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Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by repetitive episodes of transient hemiplegia. Although autonomic nervous system dysfunction is believed to be associated with AHC, there are no reports of heart rate variability (HRV) in patients with AHC. In the current study, we analyzed HRV in a 20-year-old female with this disorder. The frequency of paralytic attacks have decreased since the patient was a teenager, compared to when she was < ten years old; however, as a 20-year-old, she still experiences paralytic attacks several times per month to more than ten times per month. Thus far, she has only suffered paralytic attacks and no epileptic seizures. Using Sanger sequencing, Gly947Arg (2839G>A) in the sodium-potassium (Na(+)/K(+))-ATPaseα3 subunit gene (ATP1A3) was confirmed from her blood sample. An elevated heart rate lasting one to two minutes and sometimes longer, was primarily observed at night while the patient was sleeping. Large fluctuations in HRV, including low- and high- frequency components, were primarily observed while the patient was sleeping but suppressed during paralytic attacks. These results confirm the presence of an autonomic nervous system disorder in AHC. Because large variation of the autonomic nervous function was observed at night, the pathophysiological function should be investigated for 24 hours.

Aim: Statins are effective in lowering cholesterol levels, but cause fatal rhabdomyolysis in susceptible individuals. Because it has been hypothesized that muscle damage could result from alterations in Ca2+ homeostasis in muscle cells, we tested whether measuring statin-induced changes in intracellular calcium ([Ca2+]i) is useful for predicting susceptibility to statin-muscle damage, using human CD19+ primary B lymphocytes.Methods: Statin-induced alterations in [Ca2+]i were studied using the human THP-1 cell line and CD19+ primary B lymphocytes. Changes in [Ca2+]i were measured directly in fluo-3- loaded cells using either single or dual-color flow cytometry.Results: The Ca2+ release study suggested that statin-induced changes in [Ca2+]i were due to Ca2+ release from ryanodine-sensitive Ca2+ stores and mitochondrial compartments. Further, statin users who experienced elevated creatine kinase (n=8) exhibited significantly greater statin-induced Ca2+ release in B cells than healthy volunteers (n=45) and statin users without elevated creatine kinase (n=16), while no difference was seen between the latter two groups.Conclusion: Statin-induced Ca2+ release from ryanodine-sensitive stores and mitochondria may contribute to myotoxicity. The laboratory test for Ca2+ release using CD19+ primary B lymphocytes may be useful to predict susceptibility to statin-induced muscle toxicity prior to statin use.

Inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) have been implicated in atherogenesis. However, the precise role of TNF-alpha in atherogenesis is still unclear. To examine the effect of TNF-alpha on atherogenesis, we generated compound-deficient mice in apolipoprotein E (apoE) and TNF-alpha (apoE-/-/TNF-alpha-/-) and compared them with apoE-/- mice. Although serum total cholesterol levels were markedly elevated in both apoE-/-/TNF-alpha-/- and apoE-/- mice compared to wild-type mice, no differences were observed between apoE-/-/TNF-alpha-/- and apoE-/- mice. The atherosclerotic plaque area in the aortic luminal surface of apoE-/-/TNF-alpha-/- mice (n=8, 3.1+/-0.4%) was significantly smaller than that of apoE-/- mice (n=7, 4.7+/-0.4%, p0.001) despite the lack of difference in serum cholesterol levels. The atherosclerotic lesion size in the aortic sinus of apoE-/-/TNF-alpha-/- mice (n=10, 5.1+/-0.3 x 10(5)microm(2)) was also significantly smaller than that of apoE-/- mice (n=11, 7.0+/-0.3 x 10(5)microm(2), p0.0001). RT-PCR analysis indicated that the expression levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) were significantly higher in apoE-/- than apoE-/-/TNF-alpha-/- mice. Macrophages from apoE(-/-) mice showed higher uptake level of oxidized LDL and increased expression level of scavenger receptor class A (SRA) compared to those from apoE-/-/TNF-alpha-/- mice. These results indicate that TNF-alpha plays an atherogenic role by upregulating the expressions of ICAM-1, VCAM-1 and MCP-1 in the vascular wall, and by inducing SRA expression and oxidized LDL uptake in macrophages.

The actions of tumor necrosis factor-alpha (TNF-alpha) produced by resident brain cells and bone marrow-derived cells in brain following a transient global ischemia were evaluated. In wild-type mice (C57Bl/6J) following 20 min ischemia with bilateral common carotid artery occlusion (BCCAo), TNF-alpha mRNA expression levels in the hippocampus were significantly increased at 3 h and 36 h and exhibited a biphasic expression pattern. There were no hippocampal TNF-alpha mRNA expression levels at early time points in either wild-type mice bone marrow transplanted (BMT)-chimeric-TNF-alpha gene-deficient (T/W) or TNF-alpha gene-deficient mice BMT-TNF-alpha gene-deficient mice (T/T), although TNF-alpha mRNA levels were detectable in T/W BMT mice at 36 h. Histopathological findings showed no intergroup differences between wild-type and TNF-alpha gene-deficient mice at 4 and 7 days after transient ischemia. In addition, nuclear factor-kappaB (NF-kappaB) was activated within 12 h after global cerebral ischemia, but electrophoretic mobility shift assays (EMSA) showed no intergroup differences between wild type and TNF-alpha gene-deficient mice. In summary, early hippocampal TNF-alpha mRNA expression may not be related to bone marrow-derived cells, and secondary TNF-alpha expression as early as 36 h after ischemia probably resulted mainly from endogenous brain cells and possibly a few bone marrow-derived cells. Although we cannot exclude the possibility of the TNF-alpha contribution to the physiologic changes of hippocampus after transient global ischemia, these results indicate that TNF-alpha does not influence the morphological changes of the hippocampal neurons under our study condition.

