Search PubMed⌕ Search

Biomedical subjects

Y Kihara

Publications and source records attributed to Y Kihara.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cardiac calcineurin during transition from hypertrophy to heart failure in rats.

We studied an alteration of calcineurin expression in the heart and its modification by cyclosporin A and an ACE inhibitor, temocapril, using Dahl salt-sensitive (DS) rats with hypertensive left ventricular hypertrophy (LVH) and congestive heart failure (CHF). Calcineurin protein expression in the LV myocardium was increased in the LVH stage, but then decreased during CHF transition. Chronic cyclosporin A treatment (10 mg/kg/day), which inhibits calcineurin activity, could not block the increases of LV weight and dimensions and did not improve the LV systolic function during the CHF transition. In contrast, chronic temocapril treatment (20 mg/kg/day) restored the downregulation of calcineurin expression, but progression of the hypertrophic process was inhibited. Therefore, cardiac calcineurin is increased in the hypertensive LVH and may be involved in the development of the adaptive hypertrophic process. However, calcineurin expression is downregulated during CHF transition and may no longer play a major role in the pathogenesis of myocardial hypertrophy in the failing hearts.

Adaptation, Physiological↗
PubMed2000

Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium.

BACKGROUND: A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts. METHODS AND RESULTS: At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane. CONCLUSIONS: The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.

Animals↗
PubMed2000

Age-dependent impairment of coronary collateral development in humans.

The purpose of this study was to evaluate whether age influences collateral development in patients with coronary artery disease. The extent of collateral development to the area perfused by the infarct-related artery was graded, depending on the degree of opacification of the occluded infarct-related artery. We evaluated the extent of collateral development using coronary cineangiography in 102 patients with an acutely occluded infarct-related coronary artery within 12 h after the onset of the first acute myocardial infarction, and who had a history of long-standing effort angina. Well-developed collateral circulation was observed in 54 (53%) of the patients. The patients were divided into two groups based on their age. The prevalence of well-developed collateral circulation in the younger group (< or = 64 years, n = 48) was 69% (33 of 48), being significantly (P = 0.003) higher than 39% (21 of 54) in the older group (> or = 65 years, n = 54). We conclude that in the presence of stimuli for collateral development i.e., long-standing effort angina accompanied by severe coronary stenosis, the age of patients is a key determinant of collateral development.

Adult↗
PubMed2000

Modulation of in vivo cardiac hypertrophy with insulin-like growth factor-1 and angiotensin-converting enzyme inhibitor: relationship between change in myosin isoform and progression of left ventricular dysfunction.

OBJECTIVES: Supplemental myocardial hypertrophy induced by insulin-like growth factor (IGF)-1 may prevent transition from hypertrophy to heart failure under chronic mechanical overload. BACKGROUND: Several studies have suggested that IGF-1 treatment may be beneficial in chronic heart failure. In addition, recent studies indicated that the amount of alpha-myosin heavy chain (MHC) plays a significant hemodynamic role in large animals including humans. METHODS: We treated Dahl salt-sensitive hypertensive rats on a long-term basis with IGF-1. The effects were compared with those produced by treatment using a sub-antihypertensive dose of temocapril, an angiotensin-converting enzyme (ACE) inhibitor. At 11 weeks, when these rats displayed compensated left ventricular hypertrophy (LVH), they were randomized to three groups: 1) IGF group (3 mg/kg/day); 2) temocapril group (1 mg/kg/day); and 3) vehicle (control) group. RESULTS: After 15 weeks, the control rats showed left ventricular (LV) enlargement and severe LV dysfunction and rapidly died of pulmonary congestion (mean survival time: 16.8+/-0.5 weeks). The survival time was significantly shortened (15.6+/-0.3 weeks) in the IGF-1 group but significantly prolonged (19.5+/-0.6 weeks) in the temocapril group. The rats in the IGF-1 group showed accelerated LV dilation and dysfunction. Of the several parameters investigated, it was found that the relative amounts of MHC isoforms differed among the three groups. The alpha-MHC mRNA level was decreased by 52% (p<0.01) in the IGF group, while it increased by 58% (p<0.01) in the temocapril group compared with the control group. These changes were related to the progression of LV dysfunction. CONCLUSIONS: Supplemental myocardial hypertrophy with long-term IGF-1 treatment may not be beneficial if concentric LVH already exists. Our data suggest that IGF-1 may not protect myocardial performance when its hypertrophic effect aggravates the reduction of alpha-MHC. By contrast, the ACE inhibitor may improve myocardial function and prognosis by preventing the down-regulation of this isoform.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts.

