Role of raising the upper limb of the non-rising side when performing rising movements from bed.

Rising movements from bed comprise an important aspect of recovery from the bedridden state; however, they have not been sufficiently investigated using motion analysis studies. In particular, the effect of using the upper limb of the non-rising side before waist flexion on rising movements remains to be analyzed; this study aimed to clarify this effect. Accordingly, motion analyses were performed on rising movements under two constraint conditions, namely raising the upper limb of the non-rising side (upper limb use-condition) and keeping it in contact with the pelvis (upper limb non-use-condition); subsequently, the kinematics and kinematics parameters were compared. In comparison with the upper limb use-condition, in the upper limb non-use-condition, the distance traveled by the center of mass of the body (CoM trajectory, p < 0.01) increased while switching from the half-side-lying to on-hand postures, horizontal body movement (movement speed (Normalized time/total time), p < 0.01 and weight of center of body mass (CoM momentum in horizontal plane), p < 0.05) during the same period increased, and the half-side-lying time approached the peak value of the waist flexion angular velocity (Time lag between from half-side-lying to waist angler peak velocity, p < 0.05). The compensatory movement that occurred due to the upper limb non-use-condition denoted an increase in body momentum in the horizontal direction, rather than in the sagittal plane. Therefore, the upper limb on the non-rising side contributed to the smooth movement of the body in the horizontal direction. Moreover, this study demonstrated that asymmetrical rising movement in the diagonal direction is a characteristic movement wherein the horizontal movement of the body constitutes the main movement.

Usefulness of Muscle Synergy Analysis in Individuals With Knee Osteoarthritis During Gait.

OBJECTIVE: To clarify whether there are any muscle synergy changes in individuals with knee osteoarthritis, and to determine whether muscle synergy analysis could be applied to other musculoskeletal diseases. METHODS: Subjects in this study included 11 young controls (YC), 10 elderly controls (EC), and 10 knee osteoarthritis patients (KOA). Gait was assessed on a split-belt treadmill at 3 km/h. A non-negative matrix factorization (NNMF) was applied to the electromyogram data matrix to extract muscle synergies. To assess the similarity of each module, we performed the NNMF analysis assuming four modules for all of the participants. Further, we calculated joint angles to compare the kinematic data between the module groups. RESULTS: The number of muscle modules was significantly lower in the EC (2-3) and KOA (2-3) groups than in the YC group (3-4), which reflects the merging of late swing and early stance modules. The EC and KOA groups also showed greater knee flexion angles in the early stance phase. Contrarily, by focusing on the module structure, we found that the merging of early and late stance modules is characteristic in KOA. CONCLUSION: The lower number of modules in the EC and KOA groups was due to the muscle co-contraction with increased knee flexion angle. Contrarily, the merging of early and late stance modules are modular structures specific to KOA and may be biomarkers for detecting KOA. SIGNIFICANCE: Describing the changes in multiple muscle control associated with musculoskeletal degeneration can serve as a fundamental biomarker in joint disease.

Polarity of helper T cell subsets represents disease nature and clinical course of experimental autoimmune myocarditis in rats.

The mechanisms of progression, remission and relapse of myocarditis remain unclear. To clarify these mechanisms, we focused on T helper-1 (Th1)/T helper-2 (Th2) subsets balance of peripheral lymphocytes and serum cytokine levels during disease progression in rats with experimental autoimmune myocarditis (EAM). Lewis rats were immunized with cardiac myosin on day 0. Blood samples were collected on days 0, 7, 15, 18, 21, 28, 35, 42, 49 and 56 following immunization. We examined percentages of interferon (IFN)-gamma and/or interleukin (IL)-4 producing cells in stimulated peripheral CD4-positive lymphocytes using flow cytometry analysis. Serum IFN-gamma, IL-2, IL-6 and IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA). The percentage of Th1/Th2 subsets in EAM on days 0, 15, 28 and 56 were 2.5 +/- 0.5/0.5 +/- 0.1%, 19.4 +/- 3.2/1.6 +/- 0.3%, 2.0 +/- 0.5/22.1 +/- 5.7% and 3.0 +/- 0.4/1.7 +/- 0.3%, respectively. Serum levels of Th1 cytokines, IFN-gamma and IL-2 significantly increased in the acute phase (from day 15-18) and immediately decreased in the early recovery phase. On the other hand, serum levels of Th2 cytokine, IL-10 significantly increased in the early recovery phase (from day 24-30). These results suggest that induction of acute myocarditis might be associated with systemic Th1 dominance, while recovery is related to systemic Th2 polarity. Thus, analysis of Th1/Th2 balance in peripheral T cells may be useful in disease monitoring in patients with myocarditis and postmyocarditic dilated cardiomyopathy.

