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Biomedical subjects

M Mohri

Publications and source records attributed to M Mohri.

At least 73 records · Page 4Linked to original sources
PubMed1998

Effects of recombinant human soluble thrombomodulin (rhs-TM) on clot-induced coagulation in human plasma.

Recent studies have suggested that clot-bound thrombin plays an important role in thrombus growth. In this study, we examined the effects of recombinant human soluble thrombomodulin (rhsTM) on clot-induced coagulation. rhsTM enhanced the activation of protein C by clots, and attenuated clot-induced thrombin generation and fibrinopeptide A (FPA) production in a dose-dependent manner. The inhibitory effect of rhsTM was abolished by anti-protein C antibody. The inhibitory effect of rhsTM on clot-induced thrombin generation continued for over 60 min after the addition of the clot, while an active site-directed thrombin inhibitor, argatroban, produced a more transient inhibition. rhsTM also inhibited the regrowth of the clot in (125)I-fibrinogen-supplemented plasma. We also examined the effect of rhsTM by thromboelastography, rhsTM reduced the growth of the clot but had little effect on the time to begin clotting, while heparin and Fragmin (low molecular weight heparin) had effects opposite to those of rhsTM. These findings suggest that rhs-TM attenuates the growth of the clot by activating protein C and inhibiting further thrombin generation in the clot.

Antithrombins↗
PubMed1997

Significance of tubal resection in surgical treatment of middle ear carcinoma.

We successfully carried out total en bloc resection of squamous cell carcinoma of the middle ear in two patients. Both patients have been free of the disease for 32-39 months. In one of the cases, the eustachian tube was resected totally with the temporal bone. Postoperative histopathological examination proved tumor invasion into the cartilaginous part of the tube. We would like to emphasize the significance of total resection of the eustachian tube when neoplastic invasion into the tube is highly suspected. Axial computed tomography is of great value for preoperative evaluation of such invasion. Anterior mobilization of the carotid artery from the carotid canal facilitates resection of the petrous apex and should be done after management of the eustachian tube. The carotid canal is best exposed ventrally, since lateral exposure is at high risk for injuring the bony part of the eustachian tube and may possibly disseminate tumor cells.

Aged↗
PubMed1997

Coordinate expression of the insulin-like growth factor system after microembolisation in porcine heart.

OBJECTIVES: Coronary microembolisation in the pig heart induces angiogenesis in a model of sterile inflammation due to focal necrosis. We have recently shown in this model that insulin-like growth factor I (IGF-I) is involved in inflammation-linked angiogenic processes due to its enhanced transcription after 72 h of ischaemia by infiltrating monocytes in areas of microsphere-induced focal necrosis where capillary sprouting could be detected. To obtain further insights into this process we studied by means of Northern blot analysis and in situ hybridisation the gene expression of other members of the IGF family, i.e. the six IGF binding proteins (IGFBPs), the insulin receptor, and the type I IGF receptor. METHODS: Myocardial injury was induced by injection of 25 microns non-radioactive microspheres into the left circumflex artery (LCx) in pigs that were killed after 3-24, 72, or 168 h of microembolisation. Tissue was collected from a non-ischaemic control area and the LCx region of the same heart for further analysis. RESULTS: We found decreased IGFBP-5 (2.7-fold; P < 0.02) mRNA concentrations after 72 h of microembolisation in ischaemic tissue versus control tissue from the same heart, preceded by a 1.9-fold elevated level of IGFBP-3 mRNA at 3-24 h (P < 0.05). IGFBP-6 was increased in ischaemic tissue at all time points studied. In situ hybridisation identified myocytes as the main producers of IGFBP-3 and IGFBP-6 mRNA. The mRNA levels of IGFBP-2, IGFBP-4, the insulin receptor, and the type I IGF receptor were constitutively expressed but did not change after microembolisation. Neither in heart nor in other organs studied transcripts of IGFBP-1 could be detected. Furthermore, we demonstrated that mRNA of the other components of the IGF system was expressed in almost all porcine organs except liver. CONCLUSION: These results indicate a coordinate gene expression of the IGF system in microembolised porcine myocardium, compatible with a role of IGF-I, IGFBP-3, IGFBP-5, and IGFBP-6 in inflammation-linked angiogenesis and/or repair processes.

