthetized dogs were subjected to 15-min left anterior descending coronary artery occlusion followed by 2-h reperfusion. Myocardial segment function was determined by sonomicrometry. Tissue levels of ATP were determined in 2-h reperfused hearts. All inhibitors significantly decreased serum cholesterol level. The three lipophilic inhibitors resulted in a worsening of segment function in the reperfused myocardium, as compared with the vehicle group. The levels of ATP in the atorvastatin, fluvastatin, and cerivastatin groups were significantly lower than that in the vehicle group. These results confirm that lipophilic HMG-CoA reductase inhibitors enhance myocardial stunning in association with ATP reduction after ischemia and reperfusion.

Adenosine Triphosphate↗