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Biomedical subjects

T Miyauchi

Publications and source records attributed to T Miyauchi.

At least 73 records · Page 4Linked to original sources
PubMed1999

Myocardial expression of endothelin-2 is altered reciprocally to that of endothelin-1 during ischemia of cardiomyocytes in vitro and during heart failure in vivo.

We and other groups have reported that endothelin (ET)-1 expression in the heart is altered in the setting of heart diseases. We have also reported that myocardial ET-1 is involved in the progression of heart failure, and that an ET receptor antagonist improves long-term survival in heart failure (Nature 384: 353-355, 1996). However, the role of myocardial ET-2 in disease states are not known. To characterize the role of ET-2, we used a) the failing hearts of rats with heart failure caused by myocardial infarction, and b) primary cultured cardiomyocytes subjected to hypoxia. In the failing heart in vivo, ET-1 mRNA increased by 390% compared with that in the non-failing heart, while ET-2 mRNA drastically decreased by 88%. Thus, gene expression of ET-1 and ET-2 was reciprocally altered in the failing heart in vivo. In in vitro studies, reciprocal alterations in ET-1 and ET-2 gene expression were also observed in isolated primary cultured cardiomyocytes, subjected to hypoxia. Specifically, acute hypoxic stress induced a significant increase (360% of the basal level) in ET-2 mRNA expression compared with that in normoxic cells, whereas it decreased ET-1 mRNA expression by 62% in primary cultured cardiomyocytes. Although these two crucial conditions, i.e., heart failure in vivo and acute hypoxic stress in vitro, are pathophysiologically distinct from each other, reciprocal alteration of ET-1 and ET-2 gene expression was observed in both cases. To further investigate the regulatory mechanism of the altered gene expression, luciferase analysis was performed using primary cultured cardiomyocytes. ET-2 promoter, which is the 5'-flanking region of preproET-2 gene (5'ET-2), showed a marked increase in luciferase activity during acute hypoxia. In contrast, the luciferase activity of 5'ET-1 (ET-1 promoter) did not change in response to hypoxic stress. The present study suggests that there are transcriptionally distinct regulatory mechanisms for ET-1 and ET-2 expression in cardiomyocytes, and therefore this study may provide a new aspect of cardiac ET system that not only ET-1 but also ET-2 can be participated in the pathophysiological conditions.

Animals↗
PubMed1999

Heart failure and endothelin receptor antagonists.

Cardiac myocytes and vascular endothelial cells produce endothelin-1, which increases the contractility of cardiac muscles and of vascular smooth muscles. Endothelin-1 also exerts long-term effects, such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes. In heart failure, the production of endothelin-1 is markedly increased in the failing heart. Here, evidence that an endothelin receptor antagonist is a useful new drug for the treatment of heart failure is discussed. Long-term treatment with an endothelin receptor antagonist greatly improves the survival rate of animals (rat, hamster, etc.) with chronic heart failure. This beneficial effect is accompanied by amelioration of left ventricular dysfunction. The myocardial endothelin system appears to be a novel and important target for therapeutic intervention in heart failure.

Animals↗
PubMed1999

Histological characterization of defective spermatogenesis in mice lacking the basigin gene.

Basigin is a transmembrane protein belonging to the immunoglobulin superfamily. In the light of the fact that knockout mice lacking the basigin gene (Bsg) are azoospermic, the phenotype in the male reproductive system was extensively examined in this study. Spermatogenesis in Bsg (-/-) mice was found to be disrupted, and arrested at the metaphase of the first meiotic division. A few germ cells differentiated into young spermatids, but they were exfoliated. The lumens of the male reproductive system were filled with round degenerated cells. Using the TUNEL method and electron microscopy, some of the degenerated cells in the testis and epididymal head were shown to be apoptotic. Crystalloids of fine tubules and unusual ectoplasmic specializations were also observed in the Sertoli cells of Bsg (-/-) mice. These specializations displayed unusual 'circular' structures. Furthermore, unusual ectoplasmic specializations covering the spermatocytes rather than the mature spermatids were found. These structures were formed as a result of the lack of mature spermatids in the Bsg (-/-) testis. Results from analyses of azoospermia in the Bsg (-/-) mice suggest that basigin, through the interactions between germ cells and Sertoli cells, is an essential factor in the growth and/or survival of spermatids.

Animals↗
PubMed1999

Pathophysiology of endothelin in the cardiovascular system.