Increases in quinolinic acid (QUIN), a neurotoxic l -tryptophan metabolite, have been observed in human serum and cerebrospinal fluid and in animal models of severe hepatic injury. The aim of this study was to evaluate the changes in QUIN accumulation and its related enzymes after acute hepatic injury induced by d -galactosamine and endotoxin. Gerbils were given an intraperitoneal injection of pyrogen-free saline alone as control, lipopolysaccharide (LPS) alone (150 ng/kg), d -galactosamine alone (500 mg/kg) or a combination of d -galactosamine with LPS. Concentrations of QUIN, its related metabolites, and related enzyme activities were determined. d -Galactosamine treatment significantly decreased activities of hepatic aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) resulting in increased QUIN concentrations in serum and tissues. The magnitude of QUIN responses was markedly increased by endotoxin due to the increased availability of l -kynurenine, a rate-limiting substrate for QUIN synthesis. Further, infiltration of monocytes/macrophages, which is a possible major source of QUIN production in the liver, was shown by immunohistochemistry after hepatic injury induced by d -galactosamine and endotoxin. Increased serum QUIN concentrations are probably due to the increased substrate availability and the decreased activity of aminocarboxymuconate-semialdehyde decarboxylase in the liver, accompanying the increased monocyte/macrophage infiltration into the liver after hepatic injury.

BACKGROUND We evaluated the role of IFN-gamma produced by bone marrow-derived cells in atherogenesis in LDLR(-/-) mice using bone marrow transplantation (BMT). METHODS AND RESULTS We generated IFN-gamma-deficient bone marrow transplanted LDLR(-/- )mice (IFN-gamma(-/-) BMT mice), and compared them with controls (IFN-gamma(+/+) BMT mice). These mice were fed a high-fat diet (HFD). Plasma total cholesterol and triglyceride levels did not differ between these two groups. After 6 weeks of HFD feeding, the atherosclerotic lesions of IFN-gamma(-/-) BMT mice were larger than those of IFN-gamma(+/+) BMT mice at the aortic sinus, aortic arch and abdominal aorta. After 12 weeks of HFD feeding, the significant differences between the two groups disappeared except for the atherosclerotic lesion in the aortic sinus. MOMA2, CD4, CD8 or alpha-smooth muscle actin-positive cells were detected in the atherosclerotic lesions. The cellular composition of the lesions was identical between the two groups, but the cellular density showed decreased concomitant with the increased extracellular matrix deposition in IFN-gamma(-/- )BMT mice. CONCLUSIONS These findings demonstrate that IFN-gamma produced by bone marrow-derived cells delays the progression of atherosclerosis without any effect on plasma lipids, and this suppression may be due to decreased extracellular matrix deposition.

Both the role and source of tumor necrosis factor (TNF-alpha) in lipopolysaccharide (LPS)-induced nasal inflammation were investigated using TNF-alpha gene deficient (TNF-alpha -/-) mice and chimeric mice that are TNF-alpha gene deficient only in bone marrow-derived cells. In the present study, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mRNA expression levels in the nasal mucosa were significantly decreased following intranasal instillation of LPS in TNF-alpha gene deficient mice compared to those in wild type mice. In contrast, ICAM-1 and VCAM-1 mRNA expressions were not significantly decreased although TNF-alpha mRNA expression was dramatically decreased in TNF-alpha gene deficient bone marrow-transplanted-chimeric (TNF-alpha -/---+/+) mice compared to those in wild type bone marrow-transplanted-control (TNF-alpha +/+--+/+) mice. These results indicate that the elevation of TNF-alpha mRNA in the nasal mucosa is mainly originated from bone marrow-derived cells. However, even low expression of TNF-alpha at local inflammation sites is sufficient to induce the expression of adhesion molecules in acute LPS-induced experimental rhinitis.

l-Tryptophan degradation by indoleamine 2,3-dioxygenase (IDO) might have an important role in gamma interferon (IFN-γ)-induced antimicrobial effects. In the present study, the effects ofToxoplasmagondiiinfection on IDO were investigated by using wild-type and IFN-γ-gene-deficient (knockout) (IFN-γ KO) mice. In wild-type C57BL/6J mice, enzyme activities and mRNA levels for IDO in both lungs and brain were markedly increased and lungl-tryptophan concentrations were dramatically decreased followingT.gondiiinfection. In contrast, these metabolic changes did not occur inT.gondii-infected IFN-γ KO mice or in uninfected IFN-γ KO mice. The levels of inducible nitric oxide synthase (iNOS) induction in infected IFN-γ KO mice were high in lungs and low in brain compared to those in infected wild-type mice. The extent of increased mRNA expression ofT.gondiisurface antigen gene 2 (SAG2) induced in lungs and brain byT.gondiiinfection was significantly enhanced in IFN-γ KO mice compared to wild-type mice on day 7 postinfection. Treatment withN-nitro-l-arginine methyl ester, an iNOS inhibitor, increased the levels of SAG2 mRNA in brain but not in lungs and of plasmal-kynurenine afterT. gondiiinfection. This in vivo study provides evidence thatl-tryptophan depletion caused byT. gondiiis directly mediated by IFN-γ in the lungs, where iNOS is not induced by IFN-γ. This study suggests that there is an antitoxoplasma mechanism of cross-regulation between iNOS and IDO and that the expression of the main antiparasite effector mechanisms for iNOS and/or IDO may vary among tissues.