Hydrodynamics-based delivery of the viral interleukin-10 gene suppresses experimental crescentic glomerulonephritis in Wistar-Kyoto rats.

Gene therapy is expected to revolutionize the treatment of kidney diseases. Viral interleukin (vIL)-10 has a variety of immunomodulatory properties. We examined the applicability of vIL-10 gene transfer to the treatment of rats with crescentic glomerulonephritis, a T helper 1 (Th 1) predominant disease. To produce the disease, Wistar-Kyoto rats were injected with a rabbit polyclonal anti-rat glomerular basement membrane antibody. After 3 h, a large volume of plasmid DNA expressing vIL-10 (pCAGGS-vIL-10) solution was rapidly injected into the tail vein. pCAGGS solution was similarly injected into control rats (pCAGGS rats). We confirmed the presence of vector-derived vIL-10 mainly in the liver and observed high serum vIL-10 levels in pCAGGS-vIL-10-injected rats. Compared with the pCAGGS rats, the pCAGGS-vIL-10 rats showed significant therapeutic effects: reduced frequency of crescent formation, decrease in the number of total cells, macrophages, and CD4+ T cells in the glomeruli, decrease in urine protein, and attenuation of kidney dysfunction. Using quantitative real-time polymerase chain reaction, we also observed that this model was Th1-predominant in the glomeruli and that the ratio of the transcripts of CD4, interferon-gamma, tumor necrosis factor-alpha, and monocyte chemotactic protein-1 to the transcripts of glucose-6-phosphate dehydrogenase in the glomeruli were all significantly lower in the pCAGGS-vIL-10 rats than in the pCAGGS rats. These results demonstrate that pCAGGS-vIL-10 gene transfer by hydrodynamics-based transfection suppresses crescentic glomerulonephritis.

High-level expression of naked DNA delivered to rat liver via tail vein injection.

BACKGROUND: High levels of foreign gene expression in mouse hepatocytes can be achieved by rapid tail vein injection of a large volume of a naked DNA solution, the 'hydrodynamics-based procedure'. Rats are more tolerant of the frequent phlebotomies required for monitoring blood parameters than mice, and thus are better for some biomedical research. METHODS: We tested this technique for the delivery of a therapeutic protein in normal rats, using a rat erythropoietin (Epo) expression plasmid vector, pCAGGS-Epo. RESULTS: We obtained maximal Epo expression when the DNA solution was injected in a volume of 25 ml (approximately 100 ml/kg body weight) within 15 s. We observed a dose-response relationship between serum Epo levels and the amount of injected DNA up to 800 microg. Using quantitative real-time PCR, the vector-derived Epo mRNA expression was mainly detected in the liver. When a lacZ expression plasmid was injected similarly, beta-galactosidase was exclusively detected in the liver, mainly in hepatocytes. Toxicity attributable to the technique was mild and transient, as assessed by histochemical analysis. Epo gene expression and erythropoiesis occurred with Epo gene transfer in a dose-dependent manner, and persisted for at least 12 weeks, the last time point examined. Repeated administration of the plasmid DNA also effectively led to erythropoiesis. CONCLUSIONS: These results demonstrate that gene transfer into the liver via rapid tail vein injection can easily be achieved in the rat, which is more than 10 times larger than the mouse, and has significant value for gene function analysis in rats.

Abnormality of c-kit oncoprotein in certain patients with chronic myelogenous leukemia--potential clinical significance.

