Biomedical subjects

T Fukushima

Publications and source records attributed to T Fukushima.

At least 73 records · Page 4Linked to original sources

PubMed2001

De novo acute myeloid leukemia in the elderly; a consistent fraction of long-term survivors by standard-dose chemotherapy.

To clarify the characteristics of de novo acute myeloid leukemia (AML) among the elderly, we reviewed 112 patients over 60 years old (median age 72 years) who were treated at hospitals in Nagasaki Prefecture with a population of 1.5 million between 1987 and 1994. Reclassification of morphological diagnosis revealed that the proportion of M3 was lower but that of M6 and the incidence of cases with trilineage dysplasia (TLD), known as poor prognostic features, were higher in the elderly than in patients less than 60 years old. Similarly, chromosomal data showed a lower frequency of favorable karyotypes such as t(8;21) and t(15;17) in the elderly. The overall survival of all 112 patients was 10.3% at 5 years. Multivariate analysis indicated that good performance status (PS), low WBC at diagnosis, standard dose multi-drug chemotherapy and all-trans retinoic acid (ATRA) treatment for M3 patients, and morphological findings without TLD were significantly correlated with longer survival. Most of the long-term survivors were found among those who received standard dose therapy in this series, although no consensus has been established how to treat elderly AML patients. We propose that a prospective controlled trial is necessary to confirm the role of standard dose chemotherapy for elderly patients with de novo AML.

Acute Disease↗

PubMed2001

Nutrient dynamics and the eutrophication of shallow lakes Kasumigaura (Japan), Donghu (PR China), and Okeechobee (USA).

We compared the nutrient dynamics of three lakes that have been heavily influenced by point and non-point source pollution and other human activities. The lakes, located in Japan (Lake Kasumigaura), People's Republic of China (Lake Donghu), and the USA (Lake Okeechobee), all are relatively large (> 30 km2), very shallow (< 4 m mean depth), and eutrophic. In all three lakes we found strong interactions among the sediments, water column, and human activities. Important processes affecting nutrient dynamics included nitrogen fixation, light limitation due to resuspended sediments, and intense grazing on algae by cultured fish. As a result of these complex interactions, simple empirical models developed to predict in-lake responses of total phosphorus and algal biomass to external nutrient loads must be used with caution. While published models may provide 'good' results, in terms of model output matching actual data, this may not be due to accurate representation of lake processes in the models. The variable nutrient dynamics that we observed among the three study lakes appears to be typical for shallow lake systems. This indicates that a greater reliance on lake-specific research may be required for effective management, and a lesser role of inter-lake generalization than is possible for deeper, dimictic lake systems. Furthermore, accurate predictions of management impacts in shallow eutrophic lakes may require the use of relatively complex deterministic modeling tools.

Conservation of Natural Resources↗

PubMed2001

Effect of primers containing N-methylolacrylamide or N-methylolmethacrylamide on dentin bond durability of a resin composite after 5 years.

OBJECTIVES: The effect of experimental dentin primers containing N-methylolacrylamide (MEAA) or N-methylolmethacrylamide (MEMA) on bond durability of a resin composite (Photo Clearfil A) with a bonding agent (Clearfil Photo Bond) to bovine dentin was investigated. METHODS: The etching agents were 10% maleic acid (10% MA), 10% phosphoric acid (10% PA) and 10% citric acid-3% ferric chloride (10-3 solution). Water solutions of 35% hydroxyethyl methacrylate (HEMA), 50% MEAA or 30% MEMA were used as dentin primers. The etched dentin was pre-treated with the dentin primers for 30s. The resin composite systems were applied in a Teflon tube positioned onto pre-treated dentin surfaces. After water immersion for 1 day and 5 years, the shear bond strengths were measured. The amounts of calcium dissolved with etching agents were measured using atomic absorption spectrometry. The thicknesses of hybrid layers at the dentin-resin interfaces treated with 6 mol/l HCl and 1% NaOCl were measured using scanning electron microscopy. RESULTS: The bond strengths of the specimens (Controls) without primers to dentin etched with 10% MA and 10-3 solution significantly decreased after immersion in water for 5 years (p<0.05) while other bond strengths did not decrease. The bond strengths of the composites to MEMA- and MEAA-primed dentin were significantly higher than that of the control after 1 day, regardless of the types of etching agents (p<0.05). The 5 year bond strengths of the composites to HEMA-, MEMA- and MEAA-primed dentin were significantly higher than that of the control, regardless of the types of etching agents (p<0.05). The 1 day and 5 year bond strengths of the composite to MEAA-primed dentin were significantly higher than those of the composites to HEMA-primed dentin, regardless of the types of etching agents (p<0.05). The highest amount (182.3+/-8.0 microg/cm(2)) of dissolved calcium was determined for the pre-treatment with 10% PA, followed by that (152.0+/-6.9 microg/cm(2)) with 10% MA and that (140.1+/-2.8 microg/cm(2)) with 10-3 solution (p<0.05). The hybrid layer thicknesses (approximately 1 microm) for 10-3 solution were thinner than those (approximately 2 microm) for others after HCl immersion. For the controls, the hybrid layers after NaOCl immersion become narrower or disappeared. The main fracture pattern of specimens was a mixture of resin-dentin interface failure and dentin cohesive fracture after the bond test. CONCLUSIONS: MEAA solution was more effective in improving the bond strength of the controls to etched dentin than was HEMA after 1 day and 5 years. Clearfil Photo Bond created good hybrid dentin layers which could resist NaOCl-attack and showed good dentin bond durability when dentin primers were used, regardless of the type of etching agent.