A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 microM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 microM. In indol-loaded isolated heart preparations, 0.3 microM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p = n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with I(Ca), and by its subsequent ability of strong myocardial protection.

Analysis of Variance↗
PubMed2000

Pericardial fluid from patients with ischemic heart disease accelerates the growth of human vascular smooth muscle cells.

The strong association between severe coronary stenosis and collateral growth continues to be a paradigm in this field of investigation. The present study was based on the hypothesis that angiogenic growth factors are produced by ischemic cardiac tissue, are diffusible and more concentrated in pericardial fluid, and accelerate the growth of vascular smooth muscle cells (VSMC). Pericardial fluid from 17 patients with stable or unstable angina or acute myocardial infarction (group A) and from 10 patients with nonischemic heart disease (group B) were collected at the time of open heart surgery. Cultured human aortic VSMC were plated at the third passage at a density of 5x10(3)/100 microl and allowed to attach for 24 h. The 3-day growth assay was preceded by 72 h of growth arrest with 0.4% fetal calf serum (FCS). Growth was restarted by the addition of 90 microl of medium containing 0.4% FCS, and 1O microl of each pericardial fluid. Cell counts on triplicate wells were performed using a dimethylthiazol (MTT) method on days 0 and 3. The effect of pericardial fluid on the growth of VSMC was evaluated as a ratio (R) of cell numbers on day 3 to those on day 0. The concentration of basic fibroblast growth factor (bFGF) in pericardial fluid was measured by an enzyme-linked immunosorbent assay. The concentration of bFGF in pericardial fluid of group A was 633+/-127 pg/ml, and significantly (p=0.003) higher than that of group B (86+/-23 pg/ml). R in group A was 2.29+/-0.18 and significantly (p=0.019) higher than that in group B (1.68+/-0.11). The level of bFGF positively correlated with R (p=0.009). These findings indicate that pericardial fluid from patients with ischemic heart disease contains some substances that mediate collateral development, and bFGF might be one of them.

Aged↗
PubMed2000

Dilated phase of hypertrophic cardiomyopathy with mid-ventricular obstruction after 20-year follow-up.

This paper reports a case of dilated phase in hypertrophic cardiomyopathy with mid-ventricular obstruction. Following the first cardiac catheterization and endomyocardial biopsy, the patient was diagnosed as having hypertrophic cardiomyopathy (HCM) with mid-ventricular obstruction. He had been first diagnosed at the age of 38 years and was subsequently followed for 20 years. Echocardiogram revealed gradually progressive dilatation of the left ventricle, associated with disappearance of the mid-ventricular obstruction. The second cardiac catheterization and endomyocardial biopsy performed at the age of 58 disclosed that the patient was in the dilated phase of HCM with a dip-and-plateau pattern diastolic pressure trace.

Adult↗
PubMed1999

Heparin potentiates collateral growth but not growth of intramyocardial endarteries in dogs with repeated coronary occlusion.

Heparin accelerates coronary collateral development in various animal models of myocardial ischemia. The purpose of this study was to clarify the beneficial effect of heparin on canine collateral development. Seventeen adult mongrel dogs were instrumented for measurements of a subendocardial segment length in the central area perfused by the left circumflex coronary artery, its flow, and left ventricular pressure. A pulsed Doppler flow probe and an externally inflatable pneumatic occluder were placed around the proximal circumflex artery. After the recovery from surgery, 2-min circumflex coronary artery occlusions were repeated eight times at 58-min intervals daily. After excluding seven dogs with well-developed preexisting collateral circulation, ten dogs were randomized into two groups with (n = 5) and without (n = 5) heparin treatment. The total occlusion time until adequate collateral development (an index of collateral growth) was 164+/-34 (SD) min in dogs with heparin treatment, being significantly less than 289+/-49 min in dogs without heparin (p<0.01). In contrast, the extent of the reduction in resting blood flow of the repeatedly occluded circumflex artery (an index of neovascularization toward the ischemic area) was comparable in dogs with and without heparin (15.4+/-12.4% vs. 21.1+/-13.6%, p=NS). Heparin promotes nonsprouting angiogenesis (arteriogenesis) of preformed collateral vessels but not neovascularization toward the ischemic area in dogs with brief repetitive coronary occlusions.