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia (Ph) chromosome and bcr/abl gene rearrangement which occurs in pluripotent hematopoietic progenitor cells expressing the c-kit receptor tyrosine kinase (KIT). To elucidate the biological properties of KIT in CML leukemogenesis, we performed analysis of alterations of the c-kit gene and functional analysis of altered KIT proteins. Gene alterations in the c-kit juxtamembrane domain of 80 CML cases were analyzed by reverse transcriptase and polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP). One case had an abnormality at codon 564 (AAT --> AAG, Asn --> Lys), and six cases had the same base abnormality at codon 541 (ATG --> CTG, Met --> Leu) in the juxtamembrane domain. Because the change from Met to Leu at codon 541 was a conservative one which was also observed in the normal population and normal tissues of CML patients, it probably represents a polymorphic variation. Although samples of hair roots and leukemic cells from the chronic phase of one CML patient showed no abnormality, an abnormality at codon 541 (ATG --> CTG, Met --> Leu) was found only at blastic crisis (BC) of this case. In the case with the abnormality at codon 564, the mutation was detected only in a sample of leukemic cells collected at BC. To examine the biological consequence and biological significance of these abnormalities, murine KIT(L540) and KIT(K563) expression vectors were introduced into interleukin-3 (IL-3)-dependent murine Ba/F3 cells to study their state of tyrosine phosphorylation and their growth rate. Ba/F3 cells expressing KIT(WT), KIT(L540) and KIT(K563) showed dose-dependent tyrosine phosphorylation after treatment with increasing concentrations of recombinant mouse stem cell factor (rmSCF). The cells expressing KIT(L540) and KIT(K563) were found to have greater tyrosine phosphorylation than cells expressing KIT(WT) at 0.1 and 1.0 ng/ml of rmSCF. The Ba/F3 cells expressing KIT(K563) proliferated in response to 0.1 and 1.0 ng/ml of rmSCF as well as IL-3. The Ba/F3 cells expressing KIT(L540)showed a relatively higher proliferative response to 0.1 ng/ml of rmSCF than the response of cells expressing KIT(WT). These mutations and in vitro functional analyses raise the possibility that the KIT abnormalities influence the white blood cell counts (P < 0.05) and survival (P < 0.04) of CML patients.

Erythroid involvement in CD36 deficiency.

OBJECTIVE: The CD36 molecule is expressed in platelets, monocytes, erythroblasts, and other different tissues. The two types of platelet CD36 deficiency, types I and II, are associated with the absence and presence of CD36 on monocytes, respectively. To clarify the involvement of the erythroid lineage in CD36 deficiency, we investigated the phenotype and RNA expression of CD36. MATERIALS AND METHODS: CD36 expression was examined in 296 patients with several cardiovascular diseases in our outpatient clinic. There were 12 patients with type I deficiency and 16 with type II CD36 deficiency. A bone marrow sample was examined in five type I and four type II patients. Expression of CD36 mRNA was examined in burst-forming unit-erythroid (BFU-E). The sequences of reverse transcriptase polymerase chain reaction (RT-PCR) products of the CD36 mRNA from monocytes were examined. RESULTS: As expected, CD36 was deficient in erythroblasts from all five patients with type I deficiency. CD36 was present in erythroblasts from three of the four with type II deficiency, suggesting that their abnormality is restricted to platelets (type IIa). CD36 was unexpectedly absent from erythroblasts of a single type II patient (type IIb). CD36-specific mRNA was identified in BFU-E from each of two normals, six type I, and six type II patients, including type IIb. The sequences of RT-PCR products of the CD36 mRNA in a patient with type IIa and another with type IIb showed homozygous wild alleles. CONCLUSION: The findings provide evidence for further heterogeneity among CD36-deficient individuals and the existence of a basic principle mechanism of type II, such as glycosylation abnormality.

Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation.

BACKGROUND: Although immunosuppressive therapy for myocarditis has attracted a great deal of attention, its effectiveness is controversial. Interleukin (IL)-10 has a variety of immunomodulatory properties. Among the nonviral techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. METHODS AND RESULTS: We examined the applicability of murine IL-10 (mIL-10) gene transfer to the treatment of rats with experimental autoimmune myocarditis. Nine-week-old Lewis rats were inoculated with pig myosin (day 0). A plasmid vector expressing mIL-10 cDNA (800 microgram per rat) was transferred into the tibialis anterior muscles by electroporation 3 times (5 days before immunization and at days 4 and 13); control rats received empty plasmid. Electroporation increased the serum mIL-10 levels to >250 pg/mL. The 21-day survival rate in rats treated with mIL-10 cDNA was higher (15 of 15; 100%) than that of the control group (9 of 15; 60%). Furthermore, mIL-10 treatment significantly attenuated myocardial lesions and improved hemodynamic parameters. CONCLUSIONS: These findings showed that gene transfer into muscle by electroporation in vivo is an effective means of delivery of IL-10 for the treatment of autoimmune myocarditis.

Changes in the occurrence of mechanical alternans after long-term beta-blocker therapy in patients with chronic heart failure.

