Hepatic arterial infusion chemotherapy with cisplatin before radical local treatment of early hepatocellular carcinoma (JIS score 0/1) improves survival.

BACKGROUND: It has not yet been determined whether hepatic arterial infusion (HAI) chemotherapy improves survival in patients with early hepatocellular carcinoma (HCC). We evaluated the effectiveness of HAI with high-concentration cisplatin (DDP-H) for the treatment of HCC by comparing outcomes between patients who received HAI with DDP-H before radical local treatment of early-stage HCC [Japan Integrated Staging (JIS) score 0/1] and patients who did not receive HAI chemotherapy. PATIENTS AND METHODS: Survival was analyzed in 114 patients with early-stage HCC who underwent radical local treatment. The patients were divided into two groups: a HAI group (n = 79) who received DDP-H infusion into the whole liver via the proper hepatic artery, and a non-HAI group (n = 35) who did not receive HAI chemotherapy. RESULTS: The cumulative survival rates at 1, 3, and 5 years were 77.4%, 69.2%, and 55.3% in the non-HAI group and 97.4%, 87.0%, and 84.4% in the HAI group, respectively. Survival time prolonged significantly in the HAI group compared with the non-HAI group (log-rank test: P = 0.023; generalized Wilcoxon test: P = 0.012) Multivariate analysis using the Cox proportional hazards model identified HAI with DDP-H as the most important factor affecting survival. CONCLUSIONS: Whole-liver HAI with DDP-H before radical local treatment can improve the prognosis of patients with early-stage HCC.

Expression of adrenomedullin and proadrenomedullin N-terminal 20 peptide in PC12 cells after exposure to nerve growth factor.

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are multi-functional peptides derived from the same precursor, proadrenomedullin. We have studied the regulatory mechanism of expression of these peptides during neuronal differentiation of rat pheochromocytoma PC12 cells by nerve growth factor (NGF). The cellular levels of the peptides increased slightly, and then progressively decreased below the control by NGF. Immunoreactive (ir)-AM in the medium was transiently increased by NGF. Cytochemical staining showed that ir-AM and ir-PAMP were abundantly present in cytoplasm in the undifferentiated cells, and were decreased during culture with NGF. There was no preferential localization of ir-AM or ir-PAMP in neurites in comparison with in cytoplasm in the differentiated cells. Northern blot analysis showed that mRNA encoding these peptides, as detected as a band of 1.6 kb, increased more than three-fold at 1 h after the addition of NGF and then progressively decreased to one fifth of the control during 72 h. Degradation rate of the mRNA was slowed by NGF even when mRNA level is decreased after 72 h of NGF treatment. The transcription rate of their gene increased transiently and then decreased by the long-term treatment with NGF. These results demonstrate that expression of AM and PAMP is regulated by NGF along with time-dependent differentiation: AM gene transcription is transiently activated by NGF, whereas it was suppressed during neuronal differentiation of the cells.

Expression and regulation of growth-regulated oncogene alpha in human endometrial stromal cells.

Growth-regulated oncogene alpha (GROalpha), a potent chemoattractant for neutrophils, has previously been detected in the endometrial stromal cells (ESC) of human endometrium. In this study, the mRNA expression of GROalpha in the endometrium was evaluated by reverse transcription-polymerase chain reaction analysis, while the localization of GROalpha protein was studied by immunohistochemistry and the concentrations of GROalpha were measured using an enzyme-linked immunosorbent assay (ELISA). The effects of known modulators of endometrial function on the production of GROalpha by ESC were also examined by ELISA and Northern blot analysis. The expression of both GROalpha mRNA and GROalpha protein was detected in the cycling endometrium. GROalpha protein was localized mainly in the stroma, and endometrial tissues in the secretory phase contained higher amounts of GROalpha protein than did those in the proliferative phase. The production of GROalpha by ESC was enhanced by in-vitro decidualization. Lipopolysaccharide, tumour necrosis factor-alpha and interleukin-1beta also stimulated the expression of GROalpha mRNA and protein by ESC. These results suggest that the production of GROalpha by ESC is regulated by ovarian steroid hormones as well as by inflammatory mediators. The modulation of GROalpha concentrations in the local environment may contribute to normal and pathological processes in the uterus by regulating leukocyte trafficking in the endometrium.

Adrenomedullin inhibits angiotensin II-induced expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat aortic endothelial cells.

