PubMed Health⌕ Search

Biomedical subjects

Masafumi Kitakaze

Publications and source records attributed to Masafumi Kitakaze.

At least 127 records · Page 7Linked to original sources
PubMed2003

The role of estrogen and estrogen-related drugs in cardiovascular diseases.

The cardiovascular effects of estrogen have recently become a focus of basic and clinical cardiovascular medicine because of the multiplicity of its beneficial effects. Various basic and clinical studies have revealed that estrogen has potent cardiovascular effects against ischemic or non-ischemic injury of the heart and vessels, leading to the concept that administration of estrogen may reduce cardiovascular disease in postmenopausal women. Indeed, among the groups of the postmenopausal women who have a higher risk of cardiovascular diseases, the hormone therapy has been associated with improved outcomes for cardiovascular events. Estrogen binds to the estrogen receptor, which is a member of the steroid hormone family of nuclear receptors and is the estrogen response element in target genes, leading to the transcriptional regulation of many genes. In addition to these genomic effects of estrogen, it has been recently reported that estrogen can have rapid "nongenomic" effects. In contrast to such data, recent clinical prevention trials in postmenopausal women treated with a combination of estrogen and progestins have not revealed any beneficial effects on cardiovascular morbidity or mortality, and estrogen itself increases the risk of endometrial and breast cancer. Under these circumstances, a selective estrogen receptor modulator (SERM), which exerts estrogenic agonistic or antagonistic actions on various tissues, has been recently introduced for new hormone therapy because it reduces the adverse effects of estrogen. Here, we summarize the effects of estrogen and SERM on the cardiovascular system and discuss cellular mechanisms that may be involved.

Animals↗
PubMed2003

[Opening of ATP-sensitive potassium channel attenuates cardiac remodeling induced by chronic inhibition of nitric oxide synthesis].

OBJECTIVES: We examined whether the ATP-sensitive potassium(KATP) channel openers (KCOs) block myocardial hypertrophy, and whether the 70 kDa S6 kinase(p70S6K)-or extracellular signal-regulated kinase(ERK)-dependent pathway is involved. BACKGROUND: Chronic inhibition of nitric oxide (NO) synthesis induces cardiac hypertrophy independent of blood pressure by increasing protein synthesis in vivo. KCOs attenuate calcium overload and confer cardioprotection against ischemic stress, and thereby prevent myocardial remodeling. METHODS: Twelve Wistar-Kyoto rat groups underwent 8 weeks of the drug treatment in combination with NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), an inactive isomer D omega-nitro-L-arginine methyl ester(D-NAME), KCOs(nicorandil; 3 and 10 mg/kg/day, or JTV-506; 0.3 mg/kg/day), or a KATP channel blocker glibenclamide. L-NAME was also treated with hydralazine, p70S6K inhibitor (rapamycin) or MAP kinase kinase inhibitor(PD98059). Finally, left ventricular weight-to-body weight ratio(LVW/BW) was quantified followed by histological examinations and kinase assay. RESULTS: L-NAME increased blood pressure and LVW/BW compared with the control. KCOs and hydralazine equally cancelled the increase in blood pressure, whereas only KCOs blocked the increase in LVW/BW and myocardial hypertrophy induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in the myocardium compared with the control(2.3-fold and 2.0-fold, respectively), which was not reversed by hydralazine. Selective inhibition of either P70S6K or ERK blocked myocardial hypertrophy. KCOs prevented the increase in activity only of p70S6K. Glibenclamide reversed the effect of nicorandil in the presence of L-NAME. CONCLUSIONS: KCOs modulate p70S6K, not ERK, to attenuate myocardial hypertrophy induced by chronic inhibition of nitric oxide synthesis in vivo.

Adenosine Triphosphate↗
PubMed2003

[Renin-angiotensin system as a potential target for the treatment with heart failure: ACE inhibitors, angiotensin-II receptor blockers and aldosterone antagonists].

Recent experimental studies and clinical trials have revealed that the modulation of either systemic or regional(cardiovascular) renin-angiotensin systems(RAS) is one of the potential targets to prevent the progression of heart failure. Either ACE inhibitor, angiotensin-II receptor blocker or aldosterone antagonist differently block RAS. Many clinical trials told us that each of them improves heart failure and might promise the better prognosis. Now, some experimental studies are encouraging us to test the comparative effects or the effects in combination of them. Here we will summarize the current outcomes from the experimental and clinical studies, and discuss the future direction.

