Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 356
Filter
1.
Clin Microbiol Infect ; 23(6): 407.e1-407.e7, 2017 Jun.
Article in English | MEDLINE | ID: mdl-27998820

ABSTRACT

OBJECTIVES: When considering treatment for chronic hepatitis B (CHB), it is important to discriminate between patients with persistent low HBV DNA and patients with active hepatitis, who may proceed to cirrhosis. In this study, we sought to identify mutations in patients expected to have persistent low HBV DNA and ultimately exhibit clearance of hepatitis B surface antigen (HBsAg). METHODS: Serum samples were obtained from 33 CHB genotype C patients, divided based on HBV DNA and alanine aminotransferase (ALT) levels following observation for >2 years: Group A (n=10), transient HBV DNA ≥5.0 log copies/mL and ALT ≥120 IU/L; Group B (n=11), persistent HBV DNA <5.0 and ALT <60; and Group C (n=12), persistent HBV DNA <4.0 and ALT <30. Full-length HBV sequences were compared among groups. Subsequently, 82 patients with CHB were evaluated for the I97L mutation and the additional mutation P79Q. We compared cumulative incidences of persistent low HBV DNA and HBsAg clearance in patients with or without I97L and P79Q by the Kaplan-Meier method. RESULTS: Incidence of Core mutation I97L differed significantly among groups: A, 30% (3/10); B, 36.4% (4/11); C, 83.3% (10/12) (p = 0.021). Cumulative incidences of persistent low HBV DNA and HBsAg clearance were significantly higher in patients with I97L than in those with wild-type I97 (p = 0.003 and p = 0.016, respectively), and even higher in those with P79Q. CONCLUSIONS: In patients with CHB, measurement of I97L and additional mutation P79Q would be useful for predicting persistent low HBV DNA, normal ALT, and HBsAg clearance.


Subject(s)
Hepatitis B Surface Antigens/metabolism , Hepatitis B virus/genetics , Hepatitis B, Chronic/virology , Mutation , Adult , Alanine Transaminase/metabolism , Female , Genotype , Hepatitis B virus/immunology , Humans , Kaplan-Meier Estimate , Male , Middle Aged
2.
Aliment Pharmacol Ther ; 44(4): 346-55, 2016 08.
Article in English | MEDLINE | ID: mdl-27291657

ABSTRACT

BACKGROUND: Acoustic radiation force impulse (ARFI) elastography is a non-invasive method for measuring liver stiffness. However, there are no reports evaluating the value of ARFI elastography for liver fibrosis in chronic hepatitis C patients with a sustained virological response (SVR). AIM: To investigate the diagnostic performance of ARFI elastography for the assessment of liver fibrosis in hepatitis C virus (HCV) infected patients with an SVR. METHODS: In this prospective study, we enrolled 336 patients: 121 HCV patients with an SVR (44.6% women) and 215 patients with HCV (47.9% women). ARFI elastography measurements of all patients were performed on the same day of liver biopsy. RESULTS: The diagnostic accuracies, expressed as areas under the receiver operating characteristic curves for ARFI elastography, in HCV patients with an SVR and those in patients with HCV were 0.818 and 0.875 for the diagnosis of significant fibrosis (≥F2), 0.909 and 0.888 for the diagnosis of severe fibrosis (≥F3), and 0.981 and 0.890 for the diagnosis of liver cirrhosis (F4), respectively. The optimum cut-off values for ARFI elastography were 1.26 m/s for ≥F2, 1.31 m/s for ≥F3 and 1.49 m/s for F4 in HCV patients with an SVR. The liver stiffness values were lower in patients with SVR compared with those in patients with HCV at the same stage of fibrosis. The liver stiffness values were affected by the necroinflammatory activity and the time after SVR. CONCLUSION: Acoustic radiation force impulse elastography is an acceptable method for predicting the severity of fibrosis in patients with hepatitis C virus and a sustained viral response.