Adrenomedullin (AM) is a potent vasodilating peptide having a variety of pharmacological properties mainly in respect to vascular pathophysiology. We have previously demonstrated that angiotensin II (Ang II) or natriuretic peptides have influence on the expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) in vascular endothelial cells. The aim of this study was to elucidate the effects of AM on TF and PAI-1 mRNA and protein expression in endothelial cells. As a result, AM inhibited Ang II-induced TF and PAI-1 mRNA expression in a dose- and time-dependent manner. Because the expression of TF and PAI-1 mRNA induced by Ang II was attenuated by the increase of intracellular concentrations of cAMP by forskolin and 8-bromo-cAMP and because AM increased the intracellular level of cAMP in rat aortic endothelial cells, it was indicated that the inhibitory effect of AM on the expressions of TF and PAI-1 was mainly mediated by the cAMP-dependent signal transduction. Furthermore, the inhibitory effect of AM on TF and PAI-1 expression was partly attenuated by an NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester. In conclusion, AM is shown to contribute to the regulation of blood coagulation and fibrinolysis by vascular endothelial cells mainly via the cAMP pathway.

Effects of platelet-activating factor on cytokine production by human uterine cervical fibroblasts.

Platelet-activating factor (PAF), a lipid that acts as a potent proinflammatory mediator, is involved in several reproductive processes including parturition. To investigate the effects of PAF on expression of various cytokines by cultured human uterine cervical fibroblasts obtained at term prior to labour, Northern blot analyses and enzyme-linked immunosorbent assays were performed. C-PAF, a stable analogue of PAF, increased expression of interleukin-6 and -8 mRNA in a dose-dependent manner (10(-10) to 10(-8) mol/l of C-PAF), and the expression peaked within 4 h. The corresponding protein concentrations were increased in culture media. Monocyte chemoattractant protein-1 mRNA showed marked induction by 10(-8) mol/l of C-PAF; this peaked by 4 h and was followed by an increase in the protein concentration. Another cytokine, RANTES (regulated upon activation, normal T cell expressed and secreted) showed marked mRNA induction by 10(-8) mol/l of C-PAF, and continued to increase in a time-dependent manner until 24 h. The protein concentration was correspondingly increased in the medium. The PAF-induced cytokine production was abolished by co-incubation with WEB 2170, a specific PAF receptor antagonist. PAF may stimulate local production of cytokines which may induce migration of leukocytes and accelerate collagenolysis in the uterine cervix, thus contributing to cervical ripening during parturition.

Optimal atrioventricular delay setting determined by evoked QT interval in patients with implanted stimulus-T-driven DDDR pacemakers.

Cardiac function is improved by optimizing the atrioventricular (AV) delay. An automatic optimizing function of AV delay may be necessary to achieve the most favourable haemodynamic state in paced patients. The QT interval may change when cardiac function is improved by optimizing the AV delay. The QT or stimulus-T interval is used as a sensor for rate-responsive pacemakers. Evoked (e) QT interval is measured as the time duration from the ventricular pace pulse (stimulus) and the T-sense point that is the steepest point of the intracardiac T wave (stimulus-T interval). The relationship between AV delay, eQT interval and cardiac function was studied in 10 patients (73 +/- 10 (SD) years old) with an implanted stimulus-T-driven DDDR pacemaker. Cardiac output (CO) and pulmonary capillary wedge pressure (PCWP) were measured by Swan-Ganz catheter. The AV delay was prolonged stepwise by 30 ms. Electrocardiogram event markers which indicated ventricular spike and sensed T wave were recorded, and the interval between two event markers was measured as eQT interval. When AV delay was changed from 240 ms to the AV delay at which CO was maximal (172 +/- 33 ms), eQT interval prolonged from 346 +/- 60 to 353 +/- 62 ms (P < 0.01). There was a significant positive correlation between the optimal AV delay at which CO was maximal (172 +/- 33 ms) and the optimal AV delay which was predicted from the maximum eQT interval (179 +/- 37 ms, r = 0.92, P < 0.001). When AV delay was changed from 240 ms to the predicted optimal AV delay, CO increased from 4.2 +/- 0.7 to 4.5 +/- 0.81.min-1 (P < 0.001) and PCWP was decreased from 7.1 +/- 4.0 to 5.7 +/- 3.1 mmHg (P < 0.05). In conclusion, the optimal AV delay can be predicted from the eQT interval which is sensed by an implanted pacemaker. Automatic setting of the optimal AV delay may be achieved by the QT sensor of an implanted pacemaker.

Serotonin induces the expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat aortic endothelial cells.