Animals↗
PubMed1997

Neovascularization of the intestinal graft transplanted in subcutaneous pocket in rats.

Clinically, the intestinal graft can survive without blood supply through its vascular pedicle for a certain period after transplantation, which is generally considered to be due to newly formed vessels from the surrounding tissue to the graft. Vascular synthesis from the surrounding tissue to the pedicled intestinal graft, transplanted subcutaneously was studied in rat model. Both the carbon dye infusion technique and hematoxylin-eosin stain were employed. After transplantation of the intestine, the number and diameter of carbon stained vessels were scored on days 2, 5, 7, 10, 14, 28, and 56, when the pedicle was ligated. All the histological specimens of the intestinal grafts were analyzed and then classified into three phases depending on the extent of surviving mucosa: 'necrosis', no live mucosa were observed; 'incomplete take', some islands of mucosa were alive; and 'complete take', all mucosa were alive. We characterized the relationship between the changes of the newly formed (carbon-dyed) vessels and the three histological phases. At 'necrosis', the newly formed vessels were rare and did not reach the intestinal graft. At 'incomplete take', random thin vascular networks were observed and some of them reached the graft. Some specimens were in the 'incomplete take' phase. At 'complete take', regular large vascular networks were observed. This transformation of the vascular networks seemed to reduce the the resistance of the vascular flow and to finally lead to the 'complete take' of the graft.

Animals↗
PubMed1997

Bradykinin-induced vasodilation of human coronary arteries in vivo: role of nitric oxide and angiotensin-converting enzyme.

OBJECTIVES: The present study aimed to determine the role of nitric oxide (NO) and angiotensin-converting enzyme (ACE) in bradykinin (BK)-induced dilation of human coronary arteries in vivo. BACKGROUND: BK, produced by way of the kinin-kallikrein system, causes endothelium-dependent vasodilation. However, little is known about the mechanism of BK-induced dilation of coronary arteries in humans in vivo. METHODS: The effects of an inhibitor of NO synthesis and of an ACE inhibitor on BK-induced coronary vasodilation were examined in 20 patients who had no significant atherosclerotic stenosis in the artery under study. Lumen diameters of the large epicardial coronary arteries and coronary blood flow (CBF) were measured by quantitative coronary arteriography and intracoronary Doppler technique. RESULTS: Intracoronary infusion of BK (0.6 and 2.0 micrograms/min) increased coronary artery diameter and CBF with no change in arterial pressure or heart rate. The BK-induced increases in coronary artery diameter and CBF were significantly reduced (p < 0.01) after pretreatment with NG-monomethyl-L-arginine (200 mumol) and were significantly increased (p < 0.01) after pretreatment with enalaprilat (50 micrograms). CONCLUSIONS: BK-induced dilation of human large epicardial and resistance coronary arteries is mediated by NO and increased by prior ACE inhibition.

Aged↗
PubMed1997

The antithrombotic effects of recombinant human soluble thrombomodulin (rhsTM) on tissue factor-induced disseminated intravascular coagulation in crab-eating monkeys (Macaca fascicularis).