Subject(s)
Elasticity Imaging Techniques/methods , Hepatitis C, Chronic/diagnostic imaging , Liver Cirrhosis/diagnostic imaging , Acoustics , Aged , Biopsy , Female , Hepatitis C, Chronic/pathology , Humans , Liver Cirrhosis/pathology , Male , Middle Aged , ROC Curve , Sustained Virologic Response
3.
J Clin Pharm Ther ; 35(6): 679-84, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21054459

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Total knee and hip joint replacement has a high risk of postoperative nausea and vomiting (PONV), and steroid cover is used for cases associated with autoimmune diseases. Our aim is to evaluate the antiemetic efficacy of methylprednisolone as steroid cover in patients undergoing the surgery. METHODS: A prospective cohort study design was used. Sixty-eight patients, aged between 20 and 80 years, were scheduled for a standardized general anaesthetic technique. Patients who were given methylprednisolone were assigned as the steroid cover group, and those who were not given methylprednisolone formed the non-steroid cover group. PONV were assessment by direct questioning or spontaneous complaints by patients 1 week after surgery. Postoperative pain was evaluated using Visual Analog Scale (VAS) 1 and 3 days after surgery. RESULTS AND DISCUSSION: The incidence of nausea in the steroid cover group was significantly less than that in the non-steroid cover group (adjusted odds ratio, 0·17, P = 0·021), but there was no significant difference in vomiting between the two groups. Postoperative pain VAS score was not significantly different between groups. WHAT IS NEW AND CONCLUSION: In total knee and hip arthroplasty, methylprednisolone is effective in preventing postoperative nausea; however, higher doses of methylprednisolone may be needed to prevent vomiting.


Subject(s)
Antiemetics/therapeutic use , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Methylprednisolone/therapeutic use , Postoperative Nausea and Vomiting/drug therapy , Vomiting/drug therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Metoclopramide/therapeutic use , Middle Aged , Pain Measurement , Pain, Postoperative/drug therapy , Young Adult
4.
J Clin Pharm Ther ; 34(4): 473-83, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19583681

ABSTRACT

OBJECTIVE: To describe the population pharmacokinetics of vancomycin in patients with gram-positive infections and to investigate the influence of type of infectious disease. METHODS: A two-compartment open model was adopted as a pharmacokinetic model. The nonlinear mixed-effects model was used to analyze the population pharmacokinetic models. RESULTS: We propose one general model and one infectious disease type-specific model. The general model showed that vancomycin clearance (CL) was linearly correlated with estimated creatinine clearance (CL(CR)) when CL(CR) was less than 85 mL/min, as expressed by CL(L/h) = 0.0322 x CL(CR) + 0.32. The distribution volumes of the central and peripheral compartment were different in healthy volunteers and patients with gram-positive infections. The infectious disease type-specific model showed that these differences were more pronounced in patients with pneumonia. CONCLUSION: The population pharmacokinetic parameters of vancomycin obtained here can be used to individualize the dosage of vancomycin in institutions with similar patient population characteristics.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Gram-Positive Bacterial Infections/drug therapy , Models, Biological , Vancomycin/pharmacokinetics , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Clinical Trials as Topic , Creatinine/blood , Creatinine/urine , Female , Humans , Male , Middle Aged , Nonlinear Dynamics , Pneumonia, Bacterial/drug therapy , Retrospective Studies , Tissue Distribution , Vancomycin/therapeutic use , Young Adult
5.
Clin Pharmacol Ther ; 86(3): 285-9, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19404248

ABSTRACT

The impact of pretransplant T-cell sensitivity testing using carboxylfluorescein diacetate succinimidyl ester (CFSE)-based flow cytometry was studied in 32 patients with chronic renal failure. There was considerable interindividual variation in the inhibitory effects of cyclosporine (CSA), tacrolimus (TAC), and prednisolone (PRD) but only a small amount of interindividual variation for mycophenolic acid (MPA). Patients with high sensitivity to CSA tended to experience viral reactivation. In addition to post-transplant blood-level monitoring, pretransplant pharmacodynamics could provide useful information on optimal and safe immunosuppressive therapy.