Serotonin (5-hydroxytryptamine, or 5-HT), released from activated platelets, not only accelerates aggregation of platelets but also is known to promote mitosis, migration, and contraction of vascular smooth muscle cells (VSMCs). These effects are considered to contribute to thrombus formation and atherosclerosis. The aim of this study was to investigate the effects of 5-HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells. Endothelial cells were stimulated with various concentrations of 5-HT (0.1 approximately 10 microM), and the expressions of tissue factor (TF), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (TPA) messenger RNAs (mRNAs) were evaluated by Northern blot analysis. The activities of TF and PAI-1 were also measured. TF and PAI-1 mRNA were increased significantly in a concentration- and time-dependent manner. However, TFPI and TPA mRNA expression did not change. The inductions of TF and PAI-1 mRNAs were inhibited by a 5-HT1/5-HT2 receptor antagonist (methiothepin) and a selective 5-HT2A receptor antagonist (MCI-9042). These results indicate that 5-HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5-HT2A receptor. It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5-HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation, VSMC contraction, and VSMC proliferation.

Effects of interleukin-4 on the in-vitro production of cytokines by human endometrial stromal cells.

A T helper (Th)1/Th2 model has been applied to as a system regulating the cytokine network during pregnancy. To evaluate the effects of interleukin (IL)-4, a Th2 cytokine, on the cytokine production by endometrial stromal cells (ESC), an enzyme-linked immunosorbent assay was used to measure the concentrations of IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and macrophage colony-stimulating factor (M-CSF) in the culture media of ESC and of an endometrial stromal sarcoma cell line, MaMi, following the addition of recombinant human IL-4. The expression of mRNAs for IL-6 and IL-8 in ESC after stimulation with IL-4 was also evaluated by Northern blot analysis. Increases in the concentrations of IL-6, IL-8, MCP-1, and M-CSF in the culture media of ESC and MaMi cells were observed on the addition of increasing amounts of IL-4. This cytokine also stimulated the transcription of IL-6 and IL-8 in ESC in a dose-dependent manner. It is suggested that IL-4 secreted by the maternal decidual tissue as well as by the developing embryo may stimulate the production of IL-6, IL-8, MCP-1, and M-CSF by ESC. The increased concentration of these cytokines in the local environment may contribute to the maintenance of early pregnancy by modulating the immune reaction at the feto-maternal interface.

Effect of ceramide analogs on interleukin-1alpha-induced production of prostaglandin E2 by amnion-derived (WISH) cells.

BACKGROUND: Prostaglandin E2 (PGE2) is reportedly synthesized in the amnion, and its levels are increased during labor. Our objective was to measure the level of PGE2 induced by interleukin (IL)-1alpha following treatment with ceramide analogs in amnion-derived cells. METHODS: Amnion-derived (WISH) cells were cultured and stimulated by IL-1alpha, IL-1 receptor antagonist (ra), C2-ceramide and C6-ceramide. The levels of PGE2 in the media were measured by ELISA. The induction of prostaglandin H synthase (PGHS)-2 mRNA was detected by reverse transcription and polymerase chain reaction (RT-PCR). RESULTS: Following stimulation with IL-1alpha, the production of PGE2 could not be detected until incubation had continued for 2 h, but this production appeared to continue after 4 h of incubation. The production of PGE2 was significantly increased by IL-1alpha, and was suppressed by IL-1 ra, in a dose-dependent manner. PGE2 production was significantly increased by IL-1alpha and C2-ceramide as compared with IL-1alpha alone. However, PGE2 production was not significantly increased by IL-1alpha and C6-ceramide as compared with IL-1alpha alone. PGHS-2 mRNA were induced by treatment with IL-1alpha, and were strongly induced by treatment with IL-1alpha and C2-ceramide by RT-PCR. CONCLUSIONS: Results suggest that IL-1alpha induce the PGHS-2 mRNA and stimulate the production of PGE2 by a mechanism that involves the sphingomyelin-ceramide system. Ceramide may be important in increasing the production of PGE2 during parturition.

Optimization of atrioventricular delay and follow-up in a patient with congestive heart failure with an implanted DDD pacemaker: case report.