Angiotensin II↗
PubMed2003

[Cauliflower-like giant left atrial thrombus successfully treated by anticoagulants without systemic complication: a case report].

A 64-year-old woman with hypertension presented with a left atrial giant mass during the treatment of congestive heart failure. She was admitted to our hospital for intensive treatment. Transesophageal echocardiography demonstrated a cauliflower-like, large (3 x 2 cm), mobile echogenic mass attached to the left atrial wall. There were no signs of systemic embolism. Anticoagulant therapy was started. Repeated echocardiography showed the mass was reduced gradually and had diminished on the 10th day. She remained asymptomatic during the anticoagulant therapy. The diagnosis was thrombus based on the response to treatment. Surgical removal should be considered for such a large thrombus, but the present case of giant thrombus was successfully treated by anticoagulants without systemic complication.

Anticoagulants↗
PubMed2003

[Impaired left ventricular systolic function in mitral stenosis].

OBJECTIVES: Left ventricular dysfunction is known in patients with mitral stenosis, but the incidence and cause remain unclear. The incidence and the factors related to left ventricular dysfunction were investigated in strictly selected patients with isolated mitral stenosis. METHODS: This study investigated 33 patients (5 males, 28 females) with isolated mitral stenosis aged 56 +/- 9 years. Left atrial dimension, left ventricular diastolic and systolic dimensions, mitral valve area, and mean transmitral pressure gradient were measured by echocardiography. Left ventricular ejection fraction was measured by Simpson's method. Patients were divided into two groups according to the ejection fraction (< 50%, > or = 50%). RESULTS: Seven patients (21%) had decreased left ventricular contraction and 26(79%) had normal contraction. The incidence of patients with atrial fibrillation in the low ejection fraction group was significantly higher than in the normal ejection fraction group(86% vs 31%, p < 0.01). There were no significant differences in the severity of mitral stenosis or other echocardiographic indices between the two groups. CONCLUSIONS: Low ejection fraction was present in 21% of patients with mitral stenosis. Since atrial fibrillation was more common in patients with low ejection fraction than those with normal ejection fraction, the rhythm disturbance may be related to the decreased left ventricular contraction.

Echocardiography, Doppler↗
PubMed2002

Plaque gruel of atheromatous coronary lesion may contribute to the no-reflow phenomenon in patients with acute coronary syndrome.

BACKGROUND: No-reflow associated with direct angioplasty (PCI) of patients with acute coronary syndromes (ACS) is associated with unfavorable results. METHODS AND RESULTS: We used a new thrombectomy device to treat 51 lesions in 48 consecutive ACS patients (40 male and 8 female; mean age 63 years) and conducted a microscopic analysis of aspirates and blood samples retrieved from the culprit coronary artery. The first aspirate was collected before PCI and the second was collected separately after percutaneous transluminal coronary angioplasty or stenting, including samples from the no-reflow lumen. Light microscopy showed that the materials obtained from the pre-PCI aspiration consisted of thrombus in 37.5%, thrombus and atheroma in 35.0%, and atheromatous plaque in 27.5%. The materials collected from the post-PCI aspiration were thrombus in 8.3%, thrombus and atheroma in 41.7%, and atheromatous plaque in 50.0%. We then compared the 9 lesions (19.1%) with no-reflow to those without no-reflow. There was no difference in the pre-PCI aspirates. However, after PCI, there was more atheromatous plaque retrieved from patients with no-reflow (P<0.001) as well as significantly more platelet and fibrin complex, macrophages, and cholesterol crystals in the blood aspirated from no-reflow cases. Aspiration of these elements improved the no-reflow in 7 of 9 lesions to TIMI-3 flow. CONCLUSIONS: No-reflow after angioplasty may be caused by gruel that formed from an atheroma attributable to mechanical plaque disruption during intervention.

Acute Disease↗
PubMed2002

Amelioration of ischemia- and reperfusion-induced myocardial injury by the selective estrogen receptor modulator, raloxifene, in the canine heart.