Apolipoproteins in the cerebrospinal fluid (CSF) play important roles in lipid metabolism in the central nervous system. Although it has been demonstrated that apo E is synthesized in the neuron, the synthesis of apo A-I has only been determined in fish and chicken. It was demonstrated that apo A-I concentrations in the CSF were increased in poliovirus-infected macaques, however, the origin of the CSF apo A-I was not determined. The present immunohistochemical study provided evidence that apo A-I was localized within the nerve cell body of the rat spinal cord. In situ hybridization also showed that apo A-I mRNA was predominantly expressed in the neurons. As a further experiment, we compared apo A-I levels in the spinal cord from control rats and rats with experimental allergic encephalomyelitis (EAE), which was induced by sensitization with myelin basic protein. Although no significant changes in serum apo A-I levels were observed, apo A-I levels in the spinal cord were significantly elevated in EAE rats. Furthermore, apo A-I in the spinal cord of rats with EAE was not seen in the nerve cell body, but at the interstitium, particularly in lesions where inflammation had occurred. The current study clearly demonstrated that apo A-I is synthesized in the neurons of the rat spinal cord and the synthesis was suppressed in EAE rats.

Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the L-tryptophan-kynurenine pathway, which converts an essential amino acid, L-tryptophan, to N-formylkynurenine. It has been speculated that IFN-γ is a dominant IDO inducer in vivo. The present study used IFN-γ or TNF-α gene-disrupted mice and IFN-γ antibody-treated mice to demonstrate that lipopolysaccharide (LPS)-induced systemic IDO is largely dependent on TNF-α rather than IFN-γ. IFN-γ-independent IDO induction was also demonstrated in vitro with LPS-stimulated monocytic THP-1 cells. These findings clearly indicate that there is an IFN-γ-independent mechanism of IDO induction in addition to the IFN-γ-dependent mechanism.

Background —It has been reported that tumor necrosis factor-α (TNF-α) is expressed in the heart with viral myocarditis and that its expression aggravates the condition. The pathophysiological effects of TNF-α on viral myocarditis, however, have not been fully elucidated. Methods and Results —To investigate the role of TNF-α in the progression of viral myocarditis, we used TNF-α gene–deficient mice (TNF-α −/− ) and induced acute myocarditis by infection with encephalomyocarditis virus (EMCV). The survival rate of TNF-α −/− mice after EMCV infection was significantly lower than that of TNF-α +/+ mice (0% versus 67% on day 14). Injection of recombinant human TNF-α (0.2 to 4.0 μg/mouse IV) improved the survival of TNF-α −/− mice in a dose-dependent manner, indicating that TNF-α is essential for protection against viral myocarditis. The levels of viral titer and viral genomic RNA of EMCV in the myocardium were significantly higher in TNF-α −/− than in TNF-α +/+ mice. Histopathological examination showed that the inflammatory changes of the myocardium were less marked in TNF-α −/− than in TNF-α +/+ mice. Immunohistochemical analysis revealed that the levels of immunoreactivity of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the myocardium were decreased in TNF-α −/− mice compared with TNF-α +/+ mice. Conclusions —These observations suggested that TNF-α is necessary for adhesion molecule expression and to recruit leukocytes to inflammatory sites, and thus, the lack of this cytokine resulted in failure of elimination of infectious agents. We concluded that TNF-α plays a protective role in the acute stage of viral myocarditis.

Bronchial asthma is associated with abnormal autonomic nervous function in childhood. Exercise is one of the most common precipitating factors of acute asthmatic crises although the exact mechanism of autonomic regulation in asthmatic children after exercise is unclear.The aim of this study was to investigate the features of autonomic regulation after exercise in asthmatic and control children.Pulmonary function tests and heart rate variability spectral analysis were performed in 15 asthmatic children and 7 control children (age 6 to 15 years) during and after an exercise challenge.The maximum % fall of forced expiratory volume in 1 second (FEV1) was significantly greater (P.01) in asthmatic subjects (9.1 +/- 5.1%) than in normal control subjects (1.0 +/- 2.5%). The high frequency band (HF) amplitude, an index of cardiac vagal tone, 5 minutes after exercise was significantly higher (P.05) in the asthmatic subjects (14.4 +/- 7.9 msec) than in control subjects (5.9 +/- 2.6 msec). Furthermore, the difference in the HF amplitude between the control group and the exercise-induced asthma group was significant both 5 minutes (P.01) and 10 minutes (P.05) after challenge. There was a significant correlation (P = .565, P = .0165) between HF amplitude 5 minutes after exercise and the magnitude of the decrease in FEV1. On the other hand, no significant difference was observed in the low frequency band amplitude between the controls and the asthmatic subjects. The ratio of low frequency to high frequency power, which is suggested to correlate with cardiac sympathetic activity, did not differ between the two groups.These findings suggest that autonomic nervous activities, particularly vagal response after exercise, in asthmatic children is different from that in control children.