In this article, we review the basic pharmacological and biochemical features of endothelin and the pathophysiological roles of endothelin in cardiovascular diseases. Development of receptor antagonists has accelerated the pace of investigations into the pathophysiological roles of endogenous endothelin-1 in various diseases, e.g. chronic heart failure, renal diseases, hypertension, cerebral vasospasm, and pulmonary hypertension. In chronic heart failure, the expression of endothelin-1 and its receptors in cardiomyocytes is increased, and treatment with an endothelin receptor antagonist improves survival and cardiac function. Endothelin receptor antagonists also improve other cardiovascular diseases. These results suggest that the interference with endothelin pathway either by receptor blockade or by inhibition of endothelin converting enzyme may provide novel therapeutic drugs strategies for multiple disease states.

Animals↗
PubMed1999

Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart.

Endothelin (ET)-1 has a positive inotropic effect and induces hypertrophy in cardiomyocytes. We previously reported that the peptide level of ET-1 is increased in the failing heart of rats with chronic heart failure (CHF) and that treatment with an ETA-receptor antagonist greatly improves survival in rats with CHF. However, precise analysis for alteration of the myocardial ET system in the failing heart is not known. In this study, we used rats with CHF due to chronic myocardial infarction. Sham-operated rats served as a control. The results showed that the level of preproendothelin (preproET)-1 mRNA and the peptide level of ET-1 were markedly increased in the heart of rats with CHF, whereas the expression of endothelin-converting enzyme (ECE)-1 mRNA in the heart did not differ between CHF and control rats. The intensity of ET-1 staining (ET-1-like immunoreactivity) in cardiomyocytes was markedly stronger in rats with CHF than in control rats, and the fibrotic tissues of the infarcted area were not stained. The mRNA and protein levels of both ETA and ETB receptors in the heart were significantly higher in rats with CHF than in control rats. The present study suggests that the increase in ET-1 peptide level in the heart of the rats with CHF originated from upregulation of preproET-1 mRNA, which was not attendant with the alteration of ECE-1 mRNA expression, and that both the ETA- and ETB-receptor systems are greatly accelerated in the failing heart.

Animals↗
PubMed1999

Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors.

Endothelin (ET)-1 has potent positive inotropic and chronotropic activity in the heart and induces cardiac hypertrophy. The production of ET-1 in the heart is reported to be increased under some conditions. In normal circulation, the pressure load to the left ventricle (LV) is much greater than that to the right ventricle (RV). In this study, we investigated the gene expression of the myocardial ET-1 system (ET-1, ET(A) receptor, and ET(B) receptor) in the RV and LV of normal rats and also investigated these genes in hypertrophied RV due to pathological pulmonary hypertension (PH). Normal rats showed no differences between the RV and LV in the gene expression of either ET-1, ET(A) receptor, or ET(B) receptor in either the adult stage (11 wk old) or the neonatal stage (1 and 8 days old). On the other hand, the expression of both atrial natriuretic peptide (ANP) mRNA and B-type natriuretic peptide (BNP) mRNA was significantly greater in the LV than in the RV in adult rats. Gene expression of ET-1, ET(A) receptor, and ET(B) receptor in the RV was markedly higher in rats with monocrotaline-induced (pathological) PH than that in control rats. The expression of ANP mRNA and BNP mRNA in the RV was also markedly higher in the rats with PH. In conclusion, the data suggest that gene expression of the ET-1 system in the myocardium is not affected by physiological pressure load in either the adult stage or neonatal stage; however, it is enhanced by pathological pressure overload such as that in PH.

Animals↗
PubMed1999

Pathophysiological roles of endothelin-1 in Dahl salt-sensitive hypertension.

The purpose of the present experiment was to study the pathophysiological roles of endothelin-1 (ET-1) in salt-sensitive hypertension with the use of Dahl salt-sensitive (DS) and salt-resistant (DR) rats. PreproET-1 mRNA expression was determined by reverse transcription-polymerase chain reaction. In the kidney, expression of preproET-1 mRNA was greater in DS rats on a normal salt diet compared with DR rats of the same age. In DS rats, the level of preproET-1 mRNA expression in kidney had a significant correlation with systolic blood pressure. The expression of preproET-1 mRNA in aorta and kidney was increased by 3-week high salt intake in DS rats but not in DR rats. Expression of preproET-1 mRNA and ET-1 levels in left ventricle was exaggerated by high salt intake in DS rats. However, there was no significant difference in plasma ET-1 levels between DS and DR rats regardless of salt intake. Pressor response curves for ET-1 in DS rats with or without high salt intake were significantly shifted to the left compared with those in DR rats. A single oral dose (3 to 10 mg/kg) of J-104132 (L-753 037), a potent, orally active mixed endothelin A and B (ET(A)/ET(B)) receptor antagonist, reduced blood pressure to normotensive levels in DS rats with high salt intake, and its action was maintained for >/=24 hours. In DS rats with normal salt intake, J-104132 (10 mg/kg) slightly but significantly decreased blood pressure. DR rats did not show obvious depressor responses to J-104132 (10 mg/kg) regardless of salt intake. These results suggest that ET-1 acts as one of the pathophysiological factors in the development and maintenance of salt-sensitive hypertension, and a mixed ET(A)/ET(B) receptor antagonist could be useful in the treatment for salt-sensitive hypertension.