We evaluated the antithrombotic effects of recombinant human soluble thrombomodulin (rhsTM) in plasma and in a monkey model. rhsTM dose-dependently prolonged activated partial thromboplastin time (APTT) in the following order: humans > monkeys > rats >> rabbits. The prolongation of APTT by rhsTM was also observed in protein C-deficient plasma. rhsTM activated protein C and inactivated factor Va in human and monkey plasma, but not in rat plasma. These findings suggest that the antithrombotic activities of rhsTM are fully expressed in human and monkey. Therefore, to evaluate the whole activity of rhsTM in a clinical model, tissue factor (TF) was intravenously infused into crab-eating monkeys to induce disseminated intravascular coagulation (DIC). Pretreatment with rhsTM reduced fall in fibrinogen with a biphasic and moderate dose-dependency curve, and reduced thrombin-antithrombin III (TAT) levels with a flat linear dose-dependency, while heparin prevented fall in fibrinogen with a steep linear dose-dependency curve without reducing TAT levels. Further evidence suggesting that rhsTM activates protein C in vivo was also obtained. Taken together, the data indicate that rhsTM fully expresses its antithrombotic activities in human and monkey but not in rat and rabbit, and rhsTM prevents TF-induced DIC in monkeys by suppressing thrombin generation.

Animals↗
PubMed1997

Role of nitric oxide in substance P-induced vasodilation differs between the coronary and forearm circulation in humans.

It has been shown that substance P causes endothelium-dependent vasodilation in the human coronary and forearm vessels. However, the precise mechanism whereby substance P dilates the coronary and peripheral vasculatures is unknown in humans. The aim of this study was to examine whether the vasodilator effect of substance P is mediated by nitric oxide in the human coronary and forearm vessels. Eight patients with normal coronary angiograms were studied for the measurements of coronary blood flow (intracoronary Doppler guide wire and quantitative coronary arteriography) and forearm blood flow (strain-gauge plethysmograph). Intracoronary acetylcholine (10 micrograms/min for 2 min) and substance P (30 and 90 ng/min for 2 min) increased coronary blood flow from the baseline value. Intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA) at 200 mumol significantly attenuated the magnitudes of increase in coronary blood flow induced by both acetylcholine (p < 0.01) and substance P (p < 0.01). Acetylcholine (4, 8, and 16 micrograms/min for 2 min) and substance P (0.8, 1.6, and 3.2 ng/min for 2 min) also increased forearm blood flow in a dose-dependent manner. Intraarterial L-NMMA (8 mumol/min for 5 min) decreased the magnitudes of increase in forearm blood flow induced by acetylcholine (p < 0.01). L-NMMA at the same dosage decreased the increase in forearm blood flow induced by substance P, but the magnitude of the inhibitory effect of L-NMMA on blood-flow responses to substance P was significantly smaller in the forearm than in coronary vessels. It is suggested that endothelium-derived nitric oxide contributes to substance P-induced vasodilation, and that the contribution of nitric oxide to substance P-induced vasodilation is smaller in the forearm than in coronary circulation.

Acetylcholine↗
PubMed1997

rhs-TM prevents ET-induced increase in pulmonary vascular permeability through protein C activation.

We have previously demonstrated that recombinant human soluble (rhs) thrombomodulin (TM) inhibits the endotoxin (ET)-induced increase in pulmonary vascular permeability by inhibiting leukocyte activation. In the present study, we examined whether rhs-TM could inhibit the ET-induced increase in pulmonary vascular permeability in rats by activating protein C. rhs-TM did not inhibit ET-induced increases in pulmonary vascular permeability when its protein C activation ability was selectively inhibited by a monoclonal antibody (MAb) against rhs-TM (MAb R5G12). Histological examination revealed that neutrophil infiltration in lung tissues after ET administration was significantly reduced by rhs-TM, but infiltration was not reduced by MAb R5G12-pretreated rhs-TM. ET-induced intravascular coagulation was prevented by rhs-TM and by MAb R5G12-pretreated rhs-TM. However, ET-induced coagulation was not prevented by rhs-TM that had been treated with MAb F2H5, which cannot bind thrombin or activate protein C. These observations strongly suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes through thrombin binding and the subsequent protein C activation and may prevent ET-induced intravascular coagulation through thrombin binding.