To define the coupling mechanism between cardiac load and the rate of protein synthesis, changes in the extent of eIF-4E phosphorylation were measured after imposition of a load. Electrically stimulated contraction of adult feline cardiocytes increased eIF-4E phosphorylation to 34% after 4 h, as compared with 8% phosphorylation in quiescent controls. However, eIF-4E phosphorylation did not increase upon electrical stimulation in the presence of 7.5 mM 2,3-butanedione monoxime, an inhibitor of actin-myosin cross-bridge cycling and active tension development. Treatment of adult cardiocytes with either 0.1 μM insulin or 0.1 μM phorbol 12-myristate 13-acetate increased eIF-4E phosphorylation to 23 and 64%, respectively, but these increases were not blocked by 2,3-butanedione monoxime. In canine models of acute hemodynamic overload in vivo, eIF-4E phosphorylation increased to 23% in response to left ventricular pressure overload as compared with 7% phosphorylation in controls. Acute volume overload had no effect on eIF-4E phosphorylation. These changes in eIF-4E phosphorylation account for differences in anabolic responses to acute pressure versus acute volume overload. These data suggest that eIF-4E phosphorylation is a mechanism by which increased cardiac load is coupled to accelerated rates of protein synthesis.

Background: Recent studies have focused on whether different hepatitis C virus (HCV) genotypes are associated with different profiles of pathogenicity, infectivity, and response to antiviral therapy. We needed to develop a convenient screening test for HCV genotypes 1 and 2. Method: We tested 55 patients with known chronic HCV infection. Viral RNA was extracted from serum samples using an automatic viral RNA purification system, and HCV genotypes were determined by reverse transcriptase-polymerase chain reaction using LightCycler melting curve analysis with SYBR Green I. Results: HCV RNA was detected in all samples and each genotype was determined. The mean (standard deviation) melting temperatures for subtypes 1b ( n = 32), 2a ( n = 15) and 2b ( n = 8) were 93.14°C (0.51°C), 91.08°C (0.49°C) and 91.77°C (0.27°C), respectively. Genotypes 1 and 2 were differentiated within 3 h by this method. Conclusions: Our melting curve analysis is a rapid and convenient screening test for differential identification of HCV genotypes 1 and 2.

In anesthetized open-chest dogs, an intravenous bolus injection of endothelin-1 (ET-1, 400 pmol/kg) caused transient hypotension (initial hypotensive phase; phase 1), followed by a continuous elevation of blood pressure (late hypertensive phase; phase 2). The constriction and dilation of the systemic capacitance and resistance vessels were evaluated from the change in mean circulatory pressure (MCP) and in total peripheral resistance (TPR) in phases 1 and 2. To examine the modification of the action of ET-1 on the blood vessels by the baroceptor reflex or by the endothelium-derived relaxing factor (EDRF) released by ET-1 in phase 1, we performed experiments in dogs under total spinal anesthesia (TSA group), methylene blue-treated dogs (MB group) as well as in the untreated dogs (control group). ET-1 decreased the TPR significantly, and increased the MCP significantly in phase 1 in the control (n = 8) and TSA (n = 8) groups; there was no difference between the groups. ET-1 had no significant effect on TPR but increased the MCP significantly in MB group (n = 8) during phase 1. The percentage increase of MCP in the MB group significantly exceeded that of the control group. ET-1 increased both the TPR and MCP significantly in phase 2 in the control group (n = 8). This study indicated that the vasoconstrictor action of ET-1 on the systemic capacitance vessels in phase 1 did not result from a baroceptor reflex, and that the vasodilator action of ET-1 on the systemic resistance vessels may be at least in part mediated via EDRF released by ET-1. We suggest that the vasoconstrictor action of ET-1 on the systemic capacitance vessels is strong, but the vasodilator action of EDRF on the systemic capacitance vessels is weak.

To investigate the effect of milrinone (MIL) on systemic capacitance vessels, we measured the mean circulatory filling pressure (MCP) in anesthetized open chest dogs. We measured hemodynamic parameters (a) at baseline blood volume (BV), (b) immediately after bloodletting (5 ml/kg), and (c) immediately after dextran injection (5 ml/kg). These measurements were taken in a control group (n = 8) and in a MIL group (n = 8), where MIL (100 + 2.5 micrograms/kg/min) was administered i.v. The extra volume (EV) was obtained by extrapolating the straight line that was fit to the MCP-BV plot. MIL significantly decreased the EV, from 22.8 +/- 1.0 to 19.1 +/- 0.4 ml/kg, indicating that MIL dilates the systemic capacitance vessels. MIL shifted the right ventricular output curve to the left and upward and shifted the venous return curve to the left and rotated it clockwise. Thus, venous return was increased by decreasing the resistance to venous return and by improving right ventricular pump function. Next we evaluated the effects of MIL (100 micrograms/kg) on systemic capacitance and resistance vessels from changes seen in the MCP and the total peripheral resistance (TPR), respectively. In the untreated dogs, MIL decreased TPR significantly without affecting MCP. In dogs pretreated with total spinal anesthesia or phenoxybenzamine, MIL significantly decreased both MCP and TPR. This suggests that the intrinsic venodilator action of MIL is modified by the baroreflex in untreated animals. MIL decreased the MCP and TPR elevated previously by norepinephrine. One would, therefore, predict that MIL would dilate the systemic capacitance vessels in patients with congestive heart failure.

