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Biomedical subjects

T Kuga

Publications and source records attributed to T Kuga.

At least 73 records · Page 4Linked to original sources
PubMed1996

Pulmonary veno-occlusive disease accompanied by microangiopathic hemolytic anemia 1 year after a second bone marrow transplantation for acute lymphoblastic leukemia.

Although hepatic veno-occlusive disease (HVOD) is a common complication of allogenic bone marrow transplantation (BMT), pulmonary veno-occlusive disease (PVOD) is very rare. Only three cases have been described in the literature. We report the case of a 19-year-old woman who developed PVOD accompanied by microangiopathic hemolytic anemia (MAHA) and hemolytic uremic syndrome (HUS) 1 year after a second BMT for relapsed acute lymphoblastic leukemia (ALL). Autopsy examination revealed obstruction of the small pulmonary veins with edematous thickening of the intima. These findings are compatible with PVOD. Pulmonary GVHD and pulmonary aspergillosis were also observed. Various etiologic factors have been implicated in PVOD after BMT. We postulate that pulmonary GVHD and pulmonary infection including aspergillosis played an important role in the occurrence of both PVOD and HUS in our patient. Microangiopathic cytokines released in response to the GVHD and infection may damage the intima of microvessels that were previously injured by the two BMT. Despite appropriate therapy, the microangiopathic process was irreversible and the patient died. Thus, measures must be taken to prevent and treat PVOD after BMT.

Adolescent↗
PubMed1996

Tyrosine kinase inhibitor suppresses the (re) stenotic changes of the coronary artery after balloon injury in pigs.

OBJECTIVE: Restenosis after percutaneous transluminal coronary angioplasty (PTCA) still remains a serious late complication. Many growth factors induced in restenotic lesions may be responsible for restenosis after PTCA. Most of the receptors for such growth factors possess tyrosine kinase activity. This study was designed to determine whether or not a specific tyrosine kinase inhibitor, ST 638, can prevent (re)stenotic changes of the coronary artery after balloon injury. METHODS: A segment of the porcine coronary artery was aseptically wrapped with cotton mesh absorbing either ST 638 or vehicle, followed by balloon injury. Two weeks after the procedure, coronary stenosis and vasoconstricting responses were examined by coronary arteriography and (re)stenotic changes of the coronary artery were histologically examined. Antiphosphotyrosine immunoblotting was also performed to examine the inhibitory effects of ST 638. RESULTS: Coronary arteriography showed the development of mild stenotic lesions at the balloon-injured sites, where hyperconstrictive responses were repeatedly induced by intracoronary serotonin and histamine. Histologically, neointimal formation was noted at the balloon-injured site, where the total vessel area also tended to decrease (geometric remodeling). The treatment with ST 638 suppressed all the hyperconstrictive responses, the neointimal formation, and the geometric remodeling induced by balloon injury. Immunoblotting for phosphotyrosine proteins demonstrated the elevation of proteins at the balloon-injured site, which was suppressed by ST 638. CONCLUSIONS: These results indicate that tyrosine kinases are activated at the balloon-injured site and the inhibition of such kinase activities is effective in reducing both the (re)stenotic changes (neointimal formation and geometric remodeling) and the hyperconstrictive responses of the coronary artery after balloon injury.

Angioplasty, Balloon, Coronary↗
PubMed1996

ATP-sensitive K+ channel opener pinacidil augments beta 1-adrenoceptor-induced coronary vasodilation in dogs.

The opening of ATP-sensitive K+ (K+ATP) channels contributes to the mechanism of metabolic coronary vasodilation. The aim of the present study was to determine whether K+ATP channel opener pinacidil augments coronary vasodilation induced by beta-adrenoceptor stimulation. In anesthetized dogs, coronary vasodilation in response to intracoronary infusion of a beta 1-adrenoceptor agonist denopamine, selective beta 2-adrenoceptor stimulation with isoproterenol after bisoprolol or nitroglycerin was studied before and during simultaneous intracoronary infusion of pinacidil at a dose of 1 microgram/min, which had no effect on basal hemodynamics. Pinacidil augmented the denopamine-induced increase in coronary blood flow (CBF) from 38 +/- 9 to 66 +/- 16% (P < 0.05) but did not affect the denopamine-induced by isoproterenol or nitroglycerin. Thus pinacidil selectively augmented beta 1-adrenoceptor-mediated coronary vasodilation. These observations suggest that the K+ATP channel opener pinacidil may increase myocardial perfusion during metabolic stress associated with beta 1-adrenoceptor stimulation.