OBJECTIVES: We sought to investigate whether raloxifene reduces ischemia-reperfusion injury and what mechanisms are involved in the cardioprotective effects. BACKGROUND: Estradiol-17-beta reduces myocardial infarct size in ischemia-reperfusion injury. Raloxifene, a selective estrogen receptor modulator, demonstrates immediate coronary artery vasorelaxing effects. METHODS: The myocardial ischemia-reperfusion model included anesthetized open-chest dogs after 90-min occlusion of the left anterior descending coronary artery (LAD) and subsequent 6-h reperfusion. Raloxifene and/or other drugs were infused into the LAD from 10 min before coronary occlusion to 1 h after reperfusion without an occlusion period. RESULTS: Infarct size was reduced in the raloxifene (5 microg/kg per min) group compared with the control group (7.2 +/- 2.5% vs. 40.9 +/- 3.9% of the area at risk, p < 0.01). Either N(G)-nitro-L-arginine methyl ester (L-NAME), the inhibitor of nitric oxide (NO) synthase, or charybdotoxin, the blocker of Ca(2+)-activated K+ (K(Ca)) channels, partially attenuated the infarct size-limiting effect, and both of them completely abolished the effect. The incidence of ventricular fibrillation was also less in the raloxifene group than in the control group (11% vs. 44%, p < 0.05). Activity of p38 mitogen-activated protein (MAP) kinase increased with 15-min ischemia, and raloxifene pretreatment inhibited the activity. Myeloperoxidase activity of the 6-h reperfused myocardium was also attenuated by raloxifene. CONCLUSIONS: These data demonstrate that raloxifene reduces myocardial ischemia-reperfusion injury by mechanisms dependent on NO and the opening of K(Ca) channels in canine hearts. Deactivation of p38 MAP kinase and myeloperoxidase by raloxifene may be involved in the cellular mechanisms of cardioprotection.

Animals↗
PubMed2002

Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: role of 70-kDa S6 kinase and extracellular signal-regulated kinase.

OBJECTIVES: We examined whether the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel openers (KCOs) block myocardial hypertrophy and whether the 70-kDa S6 kinase (p70S6K) or extracellular signal-regulated kinase (ERK)-dependent pathway is involved. BACKGROUND: Long-term inhibition of nitric oxide (NO) synthesis induces cardiac hypertrophy independent of blood pressure, by increasing protein synthesis in vivo. The KCOs attenuate calcium overload and confer cardioprotection against ischemic stress, thereby preventing myocardial remodeling. METHODS: Twelve Wistar-Kyoto rat groups underwent eight weeks of the drug treatment in combination with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), the inactive isomer D(omega)-nitro-L-arginine methyl ester, KCOs (nicorandil, 3 and 10 mg/kg per day, or JTV-506, 0.3 mg/kg per day), or the K(ATP) channel blocker glibenclamide. The L-NAME was also used with hydralazine, the p70S6K inhibitor rapamycin, or the mitogen-activated protein kinase inhibitor PD98059. Finally, the left ventricular weight (LVW) to body weight (BW) ratio was quantified, followed by histologic examination and kinase assay. RESULTS: The L-NAME increased blood pressure and LVW/BW, as compared with the control agent. The KCOs and hydralazine equally cancelled the increase in blood pressure, whereas only KCOs blocked the increase in LVW/BW and myocardial hypertrophy induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in the myocardium (2.3-fold and 2.0-fold increases, respectively), as compared with the control group, which was not reversed by hydralazine. Selective inhibition of either p70S6K or ERK blocked myocardial hypertrophy. The KCOs prevented the increase in activity only of p70S6K. Glibenclamide reversed the effect of nicorandil in the presence of L-NAME. CONCLUSIONS: The KCOs modulate p70S6K, not ERK, to attenuate myocardial hypertrophy induced by long-term inhibition of NO synthesis in vivo.

Adenosine Triphosphate↗
PubMed2002

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers synergistically increase coronary blood flow in canine ischemic myocardium: role of bradykinin.