Animals↗
PubMed1998

A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis.

Basigin is a highly glycosylated transmembrane protein with two immunoglobulin-like domains. We generated mutant mice lacking the basigin gene (Bsg) by gene targeting. Bsg (-/-) embryos developed normally during preimplantation stages. However, the majority of Bsg (-/-) embryos died around the time of implantation. At this time, basigin mRNA was strongly expressed in the trophectoderm, embryo proper, and uterine endometrium of Bsg (+/+) mice. These results suggest that basigin is involved in intercellular recognition during implantation. Embryos which survived the critical period yielded Bsg (-/-) mutant mice. Half of the mutant mice died before 1 month after birth, due to interstitial pneumonia. The surviving adult mutant mice were small and sterile. Spermatogenesis was arrested in the mutant mice. Most of the spermatocytes in the Bsg (-/-) mouse were arrested and degenerated at the metaphase of the first meiosis, and only a small number differentiated to step 1 spermatids. In the female mutants, the ovaries and genital tract were morphologically normal, and the defect was probably in the capability of implantation of the uterus. In conclusion, basigin is an important cell-surface molecule involved in early embryogenesis and reproduction.

Animals↗
PubMed1998

Effect of donor-specific splenocytes via portal vein and FK506 in rat small bowel transplantation.

BACKGROUND: To investigate the role of the liver in immune responses after small bowel transplantation, donor-specific splenocytes were infused perioperatively, via the portal vein, in a rat heterotopic small bowel transplant model. METHODS: Heterotopic small bowel transplantation between the fully allogenic Brown Norway (BN) (RT1n) and Lewis (RT1[1]) strain rats were performed. We prepared donor splenocytes from BN or third-party WKA (RT1k) rat spleens for Lewis hosts and injected the splenocytes perioperatively via the host portal vein or the systemic vein. The hosts were treated with a short course of the immunosuppressive agent, FK506 (0.5 mg/kg, 0-3 days postoperatively), following the experimental protocols. RESULTS: Untreated Lewis hosts rejected BN small bowel grafts at 5.4+/-0.9 days (n=8). BN splenocytes given alone caused fatal graft-versus-host disease in six of eight animals, and two others died from graft rejection. FK506 alone did not significantly prolong graft survival (6.3+/-1.0 days, n=10). However, BN splenocytes injected via the portal vein, combined with FK506, prolonged graft survival to 12.7+/-2.1 days (n=12, P < 0.01) and 10 of 12 rats survived more than 70 days. This was donor antigen specific. BN splenocytes administered systemically caused fatal graft-versus-host disease in all recipients, and FK506 did not ameliorate this. Histologic findings of graft rejection were remarkably mild in the recipients of the combined therapy, compared with the recipients that were given FK506 alone. Down-regulation of one-way mixed lymphocyte reaction to BN splenocytes was observed in the splenocytes of the tolerant hosts. CONCLUSIONS: Combined administration of donor splenocytes and FK506 reduced allograft rejection and prolonged survival in this rat model of small bowel transplantation.

Animals↗
PubMed1998

Down-regulation of ET(B) receptor, but not ET(A) receptor, in congestive lung secondary to heart failure. Are marked increases in circulating endothelin-1 partly attributable to decreases in lung ET(B) receptor-mediated clearance of endothelin-1?