Acid Etching, Dental↗

PubMed2001

An alternative system for cerebrovascular reconstructions: non-penetrating arcuate-legged clips.

Non-penetrating, arcuate-legged titanium clips (VCS) have been utilized successfully over the past five years for a variety of cerebrovascular reconstructions. These applications, including both micro and macrovascular reconstructions, their clinical outcomes and technical considerations are described. Applications include patch angioplasty of cervical carotid endarterectomies, superficial temporal to middle cerebral artery 'bypass' procedures, Takayasu's arteritis and cavernous carotid reconstructions. The non-penetrating clip has proven to be a safe and reliable alternative to suture for these demanding reconstructions. Clips provide the advantages of improved anastomotic compliance, reduced operative time, and reduced incidence of post-operative anastomotic intimal hyperplasia and stenosis. Clip related pitfalls are discussed with recommendations regarding usage.

Anastomosis, Surgical↗

PubMed2001

Surgical approaches to pineal region tumors.

Direct surgical resection of pineal region tumors has become safer, more effective, and now plays an essential role in their management. Tissue diagnosis allows for the initiation of appropriate therapies and resection can be curative or improve the efficacy of adjuvant therapies. Several approaches have been reported. Based on our operative experience with 57 patients over a 20-year period, we conclude that the Infratentorial Supracerebellar and Parieto-Occipital Paramedian Transtentorial approaches provide excellent exposure while allowing minimally invasive, relatively low risk access to the majority of pineal region tumors. Indications, positioning, techniques, advantages, and disadvantages are discussed. A review of other approaches, pertinent historical remarks, and a discussion of the role of surgery in the contemporary management of pineal region tumors are presented.

Brain Neoplasms↗

PubMed2001

Efficacy of treatment with chimeric monoclonal antibody (Infliximab) to tumor necrosis factor-alpha for Crohn's disease in Japan: evaluation by rapid turnover proteins, and radiologic and endoscopic findings.

BACKGROUND: Several studies have reported that the chimeric monoclonal antibody to tumor necrosis factor (TNF)-alpha (Infliximab) is extremely valuable in the treatment of Crohn's disease. The aim of this study was to clarify the efficacy of this treatment in Japanese patients with Crohn's disease. METHODS: A 12-week multicenter, open trial of Infliximab was carried out and involved 25 patients with moderate to severe Crohn's disease who were resistant to conventional treatment. Patients received a single 2-h intravenous infusion of Infliximab at a dose of 1, 3, 5 or 10 mg/kg bodyweight. Clinical evaluation of this treatment response was defined as a reduction in the index of the inflammatory bowel disease (IOIBD) and of the Crohn's disease activity index scores (CDAI), and in serum levels of C-reactive protein (CRP) at 2, 4, 8 and 12 weeks, and as an increase in serum levels of rapid turnover proteins as well as improvement of radiologic and endoscopic findings at 4 weeks. RESULTS: The IOIBD score was reduced after 4 weeks in 66.7% of the group receiving 1 mg/kg Infliximab, 71.4% in the group receiving 3 mg/kg, 80.0% in the group receiving 5 mg/kg, and 85.7% in the group receiving 10 mg/kg. Improvement was better maintained over 12 weeks in the 5 and 10 mg/kg groups compared with the 1 and 3 mg/kg groups. Similar results were obtained for the CDAI scores. Serum levels of rapid turnover proteins significantly increased to within the normal ranges after infusion in all groups. Seven of the 11 (63.6%) patients evaluated showed improvement of radiologic and endoscopic findings. CONCLUSIONS: A single infusion of Infliximab was effective for the treatment of Japanese patients with Crohn's disease. Serum rapid turnover proteins reflected the clinical response to antibody for TNF-alpha well.