OBJECTIVES: We examined whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) synergistically mediates coronary vasodilation and improves myocardial metabolic and contractile dysfunction in ischemic hearts. BACKGROUND: Either an ACE inhibitor or ARB mediates coronary vasodilation in ischemic hearts. METHODS: In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 microg/kg/min) or ARB (RNH-6270, 10 microg/kg/min) into the coronary artery. RESULTS: Perfusion pressure of the left anterior descending coronary artery was reduced from 104 +/- 8 to 42 +/- 2 mm Hg, so that coronary blood flow (CBF) decreased to one-third of the baseline value. Ten minutes after starting the infusion of temocaprilat, the cardiac bradykinin level increased (from 32 +/- 6 to 98 +/- 5 pg/ml). Coronary blood flow (29 +/- 2 to 44 +/- 3 ml/100 g/min) and the cardiac level of nitric oxide (NO) (7.8 +/- 1.9 to 17.5 +/- 3.2 microm) also increased, with these changes being attenuated by either N(omega)-nitro-L-arginine methyl ester or HOE140. RNH-6270 alone caused a modest increase in CBF (34 +/- 3 ml/100 g/min), with no increase in the cardiac NO or bradykinin levels. Both temocaprilat and RNH-6270 caused a further increase in both CBF (51 +/- 4 ml/100 g/min) and cardiac NO levels, without increasing the bradykinin level, and these changes were inhibited by HOE140. In the nonischemic heart, RNH-6270 augmented bradykinin-induced increases in CBF. CONCLUSIONS: The combination of an ACE inhibitor and ARB mediates greater increases in CBF and more potent cardioprotective effects through bradykinin-dependent mechanisms than either drug alone.

Angiotensin II↗
PubMed2002

Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis.

Neuropilins (NP1 and NP2) are vascular endothelial growth factor (VEGF) receptors that mediate developmental and tumor angiogenesis. Transgenic mice, in which both NP1 and NP2 were targeted (NP1(-/-)NP2(-/-)) died in utero at E8.5. Their yolk sacs were totally avascular. Mice deficient for NP2 but heterozygous for NP1 (NP1(+/-)NP2(-/-)) or deficient for NP1 but heterozygous for NP2 (NP1(-/-)NP2(+/-)) were also embryonic lethal and survived to E10-E10.5. The E10 yolk sacs and embryos were easier to analyze for vascular phenotype than the fragile poorly formed 8.5 embryos. The vascular phenotypes of these E10 mice were very abnormal. The yolk sacs, although of normal size, lacked the larger collecting vessels and had less dense capillary networks. PECAM staining of yolk sac endothelial cells showed the absence of branching arteries and veins, the absence of a capillary bed, and the presence of large avascular spaces between the blood vessels. The embryos displayed blood vessels heterogeneous in size, large avascular regions in the head and trunk, and blood vessel sprouts that were unconnected. The embryos were about 50% the length of wild-type mice and had multiple hemorrhages. These double NP1/NP2 knockout mice had a more severe abnormal vascular phenotype than either NP1 or NP2 single knockouts. Their abnormal vascular phenotype resembled those of VEGF and VEGFR-2 knockouts. These results suggest that NRPs are early genes in embryonic vessel development and that both NP1 and NP2 are required.

Animals↗
PubMed2002

Is there a place for preconditioning during cardiac operations in humans?

BACKGROUND: Activation of the kinase cascade (protein kinase C (PKC), tyrosine kinase (TK), and mitogen-activated protein kinase (MAPK) is a key feature of the transduction pathway, elicited by preconditioning signals and mediating their cardioprotective effects. We assessed whether such an activation occurred during cardiac operations and could thus represent a target for cardioprotective strategies. METHODS: A total of 20 patients undergoing coronary artery bypass grafting surgery were studied. During the first 10 minutes of cardiopulmonary bypass (CPB), 10 were treated with sevoflurane (2.5 minimum alveolar concentration), an inhalational anesthetic that mimics preconditioning through a similar activation of the kinase cascade. Ten case-matched patients undergoing 10 minutes of sevoflurane-free CPB served as controls. Right atrial biopsies were taken before and 10 minutes after CPB and were then processed for the measurement of PKC, TK, and p38 MAPK activities by enzyme assay techniques. Troponin I was also monitored over the first 2 postoperative days. RESULTS: Compared with pre-CPB values, PKC and p38 MAPK activities (in nanomoles per milligram of protein per minute and arbitrary units, respectively) increased significantly and to the same extent in both groups: PKC, from 20.7+/-0.7 to 29.9+/-3.9 in controls (p = 0.037) and from 18.4+/-1.1 to 23.9+/-1.8 in sevoflurane (p = 0.016); p38 MAPK, from 88.6+/-8.5 to 312.9+/-66.2 in controls (p = 0.005) and from 114.6+/-14.7 to 213.4+/-51.8 in sevoflurane (p = 0.045). Conversely, sevoflurane triggered a significant increase in TK activity (from 68.5+/-1.4 to 83.7+/-2.9 picomoles per milligram of protein per minute p = 0.0015) which did not occur in controls (from 67.5+/-1.9 to 76.8+/-4.2 picomoles per milligram of protein per minute, p = 0.09). Likewise, the peak postoperative value of troponin I was not different between controls and sevoflurane-treated patients (3.4+/-0.6 vs 2.4+/-0.4, p = 0.21). CONCLUSIONS: Cardiopulmonary bypass triggers an activation of the kinase cascade that is mechanistically linked to opening of potassium channels. The direct opening of these channels by the anesthetic sevoflurane does not increase kinase activation further, nor does it improve markers of cell necrosis, thus suggesting that pharmacologically targeting potassium channels may overlap the preconditioning-like effects of CPB alone.