It has been reported that cardiac function can be improved by implanting a DDD pacemaker (PM) and setting a short atrioventricular (AV) delay in patients with impaired cardiac function. A previous report found that the critical AV delay that induces diastolic mitral regurgitation (MR) may represent the upper limit of the optimal AV delay. The optimal AV delay can be predicted by a simple method: slightly prolonged AV delay minus the interval between the end of the atrial kick and complete closure of the mitral valve (duration of diastolic MR) at the AV delay setting. The patient was a 84-year-old man with an old myocardial infarction. He had repeated admissions to hospital for congestive heart failure. ECG showed prolongation of the PQ interval (0.28 s) and complete left bundle branch block. Cardiac function was improved by AV sequential pacing when the AV delay was set at 120ms. After DDD-PM implantation, the cardiothoracic ratio decreased from 57 to 45% and cardiac function was improved from New York Heart Association class III to I. The AV delay was optimized during follow-up. Four years after PM implantation, the patient was in good condition without further hospital admission.

Neurotrophic action of interleukin 3 and granulocyte-macrophage colony-stimulating factor on murine sympathetic neurons.

We investigated neurotrophic effects of interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on cultured sympathetic neurons obtained from mouse superior cervical ganglia. After 1 day of culture with physiological concentrations of mouse recombinant IL-3 and GM-CSF, the numbers of process-bearing neurons were increased. Maximum responses were elicited by 10 U/ml IL-3 and 1 U/ml GM-CSF, which were equivalent to the action of a submaximal dose (5 ng/ml) of nerve growth factor (NGF). The effects of IL-3 and GM-CSF were completely blocked by their corresponding antibodies, but not by anti-NGF, indicting their action is specific and completely independent of NGF. IL-3 and, to a lesser extent, GM-CSF were also able to protect NGF-differentiated neurons from apoptotic cell death caused by NGF withdrawal. The mitogen-activated protein (MAP) kinase signal transduction pathway is known to be involved in action of IL-3 and GM-CSF on hemopoietic cells, and thus we examined the participation of this pathway in the neurotrophic activities of IL-3 and GM-CSF. IL-3 and GM-CSF stimulation of the differentiated neurons was found to result in a rapid elevation of MAP kinase activity, and PD98059, an inhibitor of MAP kinase kinase activity, blocked both the neuritogenic and neuroprotective effects of IL-3 and GM-CSF. Immunocytochemical studies showed that IL-3 and GM-CSF receptors were present on the differentiated neurons. Thus, IL-3 and GM-CSF appear to be able to stimulate sympathetic nerve growth, via specific cytokine receptors on neurons, which lead to activation of the MAP kinase pathway that then mediates the observed neurotrophic effects.

Adrenomedullin inhibits spontaneous and bradykinin-induced but not oxytocin- or prostaglandin F(2alpha)-induced periodic contraction of rat uterus.

In isolated rat uterine strips, adrenomedullin (AM) inhibited the spontaneous periodic contraction in a concentration-dependent manner (IC(50)=22.3+/-0.7 nM). The inhibitory effect of AM was prevented by either AM(22-52), a putative antagonist for AM receptors, or calcitonin gene-related peptide (CGRP)(8-37), a putative antagonist for CGRP receptors. AM also attenuated bradykinin (BK)-induced periodic uterine contraction, which was blocked by AM(22-52) or CGRP(8-37), whereas AM had no effect on the periodic contraction caused by oxytocin or prostaglandin F(2alpha) (PGF(2alpha)). RT-PCR analysis showed that mRNAs for calcitonin receptor-like receptor (CRLR), receptor-activity-modifying protein (RAMP)1, RAMP2 and RAMP3 were expressed in the rat uterus. These results demonstrate that AM selectively inhibits spontaneous and BK-induced periodic contraction via activating receptors for AM and CGRP.

Production of interleukin (IL)-6 and IL-8 by a choriocarcinoma cell line, BeWo.

To clarify the biological and pathological features of choriocarcinoma, we evaluated the in vitro production of cytokines by a choriocarcinoma cell line, BeWo. We measured the concentration of interleukin (IL)-6 and IL-8 in the culture media of BeWo cells after stimulation with various modulatory agents of cytokine expression by enzyme-linked immunosorbent assays. Northern blot analysis was used to examine the expression of IL-6 and IL-8 mRNA in these cells. A weak expression of IL-6 and IL-8 was detected in unstimulated BeWo cells by both methods. IL-6 transcription and secretion were dose-dependently enhanced by stimulation with IL-1beta, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1 and 12-O-tetradecanoyl phorbol-13-acetate (TPA). Forskolin, lipopolysaccharide and interferon-gamma had no effect on these cytokines production. The TNF-alpha-induced secretion of IL-6 was inhibited by dexamethasone. The TPA-induced production of IL-6 was inhibited by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine and sphyngosine, suggesting the involvement of a protein kinase C-dependent pathway. Levels of IL-8 mRNA and protein were also dose-dependently increased by stimulation with IL-1beta, TNF-alpha and TPA. In contrast to IL-6, the expression of IL-8 was not affected by TGF-beta1. It is suggested that, in addition to the production of steroidal and non-steroidal hormones, these cytokines may serve as part of a cytokine network that modulates the proliferation and angiogenesis of choriocarcinomas.