Subject(s)
Fluoresceins , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation/immunology , Succinimides , T-Lymphocytes/drug effects , Adult , Cell Proliferation/drug effects , Cyclosporine/pharmacokinetics , Cyclosporine/pharmacology , Female , Fluorescent Dyes , Humans , Kidney Failure, Chronic/surgery , Male , Middle Aged , Prednisolone/pharmacokinetics , Prednisolone/pharmacology , Prospective Studies , T-Lymphocytes/immunology , Tacrolimus/pharmacokinetics , Tacrolimus/pharmacology
6.
Transplant Proc ; 37(2): 1005-6, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15848605

ABSTRACT

A calcineurin inhibitor (CNI) is characterized by high affinity binding to red blood cells. There is a possibility that hematocrit levels might affect the immunosuppressive effects of cyclosporine (CsA). The purpose of this study was to examine whether the treatment with CNI was more effective in preventing acute rejection in anemic compared with nonanemic patients and to find a suitable method to monitoring immunosuppression. Ninety-five living donor renal transplant recipients who were treated with CsA were divided into five groups depending on their Ht levels. The incidences of biopsy-proven acute rejection were 1/8 (12.5%), 8/31 (25.8%), 6/28 (21.4%), 10/22 (45.5%), and 2/6 (33.3%) for Ht < or = 25%, 25% < Ht < or = 30%, 30% < Ht < or = 35%, 35% < Ht < or = 40%, and 40% < Ht, respectively. In vitro IL-2 mRNA inhibition tests were performed to evaluate lymphocyte function after stimulation of whole-blood with phorbol myristate acetate and Ca-ionophore in the presence of various concentrations of CsA. Whole blood CsA levels causing 50% inhibition of IL-2 mRNA (IC50) were 256, 310, 175, and 55 ng/mL for Ht 50%, 40%, 30%, and 20%, respectively. It is speculated that plasma concentrations of CsA may increase at low Ht levels, because lower incidences of acute rejection and lower IC50 values of CsA were observed in the anemic state. When the dosage of CsA was adjusted to its whole-blood concentration, the anemic state is likely to enhance the immunosuppressive effect of CsA. A pharmacodynamic study, such as the IL-2 mRNA inhibition test, is preferable for CsA monitoring.


Subject(s)
Anemia/physiopathology , Calcineurin Inhibitors , Cyclosporine/adverse effects , Hematocrit , Kidney Transplantation/physiology , Anemia/blood , Anemia/epidemiology , Drug Monitoring/methods , Graft Rejection/epidemiology , Humans , Immunosuppressive Agents/adverse effects , Incidence , Kidney Transplantation/immunology , Retrospective Studies
8.
Nihon Rinsho ; 59(11): 2102-8, 2001 Nov.
Article in Japanese | MEDLINE | ID: mdl-11712393

ABSTRACT

Type 2 diabetes is characterized by decreased secretion of insulin and insulin resistance. Thiazolidinediones are drugs to ameliorate insulin resistance. At present, only pioglitazone is available in Japan. The first drug of this category, troglitazone, has been withdrawn from market because of its liver toxicity in a few patients. The decrease in fasting plasma glucose begins within 2 weeks and reaches the nadir in 8-12 weeks. Plasma insulin levels usually decrease together with plasma glucose. Thiazolidinedione drugs are effective in about 50% of type 2 diabetic patients. The efficacy is higher in patients with obesity, high insulin levels and in aged people and females. The mechanism is thought to be mediated by activation of a nuclear receptor, PPAR-gamma, which is most abundantly expressed in the adipose tissue. Current concept is that, when PPAR-gamma is activated by these drugs, the number of small adipocytes is increased to replace large adipocytes, thereby decreasing the release of TNF-alpha and FFA from adipose tissue. However, there seems to be a complex relationship between the activity of PPAR-gamma and insulin sensitivity. The effect of these new category drugs should be monitored carefully on a long-term basis.


Subject(s)
Thiazoles , Thiazolidinediones , Adipocytes/metabolism , Animals , Blood Glucose/metabolism , Depression, Chemical , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/etiology , Drug Design , Fatty Acids, Nonesterified/metabolism , Humans , Insulin/metabolism , Insulin Resistance , Insulin Secretion , Receptors, Cytoplasmic and Nuclear/agonists , Thiazoles/pharmacology , Thiazoles/therapeutic use , Transcription Factors/agonists , Tumor Necrosis Factor-alpha/metabolism
9.
Cardiovasc Drugs Ther ; 15(3): 225-31, 2001.
Article in English | MEDLINE | ID: mdl-11713890