Adult↗

PubMed2001

Detection of fetal HPCs in maternal circulation after delivery.

BACKGROUND: Circulation of mature fetal blood cells in the maternal blood for a certain postpartum period has been verified, but detailed study of the fetal HPCs has not been reported. The objective of this study was to evaluate the frequency and clearance of these cells in the peripheral blood of puerperal women. STUDY DESIGN AND METHODS: PBMNCs from 15 puerperal women who gave birth to male infants were cultured in semi-solid medium containing hematopoietic stimulating factors. Colonies formed in the medium were individually characterized, collected, and subjected to PCR amplification of the SRY gene on Y chromosome to confirm fetal origin. RESULTS: The mean numbers of fetal progenitor cell colonies isolated per mL of maternal blood were 1.63, 2.48, 0.56, 0.12, and 0 on the day of delivery, at 4 days, 1 month, 6 months, and 1 year after delivery, respectively. There was no difference in the ratio of fetal versus maternal colonies between erythroid and granulocyte/macrophage lineages. CONCLUSION: The present study demonstrated that a significant number of fetal HPCs circulate in the maternal blood for a duration of at least 6 months after delivery.

Delivery, Obstetric↗

PubMed2001

Management of vascular invasion during radical resection of medial sphenoid wing meningiomas.

Invasive meningiomas involving the medial sphenoid wing are difficult tumors to resect completely. They often have invaded the surrounding arteries at the time of diagnosis making total resection challenging. Attempts at removing these tumors from adherent carotid or middle cerebral arteries have resulted in high complication rates. Nine cases of medial sphenoid wing meningiomas with arterial invasion were operated between March 1994 and August 1998. Total resection was possible in only four cases. Two arterial-related complications occurred during resection with one resulting in permanent hemiplegia.

Journal Article↗

PubMed2001

Staphylococcus aureus in inflammatory bowel disease.

BACKGROUND: The potential role of superantigens in inflammatory bowel disease (IBD), particularly Crohn disease, has been broached in studies of the functions of T cell receptors. Staphylococcal cells have been found in intestinal lymph follicles of IBDs. To clarify a role of staphylococcal superantigens in IBD, we attempted to determine whether Staphylococcus aureus could be detected in intestinal mucosa, including surgical specimens and lymph follicles of initial cases. METHODS: One-hundred-and-six colonic and ileal specimens were obtained from 38 Crohn disease, 25 ulcerative colitis and 36 non-IBD patients through therapeutic surgery or endoscopic biopsy. In Crohn disease, 23 surgical specimens and 11 biopsy specimens from initial cases were included. DNA was extracted with phenol-chloroform after homogenization and proteinase K treatment in 73 mucosal specimens. Using an inverted microscope, lymph follicle tissue was microdissected from the remaining 33, mostly biopsy, specimens. DNA was then extracted by freeze-thawing. A coagulase gene characteristic of S. aureus was sought. A nested polymerase chain reaction was performed utilizing primers that amplify a region of the coagulase gene. Polymerase chain reaction products were analyzed with polyacrylamide gel electrophoresis. RESULTS: Only one surgically resected colonic specimen, from a 42-year-old male ulcerative colitis patient, registered positive staphylocoagulase amplification. CONCLUSIONS: Staphylococcal superantigens are not involved in either the early lesions or the established lesions of Crohn disease. However, S. aureus infection occasionally may occur during the course of IBD.

Adult↗

PubMed2001

The effect of breath termination criterion on breathing patterns and the work of breathing during pressure support ventilation.