Mechanical alternans has been observed in patients with severe congestive heart failure, and the phenomenon is considered to be a terminal sign. Therapeutic strategies for chronic heart failure have significantly developed, but it is uncertain whether patients with mechanical alternans can be effectively treated or not. Seventeen consecutive patients with dilated cardiomyopathy were enrolled: 11 were treated with beta-blockers on conventional therapeutic regimens and 6 patients were not indicated for or were unable to continue beta-blockade. Mechanical alternans was detected during cardiac catheterization in the patients under physiologic tachycardia (110 beats/min) and stepwise dobutamine loading. In the initial study, mechanical alternans occurred in 70.6% of the patients: 8 of the 11 being treated with beta-blockers and 4 of the 6 without beta-blockade therapy. In the second study, none of the patients taking beta-blockers showed mechanical alternans under the same protocol; the occurrence of mechanical alternans did not change in the patients who were not being treated with beta-blockers. The left ventricular ejection fraction increased in patients whose mechanical alternans could not be induced during the follow up, but decreased in the patients in whom mechanical alternans was repeatedly inducible. It is concluded that mechanical alternans is associated with the failing myocardium and may be potentially correctable.

Enhanced expression and production of monocyte chemoattractant protein-1 in myocarditis.

Monocyte chemoattractant protein-1 (MCP-1) is a member of the C-C chemokine family that has been shown to play a major role in the migration of monocytes and T cells to an inflammatory focus. To clarify the role of MCP-1 in the pathogenesis of myocarditis, we have examined the expression of MCP-1 in rat hearts with experimental autoimmune myocarditis (EAM), and have also measured serum levels of MCP-1 in patients with histology-proven acute myocarditis. Lewis rats were immunized with cardiac myosin and were killed 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 42 and 56 days after immunization. Large mononuclear cells in the myocardial interstitium were stained with an anti-MCP-1 antibody. mRNA of MCP-1 increased in the hearts of EAM rats from days 15--27 as shown by quantitative reverse transcription-polymerase chain reaction. Serum MCP-1 levels of the rats with EAM were significantly elevated from days 15--24. In the clinical study, serum levels of MCP-1 in 24 patients with acute myocarditis at the time of admission (165.2 +/- 55.8 pg/ml) were significantly (P = 0.0301) elevated compared with those of 20 healthy volunteers (61.8 +/- 10.7 pg/ml). Serum MCP-1 levels of 8 fatal cases (371.8 +/- 145.2 pg/ml) were significantly (P = 0.0058) higher than those of 16 cases who survived (65.5 +/- 12.8 pg/ml). In conclusions, MCP-1 may play an important role in the pathogenesis of human acute myocarditis as well as in the progression of rat EAM.

Mechanical alternans in patients with chronic heart failure.

BACKGROUND: Clinical implications of mechanical alternans in patients with chronic heart failure have remained uncertain. In this study, prevalence, characteristics, and prognostic implications of mechanical alternans were investigated. METHODS AND RESULTS: Consecutive 51 patients with dilated cardiomyopathy underwent diagnostic cardiac catheterization using a micromanometer-tipped catheter. Under basal conditions, 7 of 35 patients with sinus rhythm showed mechanical alternans. Physiologic tachycardia (110 bpm) induced mechanical alternans in another 15 patients with sinus rhythm and in another 10 of 16 patients with atrial fibrillation. Low doses of dobutamine also induced mechanical alternans in another 8 patients, but a high dose of dobutamine eliminated mechanical alternans. Consequently, 40 patients (78%) showed mechanical alternans. Mechanical alternans was always accompanied by alternating changes of positive dP/dt, a parameter of contractility during isovolumetric contraction time, but negative dP/dt was occasionally constant. Concordant mechanical alternans between both ventricles was more prevalent than discordant alternans. The left ventricular end-diastolic volume indices and end-systolic volume indices of patients with mechanical alternans were larger than those of patients without. The left ventricular ejection fraction of patients with alternans was significantly lower than that of patients without. CONCLUSIONS: Mechanical alternans was highly prevalent in patients with chronic heart failure. The origin of mechanical alternans seems to exist before or at the isovolumetric contraction time.

Factors influencing in vivo transduction by recombinant adeno-associated viral vectors expressing the human factor IX cDNA.