Adenosine Triphosphate↗
PubMed1996

Cell cycle--dependent expression of L- and T-type Ca2+ currents in rat aortic smooth muscle cells in primary culture.

The expression of L- and T-type Ca2+ channels has been reported to change during various biological events, including cellular differentiation and proliferation. The present study aimed to examine whether or not the expression of L- and T-type Ca2+ channels depends on the cell cycle in rat aortic smooth muscle cells in primary culture. Both the phase of the cell cycle and the functional expression of Ca2+ channels were determined in the same single cell, using an immunocytochemical analysis of cell cycle-specific nuclear antigens and a whole-cell voltage-clamp method, respectively. In the G0 (n = 130) and M (n = 75) phases, all cells showed only L-type Ca2+ currents. The cells showing a T-type Ca2+ current appeared in the G1 phase (37%, n = 85) and increased in the S phase (90%, n = 21). For L-type Ca2+ channels, the current density was significantly greater in the G1 phase than in the G0 and M phases. However, either the voltage-dependent properties or the dose-response relationships of Bay K 8644- and second messenger-induced modulations of L-type Ca2+ current did not differ in the four phases of the cell cycle. These findings thus indicate that the expression of L- and T-type Ca2+ channels depends on the cell cycle, whereas the characteristics of L-type Ca2+ channels do not differ between the phases of the cell cycle.

Animals↗
PubMed1996

Role of endothelium-derived nitric oxide in coronary vasodilatation induced by pacing tachycardia in humans.

Endothelium-derived NO contributes to the control of coronary perfusion. We investigated the roles of NO in the metabolic coronary vasodilatation induced by rapid pacing in humans. We evaluated the dilatation of large epicardial and resistance coronary arteries during rapid atrial pacing before and after intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis, in 19 patients without significant coronary artery disease. The diameter of the large epicardial coronary artery and coronary blood flow (CBF) were assessed by quantitative coronary arteriography and by a Doppler flow velocity measurement. An increase in the heart rate increased CBF (P < .01) and the coronary artery diameter (P < .05). L-NMMA at a total dose of 200 mumol reduced basal CBF but did not significantly affect basal coronary artery diameter, arterial pressure, or heart rate. L-NMMA inhibited the pacing-induced dilatation of the large coronary arteries (P < .05) but did not affect pacing-induced increases in CBF. L-NMMA inhibited the acetylcholine-induced increase in CBF (P < .01) and acetylcholine-induced dilatation of the large epicardial coronary artery (P < .05). These results show that the contribution of NO to the metabolic vasodilatation during rapid pacing may differ between large epicardial and resistance coronary arteries in patients without significant coronary artery disease.

Acetylcholine↗
PubMed1996

Effect of cilostazol, a novel anti-platelet drug, on restenosis after percutaneous transluminal coronary angioplasty.

The possible preventive effect of cilostazol, a novel anti-platelet drug, on restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) was examined. One hundred and two consecutive patients, who underwent successful PTCA, were followed for 3 to 6 months. To prevent restenosis, 46 patients (60 PTCA sites) were treated with cilostazol alone (200 mg/day) (cilostazol group) and the remaining 56 (61 PTCA sites) were treated with other anti-platelet drugs and/or warfarin potassium (control group). Restenosis was defined as a more than 50% loss of the initial gain of the coronary diameter achieved by PTCA. Cilostazol did not significantly reduce the patient or lesion restenosis rate; the patient restenosis rate was 32% in the control group and 22% in the cilostazol group (P = 0.24), and the lesion restenosis rate was 30% in the control group and 23% in the cilostazol group (P = 0.44). However, the lesion non-progression rate, which was defined as the incidence of lesions with either no change or regression of coronary stenosis at the PTCA site, was significantly greater with cilostazol (37%) than in the control group (16%) (p < 0.05). Although cilostazol failed to show a significant reduction in restenosis after PTCA, the present results suggest that a further trial with a larger number of patients is needed to confirm its usefulness.