Nuclear accumulation of p53 protein and apoptosis induced by various anticancer agents, u.v.-irradiation and heat shock in primary normal human skin fibroblasts.

Relationship between nuclear accumulation of p53 protein and apoptosis induced by both DNA damaging agents (ultraviolet-irradiation and anticancer agents) and heat shock in normal human skin fibroblasts was investigated. Nuclear accumulation of p53 protein and apoptosis were induced dose-dependently by u.v. -irradiation and anticancer agents. Regarding heat shock treatment, intensive nuclear accumulation of p53 protein was induced by treatment at 43 degrees C for 45 min, but, apoptotic cells were never detected. These results indicated that accumulation of p53 protein and apoptosis induced by DNA damaging agents were considered to have a close relationship and the functions of induced p53 protein are different depending on the stimulating factor.

Platelet-activating factor induces an imbalance between matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 expression in human uterine cervical fibroblasts.

Platelet-activating factor (PAF) is involved in such reproductive processes as parturition. We investigated the effect of PAF on the expression of matrix metalloproteinase-1 (MMP-1) and that of tissue inhibitor of metalloproteinases-1 (TIMP-1) in human uterine cervical fibroblasts. Uterine cervical tissue was obtained from patients who underwent cesarean section at term. Collagenase-dispersed fibroblasts were cultured and used in the experiments. PAF receptor was identified in the uterine cervical fibroblasts by use of reverse transcription-polymerase chain reaction and Southern blot analysis. Northern blot analysis showed that PAF increased the expression of MMP-1 mRNA in a time-dependent manner, whereas expression of TIMP-1 mRNA was not affected by PAF. Concentration of MMP-1 protein in the PAF-treated culture media significantly exceeded that in control cultures. The PAF-induced production of MMP-1 protein was abolished by treatment with WEB 2170, a specific PAF receptor antagonist. Results suggest that PAF may accelerate collagenolysis in the human uterine cervix by inducing an imbalance in the activity between MMP-1 and TIMP-1, thus contributing to the cervical ripening during parturition.

Role of hypothermia induced by tumor necrosis factor on apoptosis and function of inflammatory neutrophils in mice.

Changes in body temperature and cell infiltration, mediated by cytokines including tumor necrosis factor-alpha (TNF-alpha), occur during inflammation, but a role of body temperature on inflammatory responses remains obscure. Intraperitoneal injection of 10% casein to mice resulted in transient hypothermia followed by neutrophil accumulation in peritoneal cavities. Peritoneal TNF-alpha was rapidly raised, and pretreatment of mice with an anti-TNF-alpha antibody promoted temperature restoration and partially inhibited neutrophil accumulation. To investigate direct effects of body temperature on neutrophils, peritoneal or peripheral blood neutrophils were cultured at 35 degrees C or 37 degrees C with or without recombinant murine TNF-alpha (100 ng/ml) or a protein synthesis inhibitor cycloheximide (1 microg/ml). Significant inhibition of spontaneous and TNF-alpha-induced apoptosis was obtained at 35 degrees C compared with 37 degrees C, an effect that was not altered by the addition of cycloheximide. Moreover, phagocytic ability of peritoneal neutrophils was significantly enhanced by incubating them at the lower temperature. These results indicate that mild hypothermia induced by endogenous TNF-alpha has enhancing roles on neutrophil survival and function during peritoneal inflammation.

Sinus node recovery time assessment by the overdrive suppression test employing an intravenous injection of disopyramide phosphate.