Animals↗
PubMed1999

Determinants of collateral development in patients with acute myocardial infarction.

BACKGROUND: The presence or absence of collateral circulation to the infarct-related coronary artery in acute myocardial infarction (AMI) significantly impacts on infarct size and resulting left ventricular function. However, the determinants of collateral development have not been clarified. HYPOTHESIS: The purpose of this study was to elucidate the determinants of collateral development in humans. METHODS: The study group consisted of 248 patients (178 men, 70 women; mean age 63 years) undergoing coronary angiography within 12 h after the onset of a first AMI. All patients exhibited complete occlusion of the infarct-related artery. The extent of collateral circulation to the area perfused by the infarct-related artery was graded as none, or poorly or well developed, depending on the degree of opacification of the occluded coronary artery on the contralateral injection of contrast. RESULTS: Well-developed collateral circulation was observed in 92 of the 248 patients (37.1%). The prevalence of well-developed collaterals was 57% in patients with a history of angina pectoris prior to AMI, which was significantly (p < 0.0001) higher than the 26% in those without a history of angina. Multivariate stepwise logistic regression analysis was then applied to identify predictors of collateral development. Possible determinants of collateral development were long-standing preinfarction angina, severity of coronary artery disease, age, gender, and coronary risk factors (hypertension, diabetes, hypercholesterolemia, smoking). This analysis revealed that only the presence of a history of angina pectoris prior to AMI was a significant predictor of collateral development (p < 0.0001). CONCLUSIONS: A history of angina pectoris prior to AMI is a clinical marker for coronary stenoses. Since severe coronary stenoses can provide stimuli that lead to collateral development, it is reasonable that a history of angina would also be a clinical marker for collateral vessels.

Age Factors↗
PubMed1999

Development of enzyme-linked immunosorbent assay for acidic fibroblast growth factor and its clinical application.

We have developed, for the first time, an enzyme-linked immunosorbent assay (ELISA) system for the measurement of human acidic fibroblast growth factor (aFGF). Anti-bovine aFGF rabbit IgG was conjugated with N-hydroxysuccimidobiotin, and the resulting IgG-biotin conjugate was used as the second antibody. This assay was highly specific and reproducible, enabling us to detect aFGF at a concentration as low as 1 microg/l without any prior processing of samples. With this method, it was possible to determine human aFGF up to 833 x 10(3) ng/l, with the use of anti-bovine aFGF IgG as the first and second antibody. There was no significant cross-reactivity of the antibody with other growth factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). The aFGF concentration in pericardial fluid was significantly higher in patients with unstable angina than in those with other heart diseases, suggesting that the aFGF plays an important role(s) in the course of collateral growth in coronary artery disease. Therefore, our ELISA system may be useful in determining unknown biological function(s) or pathological role(s) of aFGF in various disease entities.

Aged↗
PubMed1999

Metabolic abnormalities in the genetically obese and diabetic Otsuka Long-Evans Tokushima Fatty rat can be prevented and reversed by alpha-glucosidase inhibitor.

The recently developed Otsuka Long-Evans Tokushima Fatty (OLETF) rat is known to develop insulinopenic diabetes after a prolonged period in a condition resembling non-insulin-dependent diabetes mellitus (NIDDM). We examined the effect of pharmacological intervention with a potent intestinal alpha-glucosidase inhibitor, acarbose, on the metabolic and histopathologic changes in this rat model. The first two groups of rats received an acarbose-rich diet (150 mg/100 g normal chow) from 12 weeks of age (ie, before the onset of diabetes) or from 28 weeks of age (ie, after the onset of diabetes), while a third group received the acarbose-rich diet for the initial 16 weeks only (from 12 to 28 weeks of age). A control group received standard rat chow. Acarbose-fed rats gained less weight or lost weight despite increased food intake when switched to the acarbose-rich diet. Acarbose also reduced visceral adipose depots and fasting triglyceride (TG), glucose, and insulin levels. At the end of the study at 72 weeks, the pancreatic wet weight and insulin content were significantly higher in the treated groups versus control rats. The morphological changes observed in control rats, such as atrophy of the pancreas and reduced number and size of islets, were not present in acarbose-treated rats. Rats fed acarbose from 12 to 28 weeks of age gradually gained weight after switching to standard chow, and hyperinsulinemia, hyperglycemia, and hyperlipidemia appeared (in that order). The pancreatic insulin content in these rats was significantly higher and the visceral adipose depot was significantly smaller than in control rats. Our study demonstrates that acarbose prevented and reversed the metabolic derangement and histopathological changes in genetically diabetic rats. Moreover, treatment with acarbose even for a short period produced a marked delay in the development of insulin insensitivity and frank diabetes.

