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1.
Fukuoka Igaku Zasshi ; 97(2): 37-41, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16642955

ABSTRACT

We here report a case of 71-year-old man with acute extensive anterior myocardial infarction, who was complicated with ventricular tachycardia (VT) even after successful percutaneous coronary intervention. As intravenous administration of nifekalant terminated VT, we started oral administration of amiodarone (day 1). We gave 400 mg of amiodarone a day for the first week and 200 mg a day from the second week. The patient was stable with normoxia by day 20, in spite of pulmonary congestion-like infiltrates on chest X-ray. On day 21, he was complicated with acute respiratory distress syndrome. Immediate discontinuance of amiodarone and high-dose pulse glucocorticoid therapy with intubation slightly improved the infiltrations on chest X-ray. However, glucocorticoid therapy induced hyperglycemia with an increase in plasma osmolality, complicated with hypoalbuminemia, and gastrointestinal bleeding. Despite treatment with a large amount of saline, high-doses of catecholamines, and blood transfusion, the patient died on day 28. It is sometimes difficult to diagnose congestive heart failure or amiodarone-induced pulmonary infiltrates in patients with severe left ventricular dysfunction.


Subject(s)
Amiodarone/adverse effects , Anti-Arrhythmia Agents/adverse effects , Myocardial Infarction/complications , Respiratory Distress Syndrome/chemically induced , Ventricular Dysfunction, Left/etiology , Aged , Amiodarone/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Fatal Outcome , Humans , Male , Myocardial Infarction/therapy , Severity of Illness Index , Tachycardia, Ventricular/etiology , Tachycardia, Ventricular/therapy , Ventricular Dysfunction, Left/therapy
2.
J Cardiovasc Pharmacol ; 46(1): 1-6, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15965348

ABSTRACT

HMG-CoA reductase inhibitors and calcium channel blockers have antiatherogenic effects; however, their mechanisms remain to be elucidated. This study examined the effect of cerivastatin and/or nifedipine on the endothelial dysfunction in porcine balloon-injured coronary arteries. Normal male pigs were randomly divided into the following four groups: control, cerivastatin (1 mg/kg/d PO), nifedipine (4 mg/kg/d PO), and their combination (n = 10 each). We started the treatments 3 days before balloon injury in the proximal left coronary arteries and continued for 4 weeks after the procedure. Then, we examined endothelial vasodilator functions ex vivo in organ chambers and in vitro by Western blotting for eNOS expression. Endothelium-dependent relaxations to serotonin, but not those to bradykinin or the calcium ionophore A23187 or endothelium-independent relaxations to sodium nitroprusside, were significantly impaired by balloon injury. The monotherapy with cerivastatin or nifedipine partially improved, and their combination supernormalized the relaxations to serotonin without affecting those to bradykinin or A23187 or endothelium-independent relaxations to sodium nitroprusside. The expression of eNOS was significantly reduced by balloon injury and normalized by the combination therapy. These results indicate that the combination therapy improves endothelial dysfunction after balloon injury, in which the up-regulation of eNOS may be involved.


Subject(s)
Coronary Vessels/drug effects , Endothelium, Vascular/drug effects , Nifedipine/pharmacology , Pyridines/pharmacology , Administration, Oral , Animals , Blood Chemical Analysis , Blotting, Western , Bradykinin/pharmacology , Calcimycin/pharmacology , Catheterization/adverse effects , Catheterization/methods , Coronary Angiography/methods , Coronary Vessels/injuries , Coronary Vessels/physiopathology , Dose-Response Relationship, Drug , Drug Therapy, Combination , Endothelium, Vascular/injuries , Endothelium, Vascular/physiopathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , In Vitro Techniques , Male , Nifedipine/administration & dosage , Nifedipine/therapeutic use , Nitric Oxide Donors/pharmacology , Nitric Oxide Synthase Type III/metabolism , Nitroprusside/pharmacology , Pyridines/administration & dosage , Pyridines/therapeutic use , Serotonin/pharmacology , Swine , Vasodilation/drug effects , Vasodilator Agents/administration & dosage , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use
3.
Arterioscler Thromb Vasc Biol ; 24(1): 181-6, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14592842