Receptors for endothelin (ET)-1, a potent vasoconstrictor peptide, have two isoforms, i.e. ET(A) receptors and ET(B) receptors. We previously reported that an ET(A) receptor antagonist greatly ameliorated pulmonary hypertension due to congestive heart failure (CHF) in rats. In the present study of rats with pulmonary congestion secondary to CHF, we determined not only ET(A) receptor mRNA expression but also ET(B) receptor mRNA expression in the congestive lung because lung ET(B) receptors are reported to be important for the clearance of circulating ET-1. We also measured lung ET-1 and circulating ET-1 levels. The expression of ET(B) receptor mRNA in the lung was significantly lower in rats with CHF than in age-matched control rats, while the expression of ET(A) receptor mRNA did not differ between the two groups. The protein level of ET(B) receptor, determined by Western blot, in the lung was lower in the rats with CHF than in the control rats, while the protein level of ET(A) receptor did not differ between the two groups. The lung ET-1 level and plasma ET-1 level were significantly higher in the rats with CHF than in the controls by 1.4-fold and 5.3-fold, respectively. Thus, in the rats with CHF, ET-1 was increased to a much greater extent in plasma than in the lung. The present findings suggest that selective down-regulation of ET(B) receptor, but not ET(A) receptor, occurs in the congestive lung. Since lung ET(B) receptors play a role in the clearance of circulating ET-1, we propose that down-regulation of lung ET(B) receptors partly contributes to marked increases in circulating ET-1 and that increased ET-1 in the circulating plasma as well as in the lung is involved in the progression of pulmonary hypertension in CHF.

Animals↗
PubMed1998

Hypoxia and endothelin-1 induce VEGF production in human vascular smooth muscle cells.

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a secreted mitogen for vascular endothelial cells, and it promotes vascular permeability and neovascularization in vivo. We investigated the mechanisms by which low oxygen tension modulates the expression of VEGF in human aortic vascular smooth muscle cells (h-SMC) in vitro. Moreover, we measured VEGF levels in the cultured medium with or without endothelin-1 (ET-1) using a newly developed, highly sensitive, enzyme-linked immunosorbent assay. Hypoxia resulted in a substantial induction of VEGF transcripts at 3 and 24 hr. VEGF levels were significantly higher when h-SMC were cultured in medium containing ET-1 than when cultured in medium without ET-1. In conclusion, hypoxia and ET-1 constitute potent stimuli for VEGF production in h-SMC.

Cell Hypoxia↗
PubMed1998

Enhanced depressor and hyperemic responses to calcitonin gene-related peptide in spontaneously hypertensive rats.

Intravenous (i.v.) bolus injection of calcitonin gene-related peptide (CGRP) caused a depressor response, which was significantly larger in 12-week-old spontaneously hypertensive rats (SHR) than in Wistar-Kyoto rats (WKY). CGRP also caused decreases in carotid and hindquarter vascular resistance, the magnitude of which was larger in the carotid than the hindquarter. In both regions, the vasodilator response to CGRP was significantly larger in SHR than WKY. Plasma CGRP level was significantly lower in SHR than WKY. These results suggest that depressor and vasodilator responses to CGRP are enhanced in SHR and that decreased plasma CGRP level in SHR may contribute to the enhanced responses.

Age Factors↗
PubMed1998

Cloning of hamster preproendothelin-1 cDNA and its expression in the heart.

To elucidate the pathophysiologic roles of endothelin-1 (ET-1) in the heart, we first cloned and sequenced a part of hamster preproET-1 cDNA from the heart of the CHF146 hamsters. The amino acid sequence has 89% homology to that of rat preproET-1 in the cloned part. The deduced hamster 21-residue mature ET-1 is identical to human, rat, canine, and mouse ET-1. In the next step we investigated the expression of preproET-1 mRNA in the failing heart of CHF146 hamsters. For this purpose, we used 46-week-old CHF146 hamsters and age-matched control healthy hamsters. Left ventricular (LV) + dP/dtmax was significantly lower in CHF146 hamsters than in control hamsters. LV end-diastolic pressure was significantly higher in CHF146 hamsters than in control hamsters, as was central venous pressure. These results suggested that the CHF146 hamsters developed congestive heart failure. The expression of preproET-1 mRNA was greatly enhanced in the LV of the CHF146 hamsters. Because it has been reported that ET-1 induces cardiac hypertrophy and injury to cardiac myocytes in addition to its potent positive inotropic and chronotropic actions, the present findings suggest that endogenous ET-1 plays pathophysiologic roles in the failing heart of CHF146 hamsters.

Amino Acid Sequence↗
PubMed1998

Altered expression of isoforms of myosin heavy chain mRNA in the failing rat heart is ameliorated by chronic treatment with an endothelin receptor antagonist.