Statins are effective in lowering cholesterol levels, but cause fatal rhabdomyolysis in susceptible individuals. Because it has been hypothesized that muscle damage could result from alterations in Ca(2+) homeostasis in muscle cells, we tested whether measuring statin-induced changes in intracellular calcium ([Ca(2+)](i)) is useful for predicting susceptibility to statin-muscle damage, using human CD19+ primary B lymphocytes.Statin-induced alterations in [Ca(2+)](i) were studied using the human THP-1 cell line and CD19+ primary B lymphocytes. Changes in [Ca(2+)](i) were measured directly in fluo-3- loaded cells using either single or dual-color flow cytometry.The Ca(2+) release study suggested that statin-induced changes in [Ca(2+)](i) were due to Ca(2+) release from ryanodine-sensitive Ca(2+) stores and mitochondrial compartments. Further, statin users who experienced elevated creatine kinase (n=8) exhibited significantly greater statin-induced Ca(2+) release in B cells than healthy volunteers (n=45) and statin users without elevated creatine kinase (n=16), while no difference was seen between the latter two groups.Statin-induced Ca(2+) release from ryanodine-sensitive stores and mitochondria may contribute to myotoxicity. The laboratory test for Ca(2+) release using CD19+ primary B lymphocytes may be useful to predict susceptibility to statin-induced muscle toxicity prior to statin use.

Background Ovalbumin, ovomucoid, ovotransferrin, lysozyme, and ovomucin are known to be major allergens found in egg white. Egg white protein is composed of over 30 proteins; many of which have neither been identified nor their allergenicities characterized. This study set out to analyze whether unknown proteins that bind to IgE antibodies in serum from patients with egg allergy exist in egg white. Methods Diluted egg white proteins were separated by 2-dimensional (2-D) gel electrophoresis. Immunolabeling was performed on individual patient sera from 19 child patients with egg white allergy and 11 negative control subjects. Spots of egg white proteins that bound to the patients' IgE were identified by mass spectrometry-based proteomics. Results Egg white proteins were separated into 63 spots. Twenty-five of the 63 reacted with egg allergy patients' sera, and 10 of the 25 reactive spots showed IgE-reactivity to controls as well. Specific bindings to the IgE from egg allergy patients were found in 15 spots; one of which was confirmed as ovotransferrin. Among the other 14 protein spots, egg white cystatin and lipocalin-type prostaglandin D synthase (L-PGDS) were newly identified proteins that reacted with IgE in patients with egg allergy. Conclusions We demonstrated that L-PGDS and cystatin reacted with serum IgE in patients with egg allergy. Our proteomics-based analysis in egg white gives a comprehensive map of proteins bound with IgE and should assist in enabling more accurate diagnoses and recommendations of desensitizing treatments for individual patients.

We investigated the vasodilator effects of captopril (CAP) on the systemic capacitance and resistance vessels by measuring changes in the mean circulatory pressure (MCP) and total peripheral resistance (TPR) that occurred in response to the intravenous injection of CAP (1 mg/kg) in open-chest dogs. The following five groups of dogs received CAP: (1) Group of untreated dogs, (2) TSA Group in which the dogs were subjected to total spinal anesthesia (TSA), (3) Ang II Group in which the dogs received a continuous intravenous infusion of angiotensin II (Ang II), (4) APR + Ang II Group in which the dogs received a continuous intravenous infusion of Ang II after pretreatment with aprotinin (APR, 25,000 K.I.E.), a kallikrein inhibitor, and (5) IND + APR + Ang II Group in which the dogs received a continuous intravenous infusion of Ang II after pretreatment with indomethacin (IND, 5 mg/kg), a prostaglandin synthesis inhibitor, and APR. 1) CAP significantly decreased TPR and MCP in the untreated Group. 2) CAP significantly decreased TPR and MCP in the TSA Group. There were no significant differences in percentage change of TPR (% delta TPR) and percentage change of MCP (% delta MCP) between the untreated and TSA Groups. 3) In the Ang II Group, CAP decreased the elevated TPR significantly, but hardly affected the elevated MCP. 4) CAP significantly decreased TPR without significant change in MCP in the APR + Ang II Group. The % delta TPR was significantly smaller in this Group than in the Ang II Group. 5) CAP significantly decreased TPR without significant change in MCP in the IND + APR + Ang II Group.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the presence of alpha-adrenoceptor subtypes in systemic capacitance vessels by examining the effects of alpha 1- and alpha 2-agonists or antagonists on the mean circulatory pressure (MCP). Dogs were anesthetized with pentobarbital, and after total spinal anesthesia, epinephrine was given intravenously to maintain mean blood pressure at about 80 mmHg. 1. With intravenous injection of phenylephrine (alpha 1-agonist, 10 micrograms/kg, n = 7), and of BHT 920 (alpha 2-agonist, 5 micrograms/kg, n = 7), MCP increased significantly from 9.8 +/- 0.4 (mean +/- SE) to 10.9 +/- 0.3 mmHg (+11.2%, p less than 0.01), and from 9.3 +/- 0.4 to 10.3 +/- 0.4 mmHg (+10.8%, p less than 0.05), respectively. 2. Intravenous injection of prazosin (alpha 1-antagonist, 150 micrograms/kg, n = 7) and of yohimbine (alpha 2-antagonist, 30 micrograms/kg, n = 7) decreased MCP significantly from 9.9 +/- 0.4 to 8.2 +/- 0.5 mmHg (-17.2%, p less than 0.01), and from 9.8 +/- 0.2 to 7.6 +/- 0.3 mmHg (-22.4%, p less than 0.01), respectively. 3. Intravenous injection of phenylephrine (10 micrograms/kg, n = 7) after pretreatment with prazosin (150 micrograms/kg) decreased MCP significantly from 9.5 +/- 0.3 to 7.8 +/- 0.3 mmHg (-17.9%, p less than 0.01). MCP decreased significantly from 9.9 +/- 0.3 to 8.2 +/- 0.3 mmHg (-17.2%, p less than 0.01) after intravenous injection of BHT 920 (5 micrograms/kg, n = 7) following pretreatment with yohimbine (30 micrograms/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