UNLABELLED: With pressure support ventilation (PSV), each PSV breath is flow-cycled, and the breath termination criterion (TC) is usually nonadjustable. When TC does not match the interaction between the patient's inspiratory-expiratory efforts to the opening and closing of the inspiratory and expiratory valves, patient-ventilator asynchrony may occur, and the work of breathing (WOB) may increase. Therefore, we studied the effect of TC on breathing patterns and WOB during PSV in eight patients with acute respiratory distress syndrome or acute lung injury. We studied five levels of TC during PSV-1%, 5%, 20%, 35%, and 45% of the peak inspiratory flow. With increasing levels of TC, the tidal volume decreased and respiratory frequency increased, along with a decrease in duty cycle. WOB markedly increased with increasing levels of TC from 0.31 +/- 0.12 J/L with TC 1% to 0.51 +/- 0.11 J/L with TC 45%. Premature termination with double breathing occurred in one patient with TC 35% and four patients with TC 45%. Delayed termination with a duty cycle of >0.5 occurred in two patients with TC 1%. In conclusion, the proper adjustment of TC improves patient-ventilator synchrony and decreases WOB during PSV. IMPLICATIONS: Although termination criterion (TC) is usually nonadjustable, it influences the effectiveness of pressure support ventilation for mechanical ventilation. The proper adjustment of TC is crucial to improve patient-ventilator synchrony and decrease work of breathing. TC 5% of the peak inspiratory flow may be the optimal value for patients with acute respiratory distress syndrome or acute lung injury.

Aged↗

PubMed2001

Expression of nuclear factor kappaB and tumor necrosis factor alpha in the mouse brain after experimental thermal ablation injury.

OBJECTIVE: Nuclear factor kappa B (NFkappaB) participates in the regulation of a diverse range of genes involved in inflammation and acute phase responses. We investigated the expression of the activated form of NFkappaB and tumor necrosis factor alpha (TNFalpha), an inflammatory cytokine, in experimental brain injury. METHODS: We generated focal brain injury in mice using radiofrequency thermal ablation at the caudate putamen in mice. Intracerebral expression of TNFalpha and the p50 and p65 subunits of NFkappaB were studied using immunohistochemistry at 1, 4, and 8 hours and at 1, 2, 4, 8, 14, and 28 days postinjury. RESULTS: Coagulative necrosis approximately 2 mm in diameter was produced at the site of injury. No immunoreactivity for TNFalpha, NFkappaB p50, or NFkappaB p65 was detected in the injured area in the early phase postinjury. On posttrauma Day 2, however, weak expression of TNFalpha, NFkappaB p50, and NFkappaB p65 was detected in mononuclear cells that infiltrated edematous tissue surrounding the lesion. On posttrauma Days 4 to 8, the expression of TNFalpha, NFkappaB p50, and NFkappaB p65 was prominently increased in infiltrating and proliferating mononuclear cells (macrophages and microglia) and in proliferating reactive astrocytes surrounding the lesion. Nuclear subcellular localization of the expression of NFkappaB p50 and p65 was observed, which indicated that these subunits might be activated in these cells. On posttrauma Day 14, the expression of TNFalpha, NFkappaB p50, and NFkappaB p65 decreased and was limited to mononuclear cells, and it finally disappeared on Day 28. The temporal profiles of TNFalpha, NFkappaB p50, and NFkappaB p65 were closely associated with the occurrence of secondary insults and the tissue-remodeling process in wound healing. CONCLUSION: These results suggest that TNFalpha, NFkappaB p50, and NFkappaB p65 may play a central role in the injury-induced immune response that leads to secondary insults or wound healing after brain injury. Inappropriate and deregulated activation of NFkappaB in injured brain tissue may be implicated in the development of secondary brain damage.

Animals↗

PubMed2001

Utility of three-dimensional computed tomographic angiography for assessment of relationships between the vertebrobasilar system and the cranial base.