Long-term expression of coagulation factor IX (FIX) has been observed in murine and canine models following administration of recombinant adeno-associated viral (rAAV) vectors into either the portal vein or muscle. These studies were designed to evaluate factors that influence rAAV-mediated FIX expression. Stable and persistent human FIX (hFIX) expression (> 22 weeks) was observed from 4 vectors after injection into the portal circulation of immunodeficient mice. The level of expression was dependent on promoter with the highest expression, 10% of physiologic levels, observed with a vector containing the cytomegalovirus (CMV) enhancer/beta-actin promoter complex (CAGG). The kinetics of expression after injection of vector particles into muscle, tail vein, or portal vein were similar with hFIX detectable at 2 weeks and reaching a plateau by 8 weeks. For a given dose, intraportal administration of rAAV CAGG-FIX resulted in a 1.5-fold or 4-fold higher level of hFIX compared to tail vein or intramuscular injections, respectively. Polymerase chain reaction analysis demonstrated predominant localization of the rAAV FIX genome in liver and spleen after tail vein injection with a higher proportion in liver after portal vein injection. Therapeutic levels of hFIX were detected in the majority of immunocompetent mice (21 of 22) following intravenous administration of rAAV vector without the development of anti-hFIX antibodies, but hFIX was not detected in 14 immunocompetent mice following intramuscular administration, irrespective of strain. Instead, neutralizing anti-hFIX antibodies were detected in all the mice. These observations may have important implications for hemophilia B gene therapy with rAAV vectors.

Inhibition of progression of heart failure and expression of TGF-beta 1 mRNA in rats with heart failure by the ACE inhibitor quinapril.

The cardioprotective effects of quinapril, an angiotensin-converting enzyme inhibitor, were studied in a rat model of heart failure. Twenty-six rats were divided into two groups: one given 20 mg/kg/day quinapril (n = 11), and controls given 0.5% methylcellulose (n = 15). After oral administration for 1 month, quinapril reduced heart weight (from 1.28+/-0.05 to 0.87+/-0.02 g; p < 0.05) without changing body weight. Quinapril lowered left ventricular end-diastolic pressure (from 14.1+/-2.0 to 6.6+/-1.5 mmHg; p < 0.05) and central venous pressure (from 2.7+/-0.9 to 0.7+/-0.4 mmHg), and increased +/- dP/dt (from +2409+/-50 to +3569+/-169 mmHg/s, and from -2318+/-235 to -3960+/-203 mmHg/s; both p < 0.01). The area of myocardial fibrosis was markedly reduced by quinapril (6+/-3%) as compared with controls (29+/-6%; p < 0.01). Expression of transforming growth factor (TGF)-beta1 mRNA was markedly increased in controls as compared with age-matched normal rats. The increase in level of TGF-beta1 mRNA was significantly suppressed by quinapril (from 17.1+/-6.2 to 9.00+/-2.40; p < 0.05). These observations indicated that quinapril has cardioprotective effects on heart failure, and that the beneficial effects may be partly explained by attenuation of fibrotic response through suppression of TGF-beta1 mRNA expression.

Bisoprolol improves survival in rats with heart failure.

The cardioprotective effects of bisoprolol were studied in a rat model of severe heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization, Lewis rats were divided into four groups: 0.1 mg/kg/day bisoprolol (Group 0.1), 1.0 mg/kg/day bisoprolol (Group 1) and 10 mg/kg/day bisoprolol (Group 10), and vehicle (0.5% methylcellulose; Group V) (all groups, n = 13). After oral administration for 1 month, heart weight, mean blood pressure, heart rate, central venous pressure, peak left ventricular pressure, left ventricular end-diastolic pressure, +/- dP/dt, and area of fibrosis were measured. Although bisoprolol reduced heart rate (399+/-11/min in Group V, 382+/-10/min in Group 0.1, 348+/-8/min in Group 1 and 302+/-9/min in Group 10) and increased survival (62% in Group V, 69% in Group 0.1, and 100% in Group 1 and Group 10) in a dose-dependent manner, this drug did not change heart weight, the area of myocardial fibrosis or hemodynamic parameters. These observations suggested that bisoprolol may improve survival independently of its effect on left ventricular function by reducing sudden death in patients with severe heart failure.

Levels of serum interleukin-10 reflect disease activity in patients with cardiac sarcoidosis.