Animals↗
PubMed1997

Basal release of nitric oxide is decreased in the coronary circulation in patients with heart failure.

It is unknown whether basal release of endothelium-derived nitric oxide in the coronary artery is altered in heart failure in humans. The aim of the present study was to evaluate the effect of inhibition of nitric oxide synthesis on basal tone of the conduit and resistance coronary arteries in awake patients. Coronary blood flow velocity (Doppler guide wire) and coronary arterial diameter (quantitative coronary angiography) were measured in 14 patients with heart failure caused by nonischemic left ventricular dysfunction (7 idiopathic dilated cardiomyopathy and 7 valvular insufficiency) and 7 patients with normal ventricular function (controls). Intracoronary N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, at graded doses decreased coronary blood flow in both groups. However, the magnitude of flow reduction was smaller in patients with heart failure than in control patients (P<.0001). The magnitude of coronary blood flow reduction in response to L-NMMA inversely correlated to indexes of left ventricular contractile function (P<.01) but was not affected by the cause of heart failure. Constriction of the large epicardial coronary artery with L-NMMA also tended to be attenuated in patients with heart failure. In summary, vasoconstricting response to L-NMMA was blunted in the coronary resistance artery in heart failure in vivo. These findings suggest that basal release of nitric oxide in the coronary circulation is decreased in patients with heart failure.

Adult↗
PubMed1997

Abnormalities in the protein C anticoagulant pathway detected by a novel assay using human thrombomodulin.

We developed a novel assay using human thrombomodulin (TM), which detected overall abnormalities in the protein C anticoagulant pathway (PC pathway). This assay indicates the degree of inhibition of prothrombinase by TM, which is represented as the percentage of prothrombinase inhibition by 25 ng/ml of TM, termed PIP25 (Prothrombinase Inhibition Percentage). We examined PIP25 in plasma samples from patients with systemic lupus erythematosus (SLE) with or without lupus anticoagulant (LA), patients with Behcet's disease (BD), and patients with miscellaneous thrombotic vasculitis and compared these with the PIP25 of plasma samples from healthy volunteers in Japan. The PIP25S were significantly lower in SLE alone (35.5 +/- 12.8%, P = 0.036) and SLE with LA (33.0 +/- 13.3%, P = 0.030) and BD (33.3 +/- 13.4%, P = 0.010) than those in healthy volunteers (43.5 +/- 10.7%). There was no significance between healthy PIP25 and those with miscellaneous thrombotic vasculitis (44.2 +/- 8.4%, P = 0.823). These results suggest that the abnormalities of the protein C anticoagulant pathway were present in patients with SLE(LA) and BD.

Behcet Syndrome↗
PubMed1997

Correlations between recruitable coronary collateral flow velocities, distal occlusion pressure, and electrocardiographic changes in patients undergoing angioplasty.

Direct assessment of coronary collateral flow has been difficult in humans. The goal of this study was to correlate the magnitudes and waveform characteristics of recruitable coronary collateral flow velocity measured with Doppler guidewire with other hemodynamic and functional indexes of collateral circulation in patients during angioplasty. Twenty-six patients [age 60 +/- 10 (SD) years] were studied for measurements of flow velocity at the distal segment of the dilated vessel. Collateral flow signals were demonstrated in 18 patients (69%) during balloon inflation. There was a weak yet significant positive correlation between the magnitude of collateral flow velocity and distal occlusion pressure (p < 0.01). The sum of ischemic ST elevation on the 12-lead electrocardiogram was inversely correlated with distal occlusion pressure, but not with the magnitude of collateral flow velocity. Subgroup analysis between patients with (n = 18) and without (n = 8) ST elevation during balloon inflation revealed higher collateral flow velocity signals (p < 0.0001) and greater systolic components of collateral flow in the latter group (p < 0.0001). Thus, functionally significant coronary collaterals showed greater velocity signals and systolic predominance in flow pattern. The functional capacity of human coronary collaterals may be semiquantitated using the Doppler guidewire technique.