OBJECTIVE: The optimal surgical exposure for basilar tip aneurysms is dictated by the relationship of the basilar bifurcation to the cranial base. This study was designed to evaluate three-dimensional computed tomographic angiography as a means of obtaining detailed anatomic information on the basilar artery and the surrounding cranial base in individual patients before surgery. METHODS: We studied 30 patients using three-dimensional computed tomographic angiographic reconstructions from 1-mm computed tomographic slices. Detailed anatomic measurements were performed to define the relationship between the basilar artery and the cranial base. Particular attention was paid to the height of the dorsum sellae and its relationship to the basilar bifurcation. RESULTS: The heights of the basilar apex and the vertebrobasilar junction, relative to the cranial base, were extremely variable. Considerable asymmetries in the heights of the left and right posterior clinoid processes were identified; in one case, this difference was more than 1 cm (mean difference in height, 0.9 mm; range, 0-10.3 mm). The heights of the posterior clinoid processes above the sellar floor ranged from 5.8 to 14.1 mm (mean height, 9.5 mm). We were able to determine the feasibility of the pterional/orbitozygomatic, middle fossa/ anterior petrosal, and presigmoid retrolabyrinthine approaches to an individual basilar bifurcation. We also estimated the amount of bone removal required and determined the operative distances via those approaches. CONCLUSION: Three-dimensional computed tomographic angiography is a useful tool for assessing critical anatomic relationships and represents an adjunct to conventional angiography in the planning of individualized, precisely tailored, cranial base approaches to the vertebrobasilar system.

Adult↗

PubMed2001

Digital camera documentation system for facial nerve outcome assessment.

OBJECTIVE: To describe the use of a digital camera to document facial nerve function after skull base surgery. SETTING: Patients undergoing skull base surgery at a tertiary care otologic and neurotologic clinic were used in the study. INTERVENTIONS: None. RESULTS: A digital camera system provided still images and a video strip lasting less than a minute to document facial nerve motion. CONCLUSIONS: An inexpensive digital camera system can be used to capture still and moving images of facial nerve function on a floppy disk. The images can then be transferred to compact disks for storage of many patient files. Such a system allows documentation for research, exchange of data between offices, and patient education, and it can be used for medical-legal purposes among other uses.

Documentation↗

PubMed2001

Monitoring of intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in 1-beta-D-arabinofuranosylcytosine therapy at low and conventional doses.

1-beta-D-Arabinofuranosylcytosine (ara-C) is used empirically at a low, conventional, or high dose. Ara-C therapy may be optimal if it is directed by the clinical pharmacokinetics of the intracellular active metabolite of ara-C, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP). However, ara-CTP has seldom been monitored during low- and conventional-dose ara-C therapies because detection methods were insufficiently sensitive. Here, with the use of our newly established method (Cancer Res., 56, 1800 -- 1804 (1996)), ara-CTP was monitored in leukemic cells from acute myelogenous leukemia patients receiving low- or conventional-dose ara-C [subcutaneous ara-C administration (10 mg / m(2) ) (3 patients), continuous ara-C infusion (20 or 70 mg / m(2) / 24 h) (7 patients), 2-h ara-C infusion (70 mg / m(2) ) (4 patients), and 2-h infusion of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine, a deaminase-resistant ara-C derivative (70 mg / m(2) ) (6 patients)]. Ara-CTP could be determined at levels under 1 microM. There was a close correlation between the elimination half-life values of the plasma ara-C and the intracellular ara-CTP. The presence of ara-C in the plasma was important to maintain ara-CTP. The continuous ara-C and the 2-h N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine infusions maintained ara-CTP and the plasma ara-C longer than the subcutaneous ara-C or the 2-h ara-C infusion. They also afforded relatively higher ara-CTP concentrations, and consequently produced ara-CTP more efficiently than the 2-h ara-C infusion. Different administration methods produced different quantities of ara-CTP even at the same dose.

Adult↗

PubMed2001

Close correlation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, an intracellular active metabolite, to the therapeutic efficacy of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine therapy for acute myelogenous leukemia.

N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.

Acute Disease↗

PubMed2001

Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs.

The Rad51 protein, a eukaryotic homologue of Escherichia coli RecA, plays a central role in both mitotic and meiotic homologous DNA recombination (HR) in Saccharomyces cerevisiae and is essential for the proliferation of vertebrate cells. Five vertebrate genes, RAD51B, -C, and -D and XRCC2 and -3, are implicated in HR on the basis of their sequence similarity to Rad51 (Rad51 paralogs). We generated mutants deficient in each of these proteins in the chicken B-lymphocyte DT40 cell line and report here the comparison of four new mutants and their complemented derivatives with our previously reported rad51b mutant. The Rad51 paralog mutations all impair HR, as measured by targeted integration and sister chromatid exchange. Remarkably, the mutant cell lines all exhibit very similar phenotypes: spontaneous chromosomal aberrations, high sensitivity to killing by cross-linking agents (mitomycin C and cisplatin), mild sensitivity to gamma rays, and significantly attenuated Rad51 focus formation during recombinational repair after exposure to gamma rays. Moreover, all mutants show partial correction of resistance to DNA damage by overexpression of human Rad51. We conclude that the Rad51 paralogs participate in repair as a functional unit that facilitates the action of Rad51 in HR.