ABSTRACT

Amlodipine increases NO levels in coronary vessels and aorta via bradykinin-dependent mechanisms in vitro. We have previously reported that a long-acting Ca channel blocker, benidipine, increases cardiac NO levels in ischemic canine hearts, suggesting that benidipine may also protect against ischemia and reperfusion injury via bradykinin- and NO-dependent mechanisms. We examined this possibility. In open chest dogs, the left anterior descending coronary artery was perfused with blood through a bypass tube and was occluded for 90 min followed by 6 hours of reperfusion. Infarct size was assessed by TTC staining at 6 hours of reperfusion. When benidipine doses of 50, 100, and 200 ng/kg/min were infused via the bypass tube between 10 min prior to the onset of ischemia and after 60 min of reperfusion, systemic blood pressure did not change significantly. Infarct size decreased with the administration of benidipine (50, 100, and 200 ng/kg/min) when compared to the untreated condition (24.8+/-2.5, 17.3+/-3.1, and 16.5+/-2.0 vs. 43.4+/-5.6%, respectively) associated with the increased release of NO and bradykinin in the coronary venous blood upon reperfusion. Myeloperoxidase activity of the myocardium increased after 6 hours of reperfusion, which was attenuated by benidipine. The limitation of infarct size and the increase in myeloperoxidase activity were completely blunted by either L-NAME or HOE140. There were no significant differences in collateral blood flow assessed by the microsphere method after 45 min of ischemia for any of the groups. Thus, we conclude that the Ca channel blocker, benidipine, limits infarct size via bradykinin- and NO-dependent mechanisms.


Subject(s)
Bradykinin/analogs & derivatives , Calcium Channel Blockers/therapeutic use , Dihydropyridines/therapeutic use , Myocardial Infarction/drug therapy , Adrenergic beta-Antagonists/pharmacology , Animals , Bradykinin/pharmacology , Bradykinin/physiology , Dogs , Enzyme Inhibitors/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/physiology , Peroxidase/drug effects
10.
Int J Cardiol ; 80(2-3): 153-60, 2001.
Article in English | MEDLINE | ID: mdl-11578708

ABSTRACT

BACKGROUND: This study sought to investigate how collateral flow changes during myocardial ischemia in patients. METHODS: Myocardial contrast echocardiography (MCE) and rapid atrial pacing were performed in 20 patients with angiographically evidenced coronary collaterals from the right coronary artery (RCA) to the occluded left anterior descending coronary artery. Sonicated contrast medium was injected into the RCA before and immediately after atrial pacing to determine the peak background-subtracted contrast intensity (PI) in the collateral territory (PIA) and its ratio to PI in the control territory (PI ratio) as parameters of collateral blood flow. Lactate production in the coronary circulation during pacing was determined to assess myocardial ischemia in the collateral territory. RESULTS: PIA showed a significant correlation with regional wall motion either before (r(squared)=-0.64, P<0.01) or after pacing (r(squared)=-0.65, P<0.01). Similarly, PI ratio was significantly correlated with regional wall motion either before (r(squared)=-0.54, P<0.05) or after pacing (r(squared)=-0.64, P<0.01). Rapid atrial pacing decreased both PIA and PI ratio significantly greater in patients with lactate production than in those without (PIA: -67+/-53 vs. -15+/-34%, P<0.05; PI ratio: -68+/-49 vs. -8.2+/-32%, P<0.05, respectively), while neither PIA nor PI ratio differ between the two groups of patients before pacing (PIA: 13.8+/-19. vs. 16.2+/-13.3U, P=0.75; PI ratio: 0.70+/-0.71 vs. 0.87+/-0.65, P=0.58, respectively). CONCLUSIONS: We concluded that (1) collateral flow determined by MCE was closely associated with regional cardiac function, and (2) not the amount of collateral flow at rest, but pacing-induced change of collateral flow seemed to be a determinant of regional ischemia in patients with coronary collaterals.


Subject(s)
Collateral Circulation/physiology , Myocardial Ischemia/physiopathology , Aged , Blood Flow Velocity/physiology , Contrast Media , Echocardiography/methods , Female , Humans , Male , Middle Aged , Myocardial Ischemia/diagnostic imaging
11.
Cardiovasc Drugs Ther ; 15(2): 125-30, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11669405