We have reported that the production of endothelin (ET)-1 is markedly increased in the failing heart of rats with chronic heart failure (CHF) and that the long-term (3-month) treatment with the ETA receptor antagonist BQ-123 markedly ameliorated the long-term survival and hemodynamic parameters in rats with CHF. In this study we investigated whether this therapy affects the alteration of the mRNA expression of cardiac myosin heavy chain (MHC) isoforms in the hearts of rats with CHF. The change from alpha-MHC to beta-MHC is regarded as a molecular marker for heart failure. The expression of beta-MHC mRNA was dominant in the left ventricle (LV) of CHF rats treated with saline, whereas that of alpha-MHC was dominant in the LV of sham-operated rats treated with saline. Therefore, in the failing rat heart, a change from alpha-MHC to beta-MHC occurred. In the LV of CHF rats treated with BQ-123, this treatment effectively prevents the switching of MHC isoforms. These findings suggest that long-term BQ-123 treatment inhibits the change in MHC isoforms and suggest that this treatment ameliorates heart failure in CHF rats at the molecular level.

Animals↗
PubMed1998

Endothelin-1 in the heart during exercise.

In addition to its potent vasocontractile effects, endothelin-1 (ET-1) has potent positive inotropic and chronotropic effects on isolated heart muscles in vitro. However, it is not known whether the production of ET-1 in the heart is altered by exercise. In this study we investigated the production of ET-1 in the heart during exercise. Rats performed treadmill running of 45-min duration. Sedentary rats served as controls. Immediately after exercise, the heart was quickly removed. The peptide level of ET-1 in the heart was measured by a sandwich-enzyme immunoassay. The peptide level of ET-1 in the heart was significantly higher in the exercise group than in the control sedentary group. Therefore, we have demonstrated that production of ET-1 in the heart is increased by exercise. The present study suggests that myocardial ET-1 participates in the modulation of cardiac function during exercise.

Animals↗
PubMed1998

Abnormal neurohumoral responses to exercise in patients with heart disease: inhibition of an increase in endothelin-1 production during exercise.

We have reported that the plasma endothelin-1 (ET-1) level is significantly increased by exercise in healthy athletes and that it is elevated in the circulation of the non-working leg but not the working leg, suggesting that ET-1 plays an important role in redistribution of blood during exercise. This study was designed to compare alterations of neurohumoral substances by exercise in normal subjects and patients with heart disease. Study patients comprised three groups: eight patients with congestive heart failure (CHF) due to Ebstein's anomaly or single-ventricle heart after Fontan operation; six patients with complete transposition of the great arteries (TGA) after an anatomic surgical correction who may be candidates for ischemic heart disease; and five age-matched normal subjects. All patients were in New York Heart Association functional class I. All subjects performed symptom-limited treadmill exercise. It is suggested that patients with CHF or TGA have a manifest or latent exercise intolerance, respectively. In failed to increase plasma ET-1 level, although it caused a greater increase in norepinephrine, angiotensin II, and arginine vasopressin than in the controls. Exercise also caused a delay in the increased response of plasma ET-1 levels in patients with TGA after an anatomic surgical repair. On the other hand, plasma brain natriuretic peptide (BNP) level was augmented by exercise in patients with CHF and patients with TGA but not in the controls. The present results suggest that an increase in ET-1 production during exercise is absent in patients with heart disease. The mechanisms of inhibition of ET-1 production during exercise in patients with heart disease remain to be elucidated. However, the present study suggests that ET-1 plays an important role in redistribution of blood during exercise, and proposes the possibility that failure of an increase in ET-1 production results in exercise intolerance in patients with heart disease.

Child↗
PubMed1998

Endothelin-1 expression in hearts of transgenic hypertensive mice overexpressing angiotensin II.

Cardiac myocytes and vascular endothelial cells produce endothelin (ET)-1, which has potent hypertrophic effects on cardiac myocytes. Although in cultured cardiomyocytes, angiotensin II (Ang II) was reported to enhance ET-1 production in vitro, it is not known whether ET-1 production is enhanced by Ang II in vivo. We investigated the production and pathophysiologic roles of ET-1 in 20-week-old male transgenic hypertensive mice (THM), in which the renin-angiotensin system (RAS) was markedly activated because of the presence of both human renin and angiotensinogen genes. Systolic blood pressure and the ratio of left ventricular weight to body weight were significantly higher in the THM than in control mice, indicating that THM developed cardiac hypertrophy. ET-1 production was significantly increased in the heart of THM because both ET-1 mRNA expression and peptide levels were significantly higher than in controls. However, circulating plasma ET-1 levels did not differ between the groups, and blood pressure did not change after i.v. injection with a high dose (3 mg/kg) of the ETA/B-nonselective receptor antagonist SB209670. These findings suggest that increased cardiac ET-1 production may contribute to the progression of cardiac hypertrophy and that endogenous ET-1 may not be involved in the short-term modulation of blood pressure in THM of this age.

Angiotensin II↗