Animals↗

PubMed2001

No evidence of persistent mumps virus infection in inflammatory bowel disease.

BACKGROUND AND AIM: There is controversy regarding whether paramyxovirus infection is causally associated with inflammatory bowel disease (IBD). The latest cohort study claimed that atypical measles and mumps infections in childhood may be risk factors for later IBD. This study was conducted to clarify the validity of a causal link between persistent mumps virus infection and IBD. SUBJECTS AND METHODS: (1) Amplification of the mumps virus genome was performed in both intestinal specimens (ulcerative colitis 15, Crohn's disease 15, control 10) and peripheral blood lymphocytes (PBL) (ulcerative colitis seven, Crohn's disease six, control three) by reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern hybridisation using primers specific to the viral genome encoding phosphoprotein or haemagglutinin-neuraminidase. (2) Titre of serum antimumps IgG was measured in 16 patients with ulcerative colitis, in 16 patients with Crohn's disease, and in 16 normal controls using an enzyme linked immunosorbent assay. RESULTS: (1) The mumps virus genome was not detected by RT-PCR in intestinal specimens or PBL in any case. (2) Antimumps IgG titre was positive in 7/16 ulcerative colitis, 10/16 Crohn's disease, and 11/16 control specimens. The mean (SEM) titre of antimumps IgG was 12.281 (7.831) in ulcerative colitis, 7.675 (1.608) in Crohn's disease, and 8.637 (1.969) in controls, with no significant difference between the three groups. CONCLUSION: We could not find any evidence to support a causal link between persistent mumps virus infection and IBD.

Adolescent↗

PubMed2001

Differential subcellular actions of ACE inhibitors and AT(1) receptor antagonists on cardiac remodeling induced by chronic inhibition of NO synthesis in rats.

Chronic inhibition of NO synthesis induces cardiac hypertrophy independent of systemic blood pressure (SBP) by increasing protein synthesis in vivo. We examined whether ACE inhibitors (ACEIs) enalapril and temocapril and angiotensin II type-I receptor antagonists (angiotensin receptor blockers [ARBs]) losartan and CS-866 can block cardiac hypertrophy and whether changes in activation of 70-kDa S6 kinase (p70S6K) or extracellular signal-regulated protein kinase (ERK) are involved. The following 13 groups were studied: untreated Wistar-Kyoto rats and rats treated with NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME), D-NAME (the inactive isomer of L-NAME), L-NAME plus hydralazine, L-NAME plus enalapril (3 mg. kg(-1). d(-1)) or temocapril (1 or 10 mg. kg(-1). d(-1)), L-NAME plus losartan (10 mg. kg(-1). d(-1)) or CS-866 (1 or 10 mg. kg(-1). d(-1)), L-NAME plus temocapril-CS866 in combination (1 or 10 mg. kg(-1). d(-1)), and L-NAME plus rapamycin (0.5 mg. kg(-1). d(-1)). After 8 weeks of each experiment, ratios of coronary wall to lumen (wall/lumen) and left ventricular weight to body weight (LVW/BW) were quantified. L-NAME increased SBP, wall/lumen, and LVW/BW compared with that of control. ACEIs, ARBs, and hydralazine equally canceled the increase in SBP induced by L-NAME. However, ACEIs and ARBs equally (but not hydralazine) attenuated increase in wall/lumen and LVW/BW induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in myocardium (2.2-fold and 1.8-fold versus control, respectively). ACEIs inactivated p70S6K and ARBs inactivated ERK in myocardium, but hydralazine did not change activation of either kinase. Thus, ACEIs and ARBs modulate different intracellular signaling pathways, inhibiting p70S6K or ERK, respectively, to elicit equal reduction of cardiac hypertrophy induced by chronic inhibition of NO synthesis in vivo.

Angiotensin Receptor Antagonists↗