Aged↗
PubMed1995

Superoxide dismutase in SAS human tongue carcinoma cell line is a factor defining invasiveness and cell motility.

This article describes an apparent inverse relationship between cell motility and intracellular Cu-Zn superoxide dismutase (SOD) activity of two human squamous carcinoma-derived clones, SAS-H1 with high invasiveness and SAS-L1 with low invasiveness. Clone SAS-H1 exhibited significantly greater motility than SAS-L1 but had significantly lower levels of intracellular Cu-ZnSOD than SAS-L1 cells. We then transfected Cu-ZnSOD antisense cDNA into SAS-L1 to reduce the intracellular Cu-ZnSOD activity. Antisense cDNA transfected SAS-L-AS clones had lower Cu-ZnSOD activity than control vector-transfected SAS-L-Neo clones, and this was associated with increased motility. Invasiveness of SAS-H1 and SAS-L-AS1 was enhanced by superoxide treatment, while the invasiveness of SAS-L1 was unaffected. These findings indicate that intracellular SOD is involved in cell motility by virtue of its action in scavenging superoxide in the cells.

Base Sequence↗
PubMed1995

Chronic inhibition of endothelium-derived nitric oxide synthesis causes coronary microvascular structural changes and hyperreactivity to serotonin in pigs.

BACKGROUND: Endothelium-derived nitric oxide (NO) is believed to regulate myocardial perfusion and structural changes in the vascular wall. Our objective was to determine whether chronic inhibition of NO synthesis causes structural and functional changes in coronary arteries. METHODS AND RESULTS: Coronary vasomotor response was studied in pigs before and after chronic oral administration of the NO synthesis antagonist N omega-nitro-L-arginine methyl ester (L-NAME) 30 mg.kg-1.d-1 for 2 weeks. Chronic L-NAME treatment increased (P < .01) arterial pressure but did not alter baseline coronary blood flow (CBF), epicardial coronary diameter, or heart rate. Chronic L-NAME treatment augmented (P < .01) the decrease in CBF in response to intracoronary serotonin (30 micrograms/kg) from 5 +/- 14% to 40 +/- 5% but did not alter the CBF response to prostaglandin F2 alpha. The serotonin-induced decrease in CBF after acute L-NAME administration was still less before (1.3 +/- 0.4%) than after chronic L-NAME treatment (51 +/- 6%). Chronic L-NAME treatment attenuated the increase in CBF with bradykinin (100 ng/kg) but did not alter the CBF response to nitroglycerin (10 micrograms/kg). Compared with intact pigs without L-NAME treatment, L-NAME-treated pigs had significant thickening of the media in the microvessels (diameter, < 300 microns) but not in the large epicardial vessels. Chronic intracoronary infusion of L-NAME at 3 mg.kg-1.d-1 for 2 weeks, which did not produce arterial hypertension, caused similar microvascular medial thickening. CONCLUSIONS: These results indicate that chronic administration of L-NAME caused coronary microvascular structural changes and hyperreactivity to serotonin in pigs in vivo, suggesting an important role of defective NO synthesis in coronary microvascular disorders.

Animals↗
PubMed1995

Bradykinin-induced vasodilation is impaired at the atherosclerotic site but is preserved at the spastic site of human coronary arteries in vivo.