ABSTRACT

OBJECTIVE: We recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis. In this study, we examined whether Rho-kinase is also involved in in-stent restenosis and if so, what mechanism is involved. METHODS AND RESULTS: Pigs underwent stent implantation in the left coronary artery with or without administration of fasudil (30 mg/kg per day orally), a specific Rho-kinase inhibitor, starting 2 days before the procedure for a duration of 4 weeks. On day 28, reductions in coronary diameter and neointimal formation associated with macrophage accumulation, collagen deposition, and transforming growth factor (TGF)-beta1 expression were noted at the stent site, and all were significantly suppressed by fasudil. On day 7, fasudil significantly increased the frequency of TUNEL-positive apoptotic cells, while it tended to reduce that of bromodeoxyuridine-positive proliferating cells in the neointima. Western blot analysis on day 7 demonstrated that phosphorylations of the ezrin/radixin/moesin family (a marker of Rho-kinase activity in vivo) and protein expression of monocyte chemoattractant protein-1and bcl-2 were upregulated at the stent site and were significantly suppressed by fasudil. CONCLUSIONS: These results indicate that long-term inhibition of Rho-kinase suppresses in-stent neointimal formation by multiple mechanisms, including reduced vascular inflammation, enhanced apoptosis, and decreased collagen deposition.


Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Coronary Restenosis/enzymology , Enzyme Inhibitors/pharmacology , Protein Serine-Threonine Kinases/physiology , Stents , Tunica Intima/pathology , Animals , Apoptosis/drug effects , Blood Proteins/metabolism , Catheterization/adverse effects , Chemokine CCL2/biosynthesis , Chemokine CCL2/genetics , Collagen/metabolism , Coronary Restenosis/pathology , Coronary Restenosis/prevention & control , Coronary Stenosis/surgery , Coronary Stenosis/therapy , Cytoskeletal Proteins/metabolism , Drug Evaluation, Preclinical , Genes, bcl-2 , Intracellular Signaling Peptides and Proteins , Male , Membrane Proteins/metabolism , Microfilament Proteins/metabolism , Phosphoproteins/metabolism , Phosphorylation/drug effects , Protein Processing, Post-Translational/drug effects , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Single-Blind Method , Swine , Tunica Intima/drug effects , Tunica Intima/enzymology , rho-Associated Kinases
4.
Arterioscler Thromb Vasc Biol ; 23(12): 2209-14, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14592852

ABSTRACT

OBJECTIVE: We have recently demonstrated that protein kinase C (PKC) and Rho-kinase play important roles in coronary vasospasm in a porcine model. However, it remains to be examined whether there is an interaction between the two molecules to cause the spasm. METHODS AND RESULTS: A segment of left porcine coronary artery was chronically treated with IL-1beta-bound microbeads in vivo. Two weeks after the operation, phorbol ester caused coronary spasm in vivo and coronary hypercontractions in vitro at the IL-1beta-treated segment; both were significantly inhibited by hydroxyfasudil, a specific Rho-kinase inhibitor. Guanosine 5'-[gamma-thio]triphosphate (GTPgammaS), which activates Rho with a resultant activation of Rho-kinase, enhanced Ca2+ sensitization of permeabilized vascular smooth muscle cells, which were resistant to the blockade of PKC by calphostin C. The GTPgammaS-induced Ca2+ sensitization was greater in the spastic segment than in the control segment. Western blot analysis revealed that only PKCdelta isoform was activated during the hypercontraction. CONCLUSIONS: These results demonstrate that PKC and Rho-kinase coexist on the same intracellular signaling pathway, with PKC located upstream on Rho-kinase, and that among the PKC isoforms, only PKCdelta may be involved. Thus, the strategy to inhibit Rho-kinase rather than PKC may be a more specific and useful treatment for coronary spasm.


Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Coronary Vasospasm/enzymology , Disease Models, Animal , Protein Kinase C/physiology , Protein Serine-Threonine Kinases/metabolism , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Animals , Blotting, Western , Calcium/metabolism , Capillary Permeability/drug effects , Coronary Vasospasm/metabolism , Coronary Vessels/chemistry , Coronary Vessels/drug effects , Coronary Vessels/enzymology , Coronary Vessels/metabolism , Enzyme Activation , Enzyme Inhibitors/pharmacology , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , In Vitro Techniques , Intracellular Signaling Peptides and Proteins , Male , Monomeric GTP-Binding Proteins/metabolism , Monomeric GTP-Binding Proteins/physiology , Muscle Contraction/drug effects , Muscle Contraction/physiology , Muscle, Smooth, Vascular/chemistry , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/enzymology , Phorbol 12,13-Dibutyrate/metabolism , Phorbol 12,13-Dibutyrate/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Transport/drug effects , Protein Transport/physiology , Swine , rho-Associated Kinases
5.
Cardiovasc Res ; 57(2): 572-85, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12566130

ABSTRACT

OBJECTIVE: Matrix metalloproteinases (MMPs) cause extracellular matrix degradation and may be involved in the rupture of atherosclerotic plaques by degrading fibrous cap, resulting in the intravascular thrombus formation. Here we examined whether local overexpression of MMP-9 alters the characteristics of arteriosclerotic vascular lesions and promotes thrombosis after balloon injury in porcine coronary arteries in vivo. METHODS AND RESULTS: Balloon angioplasty was performed in the left coronary arteries followed by injection of adenovirus vector solution encoding either MMP-9 or beta-galactosidase (beta-gal) gene into the injured coronary arteries. Three weeks after the gene transfer, histological examination demonstrated that macroscopic intravascular thrombus formation was noted at the MMP-9-transfected site but not at the beta-gal-transfected site. Microscopic intramural thrombus area was significantly larger at the MMP-9-transfected site as compared to the beta-gal-transfected site. Co-transfection of tissue inhibitor of metalloproteinase-1 (TIMP-1) with MMP-9 prevented the intravascular thrombus formation in vivo. Western blot analysis revealed the reduced expression of intact tissue factor pathway inhibitor-1 and the increased tissue factor (TF) expression at the MMP-9-transfected sites. CONCLUSION: These results provide the first in vivo evidence that overexpression of MMP-9 promotes intravascular thrombus formation after balloon injury due in part to the activation of TF-mediated coagulation cascade.


Subject(s)
Angioplasty, Balloon, Coronary/adverse effects , Coronary Thrombosis/enzymology , Matrix Metalloproteinase 9/physiology , Adenoviridae/genetics , Animals , Coronary Artery Disease/complications , Coronary Artery Disease/therapy , Coronary Thrombosis/etiology , Coronary Thrombosis/pathology , Genetic Vectors , Lipoproteins/metabolism , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Swine , Thromboplastin/metabolism , Tissue Inhibitor of Metalloproteinase-1/genetics , Tissue Inhibitor of Metalloproteinase-1/physiology , Transfection
6.
J Cardiovasc Pharmacol ; 41(3): 372-80, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12605015

ABSTRACT

Although the importance of monocytes/macrophages in the pathogenesis of arteriosclerosis is widely accepted, effective and safe treatment to inhibit those inflammatory cells remains to be developed. It was recently found that propagermanium, which is clinically used for the treatment of chronic hepatitis type B in Japan, markedly suppresses monocyte chemotaxis in response to macrophage chemoattractant protein-1 (MCP-1) through inhibition of its receptor, C-C chemokine receptor 2, in vitro. This prompted examination of whether propagermanium suppresses the macrophage-mediated formation of coronary arteriosclerotic lesions in our porcine model in vivo. It was first confirmed that propagermanium inhibited the migration of porcine monocytes in response to MCP-1 at therapeutic concentrations in vitro. Pigs were randomly divided into two groups; one group was orally treated with propagermanium (1 mg/kg, three times/day) and another group served as a control (n = 6 each). Porcine coronary segment was treated from the adventitia with MCP-1 and oxidized low-density lipoprotein for 2 weeks. In the control group, this treatment resulted in the development of stenotic coronary lesions with hyperconstrictive responses to serotonin where arteriosclerotic lesions (neointimal formation and constrictive remodeling) were developed. Immunohistochemical analysis demonstrated the macrophage accumulation in the adventitia and the media. By contrast, in the propagermanium group, angiographic coronary stenosis, hyperconstrictive responses, histologic changes, and macrophage accumulation were all significantly suppressed. These results indicate that propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in vivo, suggesting its potential usefulness for the treatment of arteriosclerotic vascular diseases.