We examined autonomic nerve function in patients with systemic scleroderma (SSc) using power spectral analysis of heart rate variability. In the SSc group, both in nighttime (0:00a.m.-5:00a.m.) and daytime (10:00a.m.-5:00p.m.), HF elements, a parasympathetic nerve index, were lower and LF/HF ratios, a sympathetic nerve index, were higher than in the control group. This suggests that in SSc patients, sympathetic nerve activity was increased and parasympathetic nerve activity was decreased throughout the day.

The actions of tumor necrosis factor-alpha (TNF-alpha) produced by resident brain cells and bone marrow-derived cells in brain following a transient global ischemia were evaluated. In wild-type mice (C57Bl/6J) following 20 min ischemia with bilateral common carotid artery occlusion (BCCAo), TNF-alpha mRNA expression levels in the hippocampus were significantly increased at 3 h and 36 h and exhibited a biphasic expression pattern. There were no hippocampal TNF-alpha mRNA expression levels at early time points in either wild-type mice bone marrow transplanted (BMT)-chimeric-TNF-alpha gene-deficient (T/W) or TNF-alpha gene-deficient mice BMT-TNF-alpha gene-deficient mice (T/T), although TNF-alpha mRNA levels were detectable in T/W BMT mice at 36 h. Histopathological findings showed no intergroup differences between wild-type and TNF-alpha gene-deficient mice at 4 and 7 days after transient ischemia. In addition, nuclear factor-kappaB (NF-kappaB) was activated within 12 h after global cerebral ischemia, but electrophoretic mobility shift assays (EMSA) showed no intergroup differences between wild type and TNF-alpha gene-deficient mice. In summary, early hippocampal TNF-alpha mRNA expression may not be related to bone marrow-derived cells, and secondary TNF-alpha expression as early as 36 h after ischemia probably resulted mainly from endogenous brain cells and possibly a few bone marrow-derived cells. Although we cannot exclude the possibility of the TNF-alpha contribution to the physiologic changes of hippocampus after transient global ischemia, these results indicate that TNF-alpha does not influence the morphological changes of the hippocampal neurons under our study condition.

Background: Pre-β1-HDL participates in a cyclic process involved in the retrieval of cholesterol from peripheral tissues. Although pre-β1-HDL can be measured by two-dimensional electrophoresis or crossed immunoelectrophoresis, these methods are time-consuming and require technical expertise. In this study, we separated plasma lipid-poor apolipoprotein A-I (apo A-I) by high-performance size-exclusion chromatography.Methods: We measured plasma lipid-poor apo A-I in 20 male patients with coronary artery disease [CAD; mean (SD) age, 64.0 (18) years] and 15 male controls [54.7 (17) years] and in 7 female CAD patients [70.3 (7.7) years] and 9 female controls [65.1 (4.7) years].Results: Lipid-poor apo A-I was most stable when stored at −80 °C in the presence of aprotinin (final concentration, 50 kIU/L). The lipid-poor apo A-I concentration decreased during incubation at 37 °C, and this was not prevented by the addition of 2 mmol/L of the lecithin:cholesterol acyltransferase (LCAT) inhibitor 5,5′-dithiobis(2-nitrobenzoic acid). Lipid-poor apo A-I was significantly higher in CAD patients than in controls [38.3 (7.9) mg/L for male CAD patients vs 29.3 (7.3) mg/L for male controls; 43.3 (11) mg/L for female CAD patients vs 27.1 (7.4) mg/L for female controls (P Conclusions: Although the production of lipid-poor apo A-I in plasma is not fully understood, our results indicate that lipid-poor apo A-I could be used as a marker for arteriosclerosis and demonstrate that it is not identical to the pre-β1-HDL measured by other methods.