ABSTRACT

PURPOSE: Although cDNA array technique has recently become available in the cardiovascular field, it has not yet been established what kind of genes in the myocardium are expressed by acute ischemia. Since many substances contribute to the pathophysiology of acute ischemic hearts, we investigated transcription responses of murine hearts to ischemia using cDNA array representing 18,376 genes. METHODS AND RESULTS: In 29 male mice, we ligated the proximal site of the left coronary artery for 60 min. In 14 mice, we performed the sham operation without the ligation of the left coronary artery. After 60 min, the hearts were excised to obtain mRNA, and we performed cDNA array analysis. In 18,376 cDNA, 2 known genes were upregulated over 10-fold, 11 known genes were upregulated 5.0- to 9.9-fold, and 32 unknown genes were upregulated over 5.0-fold compared to sham-operated controls. In contrast, 11 known genes and 7 unknown genes were downregulated to levels below 0.2-fold. For 9 of the 13 known genes of which expression was increased as analyzed by cDNA array, subsequent Northern blot analysis also revealed an increase in expression. CONCLUSION: Using cDNA array analysis we found that cardiac expression of 24 known and 39 unknown genes was modulated by acute ischemic stress, and appeared to be related to the pathophysiology of ischemic hearts. These results show that cDNA array analysis may provide a new molecular insight to the pathophysiology of acute ischemic hearts.


Subject(s)
Myocardial Ischemia/genetics , Oligonucleotide Array Sequence Analysis/methods , Animals , Blotting, Northern , Hybridization, Genetic , Ligation , Male , Mice , Mice, Inbred ICR , RNA, Messenger/genetics
13.
J Hypertens ; 19(10): 1905-12, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11593113

ABSTRACT

OBJECTIVES: Brain natriuretic peptide (BNP) is a strong predictor of left ventricular (LV) hypertrophy (LVH) and dysfunction. However, our recent studies suggested that LVH is not necessarily associated with enhanced production of BNP in hypertension. This study aimed to clarify the relation of the characteristics of hypertrophy with the degree of gene expression of BNP in the developmental process of hypertensive heart failure. METHODS: Serial changes in LV geometry, histology and atrial natriuretic peptide (ANP) and BNP mRNA levels, were assessed in a hypertensive heart failure model using Dahl salt-sensitive rats (n = 24). We further studied effects of alpha1-receptor antagonist (doxazosin: 1 mg/kg per day, n = 5) and angiotensin II type 1 receptor (AT1R) antagonist (candesartan cilexetil: 1 mg/kg per day, n = 5). RESULTS: The BNP mRNA level was not elevated at the compensatory hypertrophic stage when ANP mRNA level was elevated. BNP mRNA level was increased with further progression of hypertrophy and development of fibrosis. AT1R blockade prevented such fibrosis and further progression of hypertrophy with normalization of BNP mRNA levels. Compensatory hypertrophy was not suppressed; therefore, ANP mRNA level, although decreased, was still beyond the normal level. The alpha1-receptor blockade slightly attenuated LV hypertrophy with a slight decrease in ANP mRNA levels. LV fibrosis was not prevented, and the BNP mRNA level was not decreased. CONCLUSIONS: BNP gene expression is not enhanced by initial compensatory hypertrophy, but is enhanced by LV fibrosis and late stage progression of hypertrophy dependent on AT1R-mediated signaling pathway.


Subject(s)
Cardiac Output, Low/etiology , Cardiac Output, Low/physiopathology , Hypertension/complications , Myocardium/metabolism , Natriuretic Agents/biosynthesis , Ventricular Remodeling , Animals , Atrial Natriuretic Factor/genetics , Cardiac Output, Low/pathology , Echocardiography , Fibrosis , Heart Ventricles , Hemodynamics , Male , Myocardium/pathology , Natriuretic Peptide, Brain/genetics , RNA, Messenger/metabolism , Rats , Rats, Inbred Dahl
14.
Basic Res Cardiol ; 96(5): 497-505, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11605997