Subject(s)
Coronary Artery Disease/drug therapy , Disease Models, Animal , Macrophages/drug effects , Organometallic Compounds/pharmacology , Animals , Coronary Artery Disease/pathology , Dose-Response Relationship, Drug , Germanium , Macrophages/pathology , Male , Organometallic Compounds/therapeutic use , Propionates , Swine
7.
Arterioscler Thromb Vasc Biol ; 23(2): 244-50, 2003 Feb 01.
Article in English | MEDLINE | ID: mdl-12588766

ABSTRACT

OBJECTIVE: This study was designed to examine why in WHHL rabbits, muscular arteries, such as the carotid artery, are relatively resistant to atherosclerosis compared with the aorta, with a special reference to monocyte chemoattractant protein (MCP)-1. METHODS AND RESULTS: MCP-1 mRNA expression was quantitated by Northern blot analysis, and its protein expression was quantitated by immunostaining and ELISA at the age of 1, 3, 6, and 12 months (n=5 to 6 each). In the aorta, atherosclerotic lesions were progressively developed with aging, and MCP-1 was highly expressed in endothelial cells and infiltrating macrophages. By contrast, in the carotid artery, atherosclerotic lesions and MCP-1 immunoreactivity were not evident throughout the experimental period. Unexpectedly, however, the extent of MCP-1 mRNA expression was comparable between the aorta and the carotid artery throughout the experimental period. Endothelial cells in primary culture from the aorta and the carotid artery expressed the same extent of MCP-1 mRNA on stimulation by oxidized LDL. There was no abnormality in primary structure of MCP-1 cDNA in WHHL. CONCLUSIONS: These results suggest that in WHHL, the atherosclerosis process, including MCP-1 protein expression, may be reduced in the carotid artery (and possibly in other muscular arteries), accounting in part for the regional resistance to atherosclerosis.


Subject(s)
Aorta, Thoracic/metabolism , Carotid Arteries/metabolism , Chemokine CCL2/biosynthesis , RNA, Messenger/biosynthesis , Age Factors , Animals , Aorta, Thoracic/chemistry , Aorta, Thoracic/cytology , Aorta, Thoracic/pathology , Arteriosclerosis/metabolism , Arteriosclerosis/pathology , Carotid Arteries/chemistry , Carotid Arteries/cytology , Carotid Arteries/pathology , Cell Line , Cells, Cultured , Chemokine CCL2/genetics , Chemokine CCL2/immunology , Chemokine CCL2/metabolism , DNA, Complementary/genetics , Disease Models, Animal , Endothelium, Vascular/chemistry , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Enzyme-Linked Immunosorbent Assay , Immunoblotting/methods , Lipoproteins, LDL/metabolism , Macrophages/chemistry , Oxidation-Reduction , Rabbits , Sequence Analysis, DNA/methods
8.
J Cardiovasc Pharmacol ; 41(2): 171-7, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12548076