The purpose of this study is to evaluate the cardiovascular function in patients with incomplete type of SSc (SSSD; Scleroderma Sjögren syndrome associated Spectrum Disorders), SSc (Systemic Scleroderma) and SLE (Systemic Lupus Erythematosus) by using ECG and digital plethysmograph. We also preformed ambulatory ECG monitoring for cases of SSSD and SSc with QT interval prolongation. 1) In ECG findings, ischemic myocardial damage, left ventricular hypertrophy or QT interval prolongation was observed in 33% cases of SSSD and 32% cases of SSc, respectively. In addition, parasympathetic disorders were observed in approximately 20% cases of SSSD, SSc and SLE. 2) Digital plethysmogram findings suggested that the peripheral vascular damage was present in both cases of SSSD and SSc, and its severity was lower in SSSD than SSc. The incidence of abnormal cardiovascular function tests in SSSD was relatively less than that in SSc. The cardiovascular function tests are useful to find cardiovascular abnormalities in these collagen diseases.

Detection of the HCV genome is crucial for diagnosis of HCV infection and for monitoring the efficacy of interferon treatment for patients with HCV. We developed a convenient screening test for HCV genotypes 1 and 2 based on the melting curve analysis with SYBER green I. Serum samples were drawn from 114 patients with known chronic HCV infection confirmed to be antibody-positive by immunoblot assay. A characteristic melting profile for each genotype was obtained by monitoring the fluorescence as the temperature increases through the melting point of the PCR product. Serum samples with HCV-RNA genotype (1b, 2a and 2b) were analyzed every test as standard samples and the genotype of unknown samples was determined by the comparison with the melting point of standard samples. Serum samples with known HCV-RNA genotype (1b, 2a and 2b) and HCV-RNA-negative sample were tested using the Light cycler system. The melting curve analysis indicated that melting points are 93.08 +/- 0.56 degrees C for genotype 1b (n = 63), 91.08 +/- 0.49 degrees C for genotype 2a (n = 33), and 91.77 +/- 0.28 degrees C for genotype 2b (n = 18). The melting points for genotypes 1b, 2a, and 2b differed by approximately 1 degree C in each other. The genotype was determined for all samples using Okamoto's method and Light cycler system, and both systems produced absolutely identical results for all the samples studied. Sixty-three of 114 were genotype 1b, 33 samples were genotype 2a, and 18 were genotype 2b. This melting curve analysis is a rapid and convenient screening test for differentiation of HCV genotypes 1 and 2.

Allergic rhinitis is an inflammation involving T(H)2-type cytokine production, with pathologic eosinophil infiltration in the nasal mucosa. Although TNF-alpha is thought to be a pro-inflammatory cytokine, the relationship between TNF-alpha and allergic rhinitis has not been clarified.The role of TNF-alpha in a murine model of ovalbumin (OVA)-sensitized allergic rhinitis was investigated by using mice deficient in the gene encoding TNF-alpha (TNF-alpha(-/-) mice).Both wild-type (TNF-alpha(+/+)) and TNF-alpha(-/-) mice were sensitized with OVA by means of intraperitoneal injection. They were then challenged with intranasal OVA, and various allergic responses were assessed.The production of OVA-specific IgE in the serum (P.05) and the frequency of sneezes (P.05) and nasal rubs (P.05) decreased significantly in TNF-alpha(-/-) mice after OVA sensitization compared with that in TNF-alpha(+/+) mice (P.05). The mRNA expression of IL-4, IL-10, and eotaxin in nasal mucosa in TNF-alpha(-/-) mice was also significantly suppressed compared with that in TNF-alpha(+/+) mice after OVA sensitization (P.05). Furthermore, the expression of both endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 mRNA in the nasal mucosa was significantly suppressed (P.05), although intercellular adhesion molecule 1 mRNA expression did not decrease significantly in TNF-alpha(-/-) mice compared with that in TNF-alpha(+/+) mice after OVA sensitization. In addition, the effect of TNF-alpha on endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 expression by means of Western blot analysis was compatible with the mRNA results. Pathologically, eosinophil infiltration in nasal mucosa was significantly restricted in TNF-alpha(-/-) mice compared with in TNF-alpha(+/+) mice after OVA sensitization (P.05).TNF-alpha is necessary for antigen-specific IgE production and for the induction of T(H)2-type cytokines and chemokines. Furthermore, TNF-alpha might be important for the expression of adhesion molecules to recruit eosinophils to the allergic inflammatory site. We conclude that the lack of TNF-alpha inhibited the development of allergic rhinitis.

We determined serum metalloproteinase-3(MMP-3) and inflammatory cytokine(IL-6, IL-8) levels in patients with rheumatoid arthritis(RA). Sera were obtained from 307 healthy subjects(female 140, male 167), 54 RA patients, and 17 osteoarthritis (OA). The MMP-3 concentrations in healthy female and male were 43.3 +/- 15.3 ng/ml and 90.7 +/- 26.0 ng/ml, respectively. The serum MMP-3 levels in male were significantly higher than those in female (p0.0001). MMP-3 levels in RA patients(259.1 +/- 34.2 ng/ml) were significantly higher than OA(43.6 +/- 6.1 ng/ml) or healthy controls. There was a significant correlation between MMP-3 and CRP(r = 0.586), IL-6(r = 0.345) levels in serum. In contrast, no significant correlation was observed between MMP-3 and IL-8(r = 0.19), or CA-RF(r = 0.052) levels. However, there were some cases with high MMP-3 levels in CA-RF-negative patients definitely diagnosed as RA. These findings suggest that MMP-3 determination is useful for the early diagnosis and the follow-up during the treatment for RA patients.