Angina Pectoris↗
PubMed1997

Changes in urinary excretion of pyridinium cross-links during Spacelab-J.

In SLJ-1 we proposed to study three major objectives. They were; 1. hormonal changes associated with fluid and electrolyte metabolism, 2. the effect of space flight on the circadian rhythms of endocrine and metabolic systems, 3. the changes in the indices of the bone and muscle metabolism during space flight. In this report, the changes in the bone metabolism during Spacelab-J will be presented with a special emphasis on urinary excretion of pyridinium cross-links. Timed urine samples from three Japanese payload specialists were obtained for 3 days from May 19 to 21, 1991 (one year before the launch = L-1 year). Immediately before the launch (L-3 to L-0), urine samples were obtained from a payload specialist who was on board the Space Shuttle Endeavor (PS). During the inflight period (flight from September 3 to 10 in 1992), urine samples from the PS were collected by using Urine Monitoring System (UMS). After the landing, they were obtained from the PS for three days (R+0-R+2). Various parameters related to bone metabolism such as hydroxyproline, pyridinium cross-links and calcium were determined. It was noted that excretion of hydroxyproline decreased during the preflight periods when compared with that in the control L-1 year period. The average excretory rate during control period was 846.2 +/- 198.7 milligrams/hour (mean +/- SD), while those in the preflight 474.6 +/- 171.1 milligrams/hour, suggesting the diminished collagen intake during the preflight period. Average excretion rate of pyridinium cross-links during the first 4 mission days (MD0-MD3) was similar to that of preflight and control L-1 year period. However, it was significantly increased during the last 4 mission days (MD4-MD7). It returned to the preflight level during postflight days (R+0-R+2). Increased urinary excretion of calcium during the last 4 mission days were also observed. These results suggest that increase in bone resorption could occur during relatively short stay in microgravity.

Aerospace Medicine↗
PubMed1997

Effects on sleep patterns during simulated oxygen-helium saturation diving at 180 and 230 m.

The standard polysomnography of four divers was recorded respectively through 188 nights in two simulated experiments under a hyperbaric saturation environment of He-O2 mixture at the depths of 180 and 230 m. In the two diving conditions on the bottom nights and decompression nights, the following was shown: A reduction of total sleep time, a decrease of sleep efficiency; an increase of sleep latency, frequency of wake after sleep, number of sleep stage shifts, and a lengthening of stage 1 sleep; and a reduction of stage 4 sleep. In the 230 m-diving condition on the bottom nights and the decompression nights, only stage 4 sleep showed a significant decrease when compared with the 180 m-diving condition. It is assumed that both were conditions in which awakening was likely to happen and there would be no disorders of fundamental sleep patterns.

Adult↗
PubMed1996

Effects of L-arginine supplementation on endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary arteriograms.

BACKGROUND: The pathogenesis of impaired endothelium-dependent coronary vasodilation in angina pectoris and normal coronary arteriograms (microvascular angina pectoris) is not known. We examined whether supplementation with L-arginine, a precursor of endothelium-derived nitric oxide, improves endothelium-dependent coronary vasodilation in patients with microvascular angina. METHODS AND RESULTS: The effect of intracoronary infusion of L-arginine (50 mg/mm) on acetylcholine-induced coronary vasomotion was studied in eight patients with microvascular angina and eight control subjects. The responses of the large epicardial coronary artery diameter and coronary blood flow were measured with coronary arteriography and an intracoronary Doppler catheter, respectively. Acetylcholine increased coronary blood flow with modest vasoconstriction of the large coronary artery without altering arterial pressure and heart rate. The acetylcholine-induced increases in coronary blood flow were significantly less (P < .01) in patients than in control subjects. L-Arginine significantly augmented the coronary blood flow responses to acetylcholine in patients, but not in control subjects. L-Arginine did not alter responses of the large coronary artery in either group. CONCLUSIONS: Study results suggest that L-arginine improved endothelium-dependent vasodilation of coronary microcirculation in patients with microvascular angina pectoris.