ABSTRACT

Macrophages play an important role in the pathogenesis of atherosclerosis, for which monocyte chemoattractant protein (MCP)-1 and CCR2 chemokine receptors may be involved. The authors have recently demonstrated that propagermanium exerts inhibitory effect on the CCR2 receptors. In the current study, the authors examined whether the organic germanium suppresses the MCP-1-induced monocyte migration in vitro and the development of atherosclerosis in WHHL rabbits in vivo. In the in vitro experiment, propagermanium concentration-dependently suppressed the MCP-1-induced migration of THP-1 cells. In the in vivo experiment, 20 WHHL rabbits were randomly divided into two groups; one group was treated with oral administration with propagermanium (9 mg/kg/day) for 3 months, and another group served as a control (n = 10 each). After 3 months, the aorta was isolated and stained with oil red O staining, and neointimal formation was quantified. Macrophage accumulation in the aorta was also evaluated by immunostaining. Long-term treatment with propagermanium did not affect the serum lipid profiles. However, the treatment significantly suppressed the oil red O-positive area of the total aorta (p < 0.05). Similarly, propagermanium significantly suppressed the intimal lesions (maximal intimal thickness and intimal area) and macrophage staining-positive area (all p < 0.05). A significant positive correlation was noted between macrophage staining-positive area and intimal lesions (p < 0.0001). These results indicate that long-term treatment with propagermanium suppresses the development of atherosclerosis in WHHL rabbits, suggesting its usefulness for the treatment of atherosclerotic vascular disease in humans.


Subject(s)
Arteriosclerosis/prevention & control , Organometallic Compounds/administration & dosage , Receptors, LDL/deficiency , Animals , Aorta, Abdominal/drug effects , Aorta, Abdominal/pathology , Aorta, Thoracic/drug effects , Aorta, Thoracic/pathology , Arteriosclerosis/drug therapy , Arteriosclerosis/genetics , Arteriosclerosis/pathology , Cell Line , Germanium , Humans , Propionates , Rabbits , Receptors, CCR2 , Receptors, Chemokine/antagonists & inhibitors , Receptors, LDL/genetics
9.
J Cardiovasc Pharmacol ; 39(4): 513-22, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11904525

ABSTRACT

Recent studies demonstrated that neointimal formation, which is caused by both neointimal proliferation and organized mural thrombus, is responsible for in-stent restenosis. Although various types of heparin coatings were effective in reducing (sub)acute thrombosis, most of them failed to reduce neointimal proliferation. This study was designed to examine the effect of the stent coated with multiple layers of releasable heparin complex from which heparin diffuses into the surrounding tissue and exerts its beneficial effects. Male Yorkshire pigs underwent balloon expandable stenting for coronary segments of both the left anterior and the left circumflex coronary arteries with a comparable diameter (n = 10). The stent implantation site was randomized for either control or heparin-coated stent. Four weeks after the procedure, quantitative coronary angiography (QCA) and intravascular ultrasonographic imaging (IVUS) were performed followed by histologic analysis. In additional animals, staining for proliferating cell nuclear antigen (PCNA) was performed 10 d after the procedure (n = 3). QCA demonstrated that coronary diameter (mm) was significantly larger at the heparin-coated stent site (2.32 +/- 0.14) compared with the control stent site (1.81 +/- 0.17) (p < 0.01). IVUS also showed that the neointimal area (mm2) was significantly suppressed at the heparin-coated stent site (2.12 +/- 0.58) compared with the control stent site (3.92 +/- 0.33) (p < 0.01). Histologic analysis also demonstrated that neointimal area (mm2) was significantly less at the heparin-coated stent (2.94 +/- 0.43) than at the control stent site (4.41 +/- 0.38) (p < 0.01), which was also the case for organized thrombus area (x10-4 mm2) (6.61 +/- 2.67 vs. 19.36 +/- 4.38, p < 0.01). The frequency of PCNA-positive vascular smooth muscle cells (%) was significantly less at the heparin-coated stent (10.8 +/- 1.0) than at the control stent site (19.1 +/- 1.7) (p < 0.01). These results suggest that the stent coated with releasable heparin is beneficial in reducing neointimal formation and subsequent in-stent restenosis.


Subject(s)
Coronary Restenosis/pathology , Coronary Vessels/pathology , Heparin/pharmacology , Tunica Intima/pathology , Angioplasty, Balloon, Coronary , Animals , Coated Materials, Biocompatible , Coronary Angiography , Coronary Vessels/diagnostic imaging , Male , Muscle, Smooth, Vascular/pathology , Proliferating Cell Nuclear Antigen/analysis , Stents , Swine , Ultrasonography, Interventional
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