BACKGROUND: Bradykinin causes endothelium-dependent vasodilation of isolated human coronary arteries in vitro. However, the effect of bradykinin on vasomotion of human coronary arteries in vivo has not been studied. The aim of this study was to examine whether bradykinin-induced vasodilation is altered at the atherosclerotic or spastic site of human coronary arteries in vivo. METHODS AND RESULTS: The effect of bradykinin on vasomotion of epicardial coronary arteries was evaluated in 8 patients with normal coronary arteries (control group), 14 patients with organic coronary stenosis (coronary artery disease [CAD] group), and 8 patients with vasospastic angina (VSA group). Changes in the diameter of epicardial coronary artery were assessed by quantitative coronary arteriography. Intracoronary administration of bradykinin at graded doses (60, 200, and 600 ng) dilated epicardial coronary arteries without altering arterial pressure or heart rate in all patients of either group. In the control group, vasomotor responses of the site where acetylcholine caused dilation were compared with the responses of the site where acetylcholine caused constriction. The magnitudes of bradykinin-induced dilation at the site with acetylcholine-induced dilation (mean +/- SD: 6 +/- 6%, 11 +/- 9%, and 15 +/- 9%) were comparable to that (3 +/- 6%, 8 +/- 8%, and 13 +/- 9%) at the site with acetylcholine-induced constriction. In the CAD group, vasomotor responses of the stenotic site (% diameter stenosis, 15% to 50%) and nonstenotic site were examined. The bradykinin-induced dilation at the stenotic site (0 +/- 4%, 3 +/- 8%, and 5 +/- 9%) was significantly less (P < .01) than at the nonstenotic site (3 +/- 4%, 8 +/- 6%, and 16 +/- 11%) and in the control group. Coronary vasodilation with nitrate at the stenotic site (20 +/- 11%) was comparable to that at the nonstenotic site (22 +/- 16%) and in the control group (21 +/- 10%). In the VSA group, vasomotor responses of the site with acetylcholine-induced spasm and the site without spasm were examined. The bradykinin-induced vasodilation at the spastic site (5 +/- 5%, 16 +/- 15%, and 33 +/- 17%) was comparable to that at the nonspastic site (4 +/- 8%, 12 +/- 14%, and 21 +/- 9%). Nitrate-induced dilation was comparable at the spastic site (51 +/- 19%) and the nonspastic site (32 +/- 13%). The ratio of bradykinin-induced vasodilation to nitrate-induced vasodilation at the spastic site was comparable to the control group. CONCLUSIONS: These results suggest that bradykinin causes vasodilation of human epicardial coronary arteries in vivo and that bradykinin-induced endothelium-dependent vasodilation is impaired at the stenotic site but is preserved at the angiographically normal site where endothelium-dependent vasodilation by acetylcholine is impaired and at the spastic site.

Acetylcholine↗
PubMed1995

Mechanisms of coronary hyperconstriction in response to serotonin induced by X-irradiation in miniature pigs: increased constrictive response of medial smooth muscle.

Experimental and clinical studies suggest that X-irradiation to the coronary artery may enhance vasoconstrictive response. This study aimed to clarify the effect of X-irradiation on the vasomotor response of porcine coronary artery. X-ray (15 Gy) was selectively irradiated to the left anterior descending coronary artery (LAD) in 14 Göttingen miniature pigs. The coronary vasomotor responses to serotonin at the irradiated site (LAD) and the control site (the left circumflex artery; LCX) were assessed by quantitative arteriography before and 1 h and 1, 2, and 4 weeks after X-irradiation. At 2 weeks, endothelium-dependent vasodilation in response to substance P was also evaluated arteriographically in vivo. At 2 weeks, isometric tension studies were performed to evaluate the constrictive responses of medial muscle strips and endothelium-dependent relaxation. Coronary vasoconstriction in response to serotonin was enhanced 1 week after, and further augmentation was noted 2 and 4 weeks after X-irradiation. Endothelium-dependent vasodilation in response to substance P in vivo was preserved 2 weeks after X-irradiation. Coronary arteriography showed no organic stenosis at the irradiated site. In vitro studies demonstrated that medial muscle strips of the irradiated site showed hypercontraction in response to serotonin and that endothelium-dependent relaxation in response to serotonin and substance P was preserved at the irradiated site. A histological study revealed no appreciable changes of the endothelial cells or intimal thickening.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Co-administration of IL3 with G-CSF increases the CFU-S mobilization into peripheral blood.