Acetylcholine↗
PubMed1996

Protein C activation in NIDDM patients.

Enhanced activation of the clotting system has been recently implicated in the pathogenesis of vascular complications in patients with diabetes mellitus. Abnormalities of the anticoagulant system may constitute a potential trigger factor for the haemostatic activation observed in diabetic subjects. The current study aimed to evaluate anticoagulant activity in diabetic patients by assessing the plasma levels of activated protein C-protein C inhibitor complex; and by measuring the anticoagulant response to exogenous thrombomodulin. This study comprised 61 patients (34 men, 27 women) with non-insulin-dependent diabetes mellitus (NIDDM) of whom 22 showed microalbuminuria and 39 normoalbuminuria. Data obtained in 31 non-obese and non-diabetic subjects were available for comparison. The plasma levels of fibrinogen (p < 0.02), prothrombin fragment 1 + 2 (p < 0.05), fibrin monomer (p < 0.0001), protein C antigen (p < 0.005), total protein S antigen (p < 0.02), soluble thrombomodulin (p < 0.005) and soluble E-selectin (p < 0.005) were significantly higher in diabetic patients than in healthy subjects. The plasma level of activated protein C-protein C inhibitor complex (7.4 +/- 3.8 vs 3.0 +/- 0.4 pmol/l) was significantly higher (p < 0.0001) and the anticoagulant response to exogenous thrombomodulin (23.4 +/- 2.6 vs 35.3 +/- 3.0 ng/ml) was markedly lower (p = 0.005) in all diabetic patients than in healthy subjects. Cases with microalbuminuria presented low plasma levels of activated protein C-protein C inhibitor complex (5.5 +/- 0.6 vs 8.6 +/- 0.7 pmol/l, p < 0.05) and significantly decreased values of the anticoagulant response to exogenous thrombomodulin (16.5 +/- 2.9 vs 23.4 +/- 2.6%, p = 0.03) as compared to those with normoalbuminuria. The present study suggests that the hyper-coagulable state in NIDDM is associated with an increased activation of protein C but with a poor plasma reactivity to the anticoagulant effect of thrombomodulin.

Adult↗
PubMed1996

Basal release of endothelium-derived nitric oxide at site of spasm in patients with variant angina.

OBJECTIVES: The aim of this study was to investigate the basal release of nitric oxide at spastic sites in patients with variant angina. BACKGROUND: We previously reported that endothelium-dependent dilator responses to acetylcholine, substance P and bradykinin are preserved at the site of coronary artery spasm. However, it is not known whether the basal release of endothelium-derived nitric oxide is altered at the spastic site. METHODS: The effects of intracoronary N(G)-monomethyl-L-arginine (L-NMMA, an inhibitor of nitric oxide synthesis) at cumulative doses of 50, 100 and 200 micromol on basal coronary artery tone were investigated in eight patients with variant angina and normal coronary angiograms and in eight control subjects. The lumen diameters of large epicardial coronary arteries were assessed by quantitative coronary arteriography. RESULTS: Coronary spasm was provoked by the intracoronary administration of acetylcholine in all patients with variant angina. L-NMMA did not alter the arterial pressure and heart rate but significantly decreased the coronary artery diameter at spastic and nonspastic sites. Constrictive responses to L-NMMA were significantly greater (p < 0.01) at the spastic site (constriction by 200 micromol, 22+/-7%, mean +/- SD) than at the nonspastic site (10+/-7%). Constrictive responses to L-NMMA at the nonspastic site in patients with variant angina were comparable to those in the control subjects. CONCLUSIONS: These findings support the hypothesis that the basal release of nitric oxide may not be decreased at the spastic site in patients with variant angina.

Aged↗
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↗