Although sinus node recovery time (SNRT) assessment by the overdrive suppression test (ODST) is important in detecting sick sinus syndrome (SSS), its sensitivity is still inadequate. We have evaluated the effect of intravenous injection (i.v.) of disopyramide phosphate (DP) in ODST. The subjects were 30 SSS patients (64.9 +/- 10.0 years old). If SNRT was <2,000 ms or the corrected SNRT (CSNRT) was < 1,000 ms, ODST was repeated after DP i.v. (2 mg. kg(-1), < or = 100 mg in total). Eleven normal subjects (59.3 +/- 9.0 years old) were also studied. Although SNRT was <2,000 ms or the CSNRT was < 1,000 ms in 13 of the 30 SSS patients (43%), SNRT was prolonged from 1,510 +/- 300ms to 3,400 +/- 1,160 ms (P<0.01), and CSNRT from 510 +/- 190 to 2,470 +/- 1,470 ms (P<0.01) after DP i.v. in these patients. Thus, SNRT was > or = 2,000 ms and the CSNRT was > or = 1,000 ms in 27 of 30 SSS patients (90%) after DP i.v. Using a combination of overdrive suppression and intravenous injection of disopyramide phosphate, the corrected sinus node recovery time was diagnostic (>525 ms) in 29 of the 30 patients (97%). In contrast, SNRT and CSNRT were shortened in the normal subjects during ODST after DP i.v. (P<0.01). The plasma concentration of DP estimated in nine patients was 4.1 +/- 1.0 microg.ml(-1). No serious side effect occurred. ODST employing DP i.v. is safe and seems to be highly effective in diagnosing SSS.

Natriuretic peptides regulate the expression of tissue factor and PAI-1 in endothelial cells.

In the present study, we demonstrate that brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) interact with angiotensin II (Ang II) in regulative blood coagulation and fibrinolysis by suppressing the expressions of both tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) induced by Ang II. The expressions of TF and PAI-1 mRNA were analyzed by northern blotting methods, and the activities of TF on the surface of rat aortic endothelial cells (RAECs) and PAI-1 in the culture media were respectively measured by chromogenic assay. Both BNP and CNP suppressed the expressions of TF and PAI-1 mRNA induced by Ang II in a time- and concentration-dependent manner via cGMP cascade, which suppressions were accompanied by respective decrease in activities of TF and PAI-1. However, neither the expression of tissue factor pathway inhibitor (TFPI) nor tissue-type plasminogen activator (TPA) mRNA was affected by the treatment of BNP and CNP.

The effects of angiotensin metabolites on the regulation of coagulation and fibrinolysis in cultured rat aortic endothelial cells.

Not only angiotensin II (Ang II) but also other angiotensin metabolites such as angiotensin I (Ang I), angiotensin III (Ang III), angiotensin IV, or angiotensin 1-7 have recently been reported to have various activities. Few data, however, are available on the regulation of thrombus formation. In this study, we investigated the effects of angiotensin metabolites on the mRNA expression of tissue factor (TF), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and tissue type plasminogen activator (TPA) in cultured rat aortic endothelial cells. None of the used angiotensin metabolites altered TFPI or TPA mRNA expression levels. Ang I, Ang II, and Ang III made TF and PAI-1 mRNA inductions which were inhibited by an selective antagonist of angiotensin II type 1 receptors. These metabolites made TF predominant to TFPI or PAI-1 to TPA, and could render endothelial cells thrombogenic.

Prediction of optimal atrioventricular delay in patients with implanted DDD pacemakers.

In patients with an implanted DDD pacemaker (PM), the atrial contribution may be interrupted by too short an atrioventricular (AV) delay, and filling time may be shortened by too long an AV delay. The AV delay at which the end of the A wave on transmitral flow coincides with complete closure of the mitral valve may be optimal. The subjects were 15 patients [70.3+/-12.3 (SD) years old] with an implanted DDD PM. Cardiac output (CO) and pulmonary capillary wedge pressure (PCWP) were measured by Swan-Ganz catheter. Transmitral flow was recorded by pulsed Doppler echocardiography. AV delay was prolonged stepwise by 25 msc. When the AV delay was set at 155+/-26 ms, the end of the A wave coincided with complete closure of the mitral valve. When the AV delay was prolonged 25, 50, 75, and 100 ms from this AV delay, the interval between the end of the A wave and complete closure of mitral the valve was prolonged 16+/-5, 39+/-6, 65+/-4 and 88+/-5 ms, respectively (r = 0.97, P<0.0001) and diastolic mitral regurgitation was observed during this period. Thus, the optimal AV delay may be predicted as follows: the slightly prolonged AV delay minus the interval between the end of the A wave and complete closure of the mitral valve. When the AV delay was set at 215 ms, there was a significant positive correlation between the predicted optimal AV delay (166+/-23 ms) and the optimal AV delay (CO: 161+/-26 msec, r = 0.93, P<0.0001, PCWP: 161+/-28 msec, r = 0.95, P<0.0001). In conclusion, optimal AV delay can be predicted by this simple formula: slightly prolonged AV delay minus the interval between end of A wave and complete closure of mitral valve at the AV delay setting.