Cardiac involvement is the major determinant of morbidity and mortality in patients with sarcoidosis, but clinical evaluation of the disease activity is occasionally difficult in cardiac sarcoidosis. The present study examined whether serum levels of interleukin-10 (IL-10) could reflect the disease activity of patients with cardiac sarcoidosis. Serum IL-10 levels were measured using an enzyme-linked immunosorbent assay, and compared with clinical manifestation, levels of angiotensin-converting enzyme (ACE), levels of lysozyme and accumulation of gallium-67 citrate. Sera were collected from 8 patients with cardiac sarcoidosis (CS group), 22 patients with miscellaneous heart diseases except for sarcoidosis (MHD group), and 8 healthy control subjects (HC group). Serum IL-10 levels of the CS group were significantly higher than those of the 2 control groups. Before steroid therapy, the levels of IL-10 in the CS group showed a significantly positive correlation with levels of ACE (r=0.868, p<0.05) and lysozyme (r=0.890, p<0.05). In 5 patients who were analyzed before and after steroid therapy, the levels of IL-10 tended to correlate with a decrease of an abnormal accumulation in gallium-67 citrate. Serum IL-10 levels may play a role in evaluation of the disease activity in patients with cardiac sarcoidosis.

Anti-CD2 monoclonal antibodies prevent the induction of experimental autoimmune myocarditis.

We investigated the effect of a monoclonal antibody against CD2 molecules (OX34) in preventing the induction of experimental autoimmune myocarditis (EAM) induced by immunizing Lewis rats with cardiac myosin. Administration of OX34 before immunization, on Days -6, -4, -2 and 0, completely prevented EAM. On the other hand, treatment with OX34 just before the appearance of myocardial lesions, on Days 9, 11, 13 and 15, had only a partial effect in preventing the disease. Flow cytometric analysis of lymph node cells showed that CD3+ T cells were immediately depleted with the administration of OX34 but had largely recovered on Day 21. Lymph node cells in OX34-treated rats had no proliferative responses to cardiac myosin-rod, but the proliferation was restored when recombinant IL-2 was added. Ultimate production of the anti-myosin antibody was not inhibited by the treatment with OX34. These results suggest that the prevention of EAM by administering the anti-CD2 monoclonal antibody OX34 resulted from T cell depletion during the induction phase, and might in addition result from T cell anergy of Th1, but not Th2 cells.

A case of chronic myeloid leukemia with minor bcr-abl transcript following fluorouracil therapy for esophageal carcinoma.

We report here a very rare case of chronic myeloid leukemia (CML) with a minor bcr-abl transcript, which developed following long-term chemotherapy with fluorouracil for esophageal carcinoma. A 64-year-old male patient was diagnosed with CML. Four years earlier, he had suffered from esophageal carcinoma, which was treated by surgical resection followed by oral administration of fluorouracil (200 mg/day) for 4 years. Molecular analysis of his Philadelphia chromosome (Ph) using reverse-transcriptase polymerase chain reaction (RT-PCR) and subsequent sequencing revealed a minor bcr-abl transcript. The clinical course of this patient was aggressive with a short chronic phase of CML. This is the first reported case of secondary CML with a minor bcr-abl transcript.

Low dose carvedilol inhibits progression of heart failure in rats with dilated cardiomyopathy.

The cardioprotective properties of carvedilol (a vasodilating beta-adrenoceptor blocking agent) were studied in a rat model of dilated cardiomyopathy induced by autoimmune myocarditis. Twenty-eight days after immunization, surviving Lewis rats (32/43=74%) were divided into three groups to be given 2 mg kg(-1) day(-1) (Group-C2, n=10) or 20 mg kg(-1) day(-1) (Group-C20, n=10) of carvedilol, or vehicle (0.5% methylcellulose, Group-V, n=12). After oral administration for 2 months, body weight, heart weight (HW), heart rate (HR), rat alpha-atrial natriuretic peptide (r-ANP) in blood, central venous pressure (CVP), mean blood pressure (mean BP), peak left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), +/-dP dt(-1) and area of myocardial fibrosis were measured. Values were compared with those for normal Lewis rats (Group-N, n=10). Two out of 12 (17%) rats in Group-V died from day 28 to day 42 after immunization. No rat died in Groups-C2, -C20 and -N. Although the CVP, mean BP, LVP and +/-dP dt(-1) did not differ among the three groups, the HW, HR and r-ANP in Group-C2 (1.14+/-0.03, 339+/-16 and 135+/-31) and Group-C20 (1.23+/-0.04, 305+/-8 and 156+/-24) were significantly lower than those in Group-V (1.36+/-0.04 g, 389+/-9 beats min(-1) and 375+/-31 pg ml(-1), respectively). The LVEDP in Group-C2 was significantly lower than that in Group-V (7.4+/-1.4 and 12.2+/-1.2 mmHg, respectively, P<0. 05). The area of myocardial fibrosis in Group-C2 was smaller than that in Group-V (12+/-1 and 31+/-2%, P<0.01). These results indicate that a low dose of carvedilol has beneficial effects on dilated cardiomyopathy.