Anesthetics, Inhalation↗
PubMed2002

Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy.

G-protein-coupled receptor (GPCR) agonists are well-known inducers of cardiac hypertrophy. We found that the shedding of heparin-binding epidermal growth factor (HB-EGF) resulting from metalloproteinase activation and subsequent transactivation of the epidermal growth factor receptor occurred when cardiomyocytes were stimulated by GPCR agonists, leading to cardiac hypertrophy. A new inhibitor of HB-EGF shedding, KB-R7785, blocked this signaling. We cloned a disintegrin and metalloprotease 12 (ADAM12) as a specific enzyme to shed HB-EGF in the heart and found that dominant-negative expression of ADAM12 abrogated this signaling. KB-R7785 bound directly to ADAM12, suggesting that inhibition of ADAM12 blocked the shedding of HB-EGF. In mice with cardiac hypertrophy, KB-R7785 inhibited the shedding of HB-EGF and attenuated hypertrophic changes. These data suggest that shedding of HB-EGF by ADAM12 plays an important role in cardiac hypertrophy, and that inhibition of HB-EGF shedding could be a potent therapeutic strategy for cardiac hypertrophy.

ADAM Proteins↗
PubMed2002

Echocardiographic assessment of LV hypertrophy and function in aortic-banded mice: necropsy validation.

We characterized the time course of the left ventricular (LV) geometric and functional changes after aortic banding, validated them by necropsy, and investigated the sensitivity of echocardiographic findings on LV hypertrophy. C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation; echocardiographic assessments were performed before or at 2, 4, 6, and 11 wk after surgery; and some of the mice were euthanized at the corresponding time points. There was a progressive increase in diastolic posterior wall thickness and LV systolic dimension; the percentage of LV fractional shortening (LV%FS) decreased progressively at 4 wk, whereas these parameters remained stable in sham-operated mice. Echo LV mass and LV%FS correlated well with actual whole heart mass and ratio of lung weight to body weight, respectively (r = 0.765 and -0.749, respectively; P < 0.0001). These results suggest that the development of myocardial hypertrophy and systolic dysfunction is a time-dependent process. Echocardiographic assessment of myocardial hypertrophy and functional changes correlate well with the actual heart mass and lung mass. Echocardiography is sensitive enough to assess myocardial hypertrophy and heart functional changes induced by pressure overload in mice.

Animals↗
PubMed2002

No-reflow following dilatation of a coronary lesion with a large lipid core.

Radiolucent findings of coronary angiogram are believed to usually represent intracoronary thrombus, but in the present case, were atheromatous plaque with a large lipid core. A 62-year-old man who suffered from an inferior acute myocardial infarction was admitted to hospital 6 h after onset. The first cine angiograms showed TIMI-1 flow in the distal-portion of the right coronary artery, so thrombectomy was initially carried out and TIMI-2 flow achieved. However, the radiolucent lesion did not disappear and so adjunctive mechanical dilatation of the lesion was prformed, which resulted in 'no-reflow' (TIMI-0). Finally, aspiration of the material from the stagnated lesion was attempted and immediately obtained TIMI-3 flow. The retrieved materials were macrophages (foam cells) and many cholesterol crystals, both of which are considered to be atheromatous gruel. Therefore, the sudden flow reduction following percutaneous transluminal coronary angioplasty was caused by mechanical disruption of an atheromatous plaque with a large lipid core.

Angioplasty, Balloon, Coronary↗