ABSTRACT

OBJECTIVES: Amlodipine increases NO levels in coronary vessels and aorta via bradykinin-dependent mechanisms in vitro. We have previously reported that nifedipine increases cardiac NO levels in the ischemic canine hearts, suggesting that nifedipine may also have protective effects against ischemia and reperfusion injury, because the enhancement of NO production limits infarct size. We tested whether nifedipine limits infarct size via NO-dependent mechanisms. METHODS: In open chest dogs, the left anterior descending coronary artery was perfused with blood through a bypass tube and occluded for 90 min followed by 6 hours of reperfusion. Infarct size was assessed at 6 hours of reperfusion. Nifedipine of 3 or 6 microg/kg/min was infused into the bypass tube between 10 min prior to the onset of ischemia and 60 min of reperfusion. RESULTS: Neither systemic blood pressure nor heart rate changed during infusion of nifedipine. Infarct size was reduced by the administration of nifedipine (3 or 6 microg/kg/min) compared with the untreated condition (25.6+/-2.6 and 19.1+/-3.5 vs. 43.4+/-5.6%, respectively), which was completely blunted by L-NAME (45.0+/-3.6 and 45.4+/-4.2 vs. 47.9+/-3.9% in the nifedipine (3 or 6 microg/kg/min) with L-NAME groups vs. the L-NAME group). Myeloperoxidase activity of the myocardium increased after 6 hours of reperfusion, which was attenuated by nifedipine. The limitation of infarct size and the attenuation in myeloperoxidase actiivity were completely blunted by L-NAME. There were no significant differences in collateral blood flow at 45 min of ischemia between each group. CONCLUSIONS: We conclude that the Ca channel blocker, nifedipine, limits infarct size via NO-dependent mechanisms.


Subject(s)
Calcium Channel Blockers/pharmacology , Myocardial Infarction/drug therapy , Myocardial Infarction/metabolism , Nifedipine/pharmacology , Nitric Oxide/metabolism , Animals , Blood Pressure , Coronary Circulation , Dogs , Endothelium/metabolism , Enzyme Inhibitors/pharmacology , Heart Rate , Myocardial Infarction/pathology , NG-Nitroarginine Methyl Ester/pharmacology , Peroxidase/metabolism
15.
Hypertension ; 38(3): 404-11, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11566913

ABSTRACT

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.


Subject(s)
Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Cardiomegaly/prevention & control , Nitric Oxide Synthase/antagonists & inhibitors , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Cardiomegaly/etiology , Cardiomegaly/physiopathology , Coronary Vessels/drug effects , Coronary Vessels/pathology , Coronary Vessels/physiopathology , Enalapril/pharmacology , Enzyme Inhibitors/pharmacology , Heart Rate/drug effects , Heart Ventricles/drug effects , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Imidazoles/pharmacology , Losartan/pharmacology , Male , Mitogen-Activated Protein Kinases/drug effects , Mitogen-Activated Protein Kinases/metabolism , Myocardium/enzymology , Myocardium/pathology , NG-Nitroarginine Methyl Ester/pharmacology , Neutrophil Infiltration/drug effects , Olmesartan Medoxomil , Organ Size/drug effects , Rats , Rats, Inbred WKY , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Ribosomal Protein S6 Kinases/drug effects , Ribosomal Protein S6 Kinases/metabolism , Tetrazoles/pharmacology , Thiazepines/pharmacology
16.
J Mol Cell Cardiol ; 33(9): 1727-37, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11549351

ABSTRACT

We tested the hypothesis that cellular acidosis modulates the production of nitric oxide (NO) in ischemic hearts. In canine hearts, we decreased coronary blood flow (CBF) to one third of the control by reduction of coronary perfusion pressure (105+/-3 to 41+/-5 mmHg), and thereafter we maintained CBF constant (89.8+/-1.6 to 30.0+/-0.5 ml/100 g/min) with an intracoronary administration of either saline, atropine, rauwolscine, HOE140, 8-sulfophenyltheophylline (8SPT), NaHCO3, or HOE642 (the inhibitor of Na+/H+ exchange). The cardiac NO levels defined as the differences of the nitrate and nitrite levels between coronary venous and arterial blood increased in the saline administration (2.9+/-0.2 to 12.7+/-1.7 micromol/l), and the extents of increases were identical in the condition of either saline, atropine, rauwolscine, HOE140 or 8SPT administration. In the condition with either NaHCO3 or HOE642, the increases in the cardiac NO levels were blunted (4.5+/-0.7 and 4.8+/-0.4 micromol/l, respectively). Cyclic GMP content of epicardial coronary artery in the ischemic area increased, which was also attenuated by either NaHCO3 or HOE642. We confirmed the acidosis-induced NO production in a more severe ischemic myocardium, and also showed that cellular acidosis produced by infusion of HCl increased NO production in non-ischemic myocardium. We conclude that cellular acidosis and subsequent activation of Na+/H+ exchanges modulate production of endogenous NO in canine ischemic myocardium.