In an attempt to establish an efficient method of collecting peripheral blood stem cells and to utilize them for allogeneic peripheral blood stem cell transplantation, the effect of a combined administration of recombinant murine interleukin-3 (IL3) and recombinant human granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow stem cells into the circulation was examined in C57BL/6 mice. Some appreciable numbers (796 +/- 112/ml) of CFU-GM were recovered 6 days after G-CSF administration (500 micrograms/kg per day), while by IL3 administration (100,000 units/kg per day), the CFU-GM count was much lower (61 +/- 9/ml) with a small peak at day 4. By a combined administration of IL3 (100,000 units/kg per day) and G-CSF (500 micrograms/kg per day), the CFU-GM count at the peak of day 5 was significantly augmented (1178 +/- 277/ml) as compared to that of G-CSF or IL3 alone (P < 0.05). The CFU-S counts at day 5 (168 +/- 12/ml) and at day 6 (172 +/- 27) were also significantly higher than those of IL3 alone (day 5, 30 +/- 15/ml; day 6, 20 +/- 10/ml) or G-CSF alone (day 5, 114 +/- 14/ml; day 6, 112 +/- 19/ml). Thus the combined administration of IL3 and G-CSF appears to be promising for high yield collection of peripheral blood stem cells.

Animals↗
PubMed1995

Inhibitory effects of aspirin on coronary hyperreactivity to autacoids after arterial balloon injury in miniature pigs.

We examined the effects of aspirin on coronary hyperreactivity to autacoids after arterial balloon injury in miniature pigs. Coronary vasoconstriction induced by histamine and serotonin were examined angiographically before, 1 h, 1 week, and 1 month after balloon injury in 29 hypercholesterolemic miniature pigs. The animals were divided into three groups: group A, no treatment (n = 16); group B, pretreated with aspirin 50 mg/day for 2 days before injury (n = 7); and group C, treated with aspirin 50 mg/day for 2 days before and 5 days after injury (7 days in all) (n = 6). In group A, coronary vasoconstriction induced by autacoids was significantly greater at the injured than at the noninjured site at all times examined (p < 0.01). Hyperconstriction induced by the autacoids 1 h after injury were significantly less in groups B and C than in group A (p < 0.01). Hyperconstriction induced by autacoids 1 week after injury were significantly less in group B than in group A (p < 0.01) and were significantly less in group C than in group A (p < 0.01) or group B (p < 0.05). Treatment with aspirin for 2 or 7 days had no effect on the constrictive responses at the injured site 1 month after injury or on those at the noninjured site at all times examined. These results suggest that platelet-vessel wall interaction may play an important role in coronary hyperconstrictive responses to autacoids 1 h and 1 week after injury.

Angiography↗
PubMed1995

Dual regulation of L-type Ca2+ channels by serotonin 2 receptor stimulation in vascular smooth muscle cells.

The purpose of the present study was to investigate regulation of voltage-dependent Ca2+ channels by serotonin in rat aortic smooth muscle cells in primary culture. L- and T-type Ca2+ currents (ICa) were recorded using the whole cell voltage-clamp method. Without pretreatment, in 25 of 30 cells examined, 10 microM serotonin decreased L-type ICa to various extents (-14 to -72%). However, in the remaining five cells, serotonin increased L-type ICa 21 +/- 4%. Thus, in 30 cells, serotonin decreased L-type ICa an average of 22 +/- 5%. In the presence of intracellular heparin (100 micrograms/ml), a blocker of inositol 1,4,5-trisphosphate binding to its receptor, serotonin increased L-type ICa in all cells 29 +/- 3% (n = 6). When stored Ca2+ was depleted by pretreatment either with 20 microM ryanodine and 20 mM caffeine or with 100 nM A-23187, serotonin also increased L-type ICa in all cells 30 +/- 5 (n = 4) or 37 +/- 5% (n = 12), respectively. In the presence of heparin, the serotonin-induced increase of L-type ICa was prevented by 100 nM staurosporine (2 +/- 3%; n = 6, P < 0.01). The serotonin-induced decrease of L-type ICa was significantly augmented by 100 nM staurosporine (-43 +/- 10%; n = 5). Phorbol 12,13-dibutylate (PDBu; 1 microM) increased L-type ICa 29 +/- 3% (n = 6), and serotonin did not further increase L-type ICa after its potentiation by PDBu.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Vasoreactivity and restenosis after coronary angioplasty in the atherosclerotic pig model.