Acarbose↗
PubMed1999

Pharmacologic profile of TS-941, a new benzodiazepine derivative cholecystokinin-receptor antagonist, in in vitro isolated rat pancreatic acini.

We investigated the pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-(-)-N-[2,3-dihydro-2-oxo-5-phenyl-1-[(1H-tetrazol-5-yl)methyl] -1H-1,4-benzodiazepine-3-yl]-2-indolecarboxamide (TS-941), a cholecystokinin type A (CCK-A)-receptor antagonist, in the isolated rat pancreatic acini and compared with those of well-known CCK-A-receptor antagonists, devazepide and loxiglumide. TS-941 inhibited CCK-8-stimulated amylase release concentration dependently, as did devazepide and loxiglumide, with a half-maximal inhibition (IC50) at 78.6 +/- 10.3 nM. TS-941 was approximately 23 times less potent than devazepide (IC50, 3.4 +/- 0.3 nM), but was 50 times more potent than loxiglumide (IC50, 3,966 +/- 544 nM) in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. TS-941 had a fivefold lower selectivity than devazepide for pancreatic CCK (CCK-A) over brain CCK (CCK-B) receptors but fourfold greater than loxiglumide when IC50 values for inhibition of [125I]CCK-8 binding in isolated acini and cerebral cortex were compared. The antagonism produced by TS-941 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. TS-941 caused a parallel rightward shift of the entire dose-response curve for CCK-8-stimulated amylase release without altering the maximal increase, as did devazepide and loxiglumide. TS-941, whether added at the beginning or 20 min after the CCK-8 stimulation, inhibited amylase release. TS-941 caused a concentration-dependent residual inhibition of the action of CCK-8. The acini, once incubated with a high concentration of TS-941 (10 microM; 127 times IC50) for 30 min, was 10-fold less sensitive to CCK-8 than the acini preincubated without TS-941, whereas the sensitivity and the responsiveness to CCK-8 stimulation of those incubated with a low concentration of TS-941 (1.0 microM) were similar to the control acini. These results indicate that TS-941 is a potent, competitive, and selective CCK-A receptor antagonist for the pancreas.

Amylases↗
PubMed1999

Cold acclimation of guinea pig depressed contraction of cardiac papillary muscle.

Guinea pigs were exposed to 5 degrees C for 3 wk, and the contractions of myocardial papillary muscle were compared with preparations dissected from control animals kept at approximately 25 degrees C. Developed tension of the papillary muscle per cross-sectional area was significantly (t-test, P < 0.05) decreased after cold exposure (19,200 +/- 8,160 vs. 3,020 +/- 2,890 dyne/cm2; 1 Hz). Time to peak tension was significantly faster in cold-exposed guinea pigs (126.4 +/- 11.1 ms; 1 Hz) than in controls (162.7 +/- 8. 7 ms). The magnitude of the developed tension after application of ryanodine (2 mM) to muscles from cold-exposed animals was decreased to 37.5 +/- 8.3% of control at 1 Hz, whereas in muscles from control animals, tension was decreased to 82.4 +/- 7.7%. The ryanodine-sensitive component of contraction was not significantly changed in control guinea pigs at frequencies >0.5 Hz, whereas in muscles from cold-acclimated guinea pigs, there was a "positive staircase." These results suggested that reversal of the Na+/Ca2+ exchanger is predominantly involved in the positive staircase in control guinea pigs, whereas rate-dependent increases in the Ca2+ store in the sarcoplasmic reticulum may be involved in the staircase after cold acclimation.

Acclimatization↗