Subject(s)
Acidosis/metabolism , Coronary Circulation/physiology , Myocardial Ischemia/metabolism , Myocardium/metabolism , Nitric Oxide/biosynthesis , Animals , Anti-Arrhythmia Agents/pharmacology , Bicarbonates/pharmacology , Coronary Vessels/drug effects , Coronary Vessels/metabolism , Cyclic GMP/metabolism , Dogs , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , Heart/drug effects , Heart/physiopathology , Hydrochloric Acid/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Sulfones/pharmacology
17.
Jpn Circ J ; 65(8): 717-22, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11502048

ABSTRACT

The diastolic deceleration slope of coronary flow velocity is steeper in patients with substantial 'no reflow' phenomenon than in those without it. This study investigated whether functional outcomes in patients with anterior wall acute myocardial infarction (AMI) can be predicted by analyzing the coronary flow velocity pattern recorded with transthoracic Doppler (TTD) echocardiography. Coronary blood flow velocity in the distal left anterior descending coronary artery was recorded with TTD at day-2 after primary percutaneous transluminal coronary angioplasty/Stent in 51 patients with anterior AMI and the diastolic deceleration half time (DHT, ms) was measured. The wall motion score index (WMSI) was measured at day-1 and -21. In the retrospective study, the DHT was much shorter in those with a poor outcome than in those with good outcome (152 +/- 109 vs 395 +/- 128 ms, p<0.05). Receiver-operating characteristic analysis documented that DHT > or = 300 ms is a suitable cut-off point (sensitivity of 83% and specificity of 93%). In the prospective study (n=30), AWMSI(dl-d21) was significantly higher in those with a DHT > or = 300 ms than those without (0.3 > or = 0.5 vs 1.6 > or = 0.7, p<0.001). DHT correlated significantly with AWMSI(dl-d21) (r=0.76, p<0.001). Patients with a shorter DHT of diastolic coronary flow velocity have a poorer functional outcome among patients with anterior AMI. The TTD-determined DHT is a useful predictor of myocardial viability after an anterior AMI.


Subject(s)
Coronary Circulation/physiology , Echocardiography, Doppler/methods , Myocardial Contraction/physiology , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/physiopathology , Adult , Aged , Blood Flow Velocity , Female , Humans , Male , Middle Aged , Prospective Studies , Retrospective Studies
18.
Circulation ; 104(6): 705-10, 2001 Aug 07.
Article in English | MEDLINE | ID: mdl-11489779

ABSTRACT

BACKGROUND: Phosphodiesterase III inhibitors (PDEIII-Is) improve the hemodynamic status of heart failure via inotropic/vasodilatory effects attributable to the increase in intracellular cAMP level. Direct cardioprotection by PDEIII-Is and its underlying mechanisms, however, have not been identified. We tested the infarct size-limiting effect of PDEIII-Is and the roles of cAMP, protein kinase (PK) A, PKC, and mitogen-activated protein kinase (MAPK) families in open-chest dogs. Methods and Results-- Milrinone, olprinone (PDEIII-Is), or dibutyryl-cAMP (db-cAMP) was injected intravenously 30 minutes before 90-minute ischemia, followed by 6 hours of reperfusion. Olprinone was also examined with an intracoronary cotreatment with a PKA inhibitor (H89), a PKC inhibitor (GF109203X), an extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) throughout the preischemic period. Either PDEIII-Is or db-cAMP caused substantial hemodynamic changes, which returned to control levels in 30 minutes. Collateral flow and percent risk area were identical for all groups. Both PDEIII-Is and db-cAMP increased myocardial p38 MAPK activity during the preischemic period, which was blocked by H89, but not by GF109203X. Both PDEIII-Is and db-cAMP reduced infarct size (19.1+/-4.1%, 17.5+/-3.3%, and 20.3+/-4.8%, respectively, versus 36.1+/-6.2% control, P<0.05 each). Furthermore, the effect of olprinone was blunted by either H89 (35.5+/-6.4%) or SB203580 (32.6+/-5.9%), but not by GF109203X or PD98059. H89, GF109203X, PD98059, or SB203580 alone did not influence infarct size. CONCLUSIONS: Pretreatment with PDEIII-Is has cardioprotective effects via cAMP-, PKA-, and p38 MAPK-dependent but PKC-independent mechanisms in canine hearts.