BACKGROUND: The effect of coronary angioplasty on coronary spasm remains unknown. We examined the effects of balloon angioplasty, using an oversized balloon, on coronary hypercontraction and eventual restenosis in a pig model of coronary spasm. METHODS: We performed balloon angioplasty, using an oversized balloon at the site of coronary spasm superimposed on atherosclerosis with 6 (group A, n = 14) or 1 (group B, n = 14) atmospheres of inflation pressure in miniature pigs. Using coronary angiography we assessed the coronary basal diameter and diameter change in response to histamine and serotonin before, immediately after, and 4 weeks after angioplasty. Histological examinations were performed immediately after and 4 weeks after the angioplasty. RESULTS: Before angioplasty, histamine- and serotonin-induced hypercontraction was reproducibly noted at the atherosclerotic site. Immediately after angioplasty, the coronary diameter became larger (P < 0.01) than before angioplasty in group A, but there was no significant difference in group B. The hypercontraction in group A was abolished immediately after and 4 weeks after angioplasty, whereas the hypercontraction in group B was unchanged. Histological examination revealed medial necrosis immediately after and medial fibrosis 4 weeks after angioplasty, which were more prominent in group A. Four weeks after angioplasty, the magnitude of restenosis was greater in group A than in group B. CONCLUSIONS: Angioplasty using an oversized balloon with the higher atmosphere of inflation pressure abolished coronary hypercontraction immediately after and 4 weeks after angioplasty, which probably resulted from the irreversible damage to medial smooth muscles; however, this did not prevent restenosis.

Angioplasty, Balloon, Coronary↗
PubMed1995

Augmentation of coronary responsiveness to serotonin at the site of X-ray-induced intimal thickening in miniature pigs.

OBJECTIVE: X-irradiation is known to enhance atherosclerotic change. We tested whether coronary vasoconstrictor responses are augmented at the sites of X-ray-induced intimal thickening in Göttingen miniature pigs. METHODS: In 17 pigs, a major branch of the left coronary artery was denuded with a balloon catheter. In 10 pigs, the denuded portion of the left coronary artery was selectively irradiated with 15 Gy of X-rays twice at 3 and 4 months after denudation (group 1). The remaining 7 pigs were not irradiated (group 2). The effects of intracoronary administration of serotonin, histamine and phenylephrine on the coronary diameter were studied 3 (3M) and 5 months (5M) after denudation. After the angiographical study at 5M, the vessels were isolated and isometric tension was measured in an organ chamber. RESULTS: The percent reduction in coronary diameter evoked with 10 micrograms.kg-1 of serotonin increased from 39(s.e.m. 4)% before X-irradiation (3M) to 75(6)% after X-irradiation (5M) in group 1 (P < 0.01), while it did not differ in group 2 [39(6)% at 3M vs. 33(8)% at 5M[ [39(6)% at 3M vs. 33(8)% at 5M]. In group 1, serotonin-induced coronary constriction was frequently accompanied by ischemic ECG changes. Histamine (10 micrograms.kg-1)-induced vasoconstriction was also augmented but to a smaller degree [47(6)% at 3M vs. 62(4)% at 5M; P < 0.05] in group 1, while it remained unchanged in group 2[52(5)% at 3M vs. 44(7)% at 5M]. Phenylephrine did not cause detectable contraction in either group at 3M or 5M. Methysergide and ketanserin attenuated serotonin-induced hypercontraction in a dose-dependent fashion. In the in vitro studies, endothelium-dependent relaxation to serotonin was impaired at the denuded site with (group 1) and without (group 2) X-irradiation to a similar extent. Isometric tension of medial smooth muscle developed by serotonin was significantly greater at the denuded site with X-irradiation (group 1) than the control site and the denuded site without X-irradiation (group 2) (P < 0.05). Intimal thickening was significantly greater at the denuded sites with X-irradiation [group 1, 238(45) microns] than at the denuded sites without X-irradiation [group 2, 58(5) microns] (P < 0.05). CONCLUSIONS: These results indicate that X-irradiation augments the coronary vasoconstrictor responses to autacoids, predominantly to serotonin, and that this augmentation is accompanied by enhanced intimal thickening. Serotonin-induced hypercontraction after X-irradiation resulted mainly from the hyperreactivity of medial smooth muscle.

Animals↗