Subject(s)
Cardiovascular Agents/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Sulfonamides , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Animals , Blood Flow Velocity/drug effects , Bucladesine/pharmacology , Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic AMP-Dependent Protein Kinases/metabolism , Cyclic AMP-Dependent Protein Kinases/physiology , Cyclic Nucleotide Phosphodiesterases, Type 3 , Dogs , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Hemodynamics/drug effects , Imidazoles/pharmacology , Indoles/pharmacology , Isoquinolines/pharmacology , Maleimides/pharmacology , Milrinone/pharmacology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/metabolism , Mitogen-Activated Protein Kinases/physiology , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Infarction/prevention & control , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/metabolism , Pyridines/pharmacology , Pyridones/pharmacology , Ventricular Fibrillation/pathology , Ventricular Fibrillation/physiopathology , Ventricular Fibrillation/prevention & control , p38 Mitogen-Activated Protein Kinases
19.
J Mol Cell Cardiol ; 33(6): 1133-42, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11444918

ABSTRACT

We have hypothesized that calpain mediates myocardial injury induced by Ca(2+)overload. However, in vitro study demonstrated that the calcium requirement for calpain activation is around 10 microm, which is difficult to reach without the cell collapsing. Furthermore, because calpastatin is abundant in the myocardial cell, calpain may not be activated in physiological conditions. To elucidate whether calpain is activated by the calcium concentration reachable in myocardial living cells, we measured the calpain activity and the calcium concentration simultaneously in isolated guinea-pig cardiomyocytes. t-Butoxycarbonyl-Leu-Met-7-amino-4chlorimethylcoumarin (Boc-Leu-Met-CMAC), a fluorescent substrate of calpain, and/or fura red, a calcium indicator, were loaded into isolated cardiomyocytes together, and their fluorescence were measured separately. Intracellular Ca overload was induced by changing the superfusate from normal Tyrode solution to a sodium-free one. After changing the solution, fluorescence intensity of fura red and Boc-Leu-Met-CMAC did not change for a while, then fluorescence intensity of fura red began to rise. This was followed by the fluorescence intensity of Boc-Leu-Met-CMAC starting to rise 160+/-45 s after [Ca(2+)](i)increase. The relative fluorescence intensity of fura red increased to 1.37+/-0.32 folds of the control at the point that calpain became active. The calcium concentration at this point was estimated as 451 n m. These results indicate that calpain is activated by the slight rise of Ca concentration in intact cardiomyocytes.


Subject(s)
Calcium/metabolism , Calpain/metabolism , Myocardium/enzymology , Animals , Enzyme Activation , Fluorescent Dyes , Fura-2 , Guinea Pigs , Heart Ventricles/cytology , Heart Ventricles/enzymology , Intracellular Fluid/metabolism , Myocardium/cytology
20.
Jpn Circ J ; 65(7): 617-20, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11446494

ABSTRACT

The onset of acute myocardial infarction (AMI) shows characteristic circadian variations; that is, a definite morning peak related to biologic rhythms and a vague nighttime peak related to socioeconomic factors. The recent economic recession in Japan may change the circadian variation, especially the nighttime peak. This study evaluated the recent circadian variation of AMI in Osaka and specified the patient subgroups showing either a morning or nighttime peak predominantly. Of 1,609 consecutive patients with AMI registered from April 1998 to January 2000, 1,252 whose onset of AMI was definitely identified were studied. The day was divided into six 4-h periods with a morning peak between 08.01 h and 12.00h, and nighttime peak between 20.01 h and 24.00h. When subgroup analysis was performed, female patients aged 65 years or more showed a morning peak alone and male patients aged less than 65 years with an occupation and the habits of cigarette smoking and alcohol intake showed a nighttime peak alone. Thus, in Osaka nighttime socioeconomic factors may currently be more potent triggers of AMI than the morning surges in younger male workers who smoke and drink.


Subject(s)
Circadian Rhythm/physiology , Myocardial Infarction/etiology , Adult , Age Factors , Aged , Alcoholism , Economics , Female , Humans , Japan/epidemiology , Male , Middle Aged , Myocardial Infarction/physiopathology , Risk Factors , Sex Factors , Smoking , Socioeconomic Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...