Objective— Atherosclerosis is considered to be a chronic inflammatory disease and many cytokines participate in the development of atherosclerosis. We focused on the role of interleukin-1β (IL-1β), one of the proinflammatory cytokines secreted by monocytes/macrophages, in the progression of atherosclerosis. Methods and Results— We generated mice lacking both apoE and IL-1β. The sizes of atherosclerotic lesions at the aortic sinus in apoE−/−/IL-1β−/−mice at 12 and 24 weeks of age showed a significant decrease of approximately 30% compared with apoE−/−/IL-1β +/+ mice, and the percentage of the atherosclerotic area to total area of apoE−/−/IL-1β−/− at 24 weeks of age also showed a significant decrease of about 30% compared with apoE−/−/IL-1β +/+ . The mRNA levels of vascular cell adhesion molecule (VCAM)-1 and monocyte chemotactic protein-1 in the apoE−/−/IL-1β−/− aorta were significantly reduced compared with the apoE−/−/IL-1β +/+ . Furthermore, VCAM-1 was also reduced at the protein level in apoE−/−/IL-1β−/− aorta compared with apoE−/−/IL-1β +/+ . Conclusions— The lack of IL-1β decreases the severity of atherosclerosis in apoE deficient mice, possibly through increased expressions of VCAM-1 and monocyte chemotactic protein-1 in the aorta.

Objectives This study sought to assess the role of tumor necrosis factor-α (TNF-α) in myocardial ischemia/reperfusion (I/R) injury using TNF-α knockout (KO) mice. Background Tumor necrosis factor-α is thought to be involved in the pathogenesis of myocardial I/R injury by promoting leukocyte infiltration of the myocardium. However, the precise role of TNF-α in I/R injury is still unknown. Methods The hearts in TNF-α KO and wild-type (WT) mice were exposed by left lateral thoracotomy, and the left coronary artery was occluded for 30 min then reperfused for 120 min. Results The infarct size in TNF-α KO mice was significantly reduced compared with WT mice. The frequency of arrhythmia was decreased, and cardiac function during reperfusion was significantly improved in TNF-α KO mice compared with WT mice. The activation of nuclear factor-κB (NF-κB), the expression of chemokines and adhesion molecules and the infiltration of leukocytes were also significantly reduced in TNF-α KO mice, compared with WT mice. These findings provide evidence that TNF-α aggravates I/R injury. Conclusions Tumor necrosis factor-α exacerbates myocardial I/R injury at an early stage of reperfusion by activating NF-κB, thereby inducing chemokines and adhesion molecules and facilitating leukocyte infiltration.

L-Tryptophan degradation by indoleamine 2,3-dioxygenase (IDO) might have an important role in gamma interferon (IFN-gamma)-induced antimicrobial effects. In the present study, the effects of Toxoplasma gondii infection on IDO were investigated by using wild-type and IFN-gamma-gene-deficient (knockout) (IFN-gamma KO) mice. In wild-type C57BL/6J mice, enzyme activities and mRNA levels for IDO in both lungs and brain were markedly increased and lung L-tryptophan concentrations were dramatically decreased following T. gondii infection. In contrast, these metabolic changes did not occur in T. gondii-infected IFN-gamma KO mice or in uninfected IFN-gamma KO mice. The levels of inducible nitric oxide synthase (iNOS) induction in infected IFN-gamma KO mice were high in lungs and low in brain compared to those in infected wild-type mice. The extent of increased mRNA expression of T. gondii surface antigen gene 2 (SAG2) induced in lungs and brain by T. gondii infection was significantly enhanced in IFN-gamma KO mice compared to wild-type mice on day 7 postinfection. Treatment with N-nitro-L-arginine methyl ester, an iNOS inhibitor, increased the levels of SAG2 mRNA in brain but not in lungs and of plasma L-kynurenine after T. gondii infection. This in vivo study provides evidence that L-tryptophan depletion caused by T. gondii is directly mediated by IFN-gamma in the lungs, where iNOS is not induced by IFN-gamma. This study suggests that there is an antitoxoplasma mechanism of cross-regulation between iNOS and IDO and that the expression of the main antiparasite effector mechanisms for iNOS and/or IDO may vary among tissues.

Background: The purpose of this study was to evaluate the performance of two homogeneous assays for LDL-cholesterol (LDL-C), a polyethylene/cyclodextrin (PC) assay and a detergent (D) assay, which are based on different principles, in cholestatic serum.Methods: We compared serum LDL-C concentrations determined by the two assays for healthy normolipidemic subjects (n = 42) and cholestatic patients (n = 51). LDL-C concentrations obtained with the homogeneous assays were also compared with those obtained by HPLC for patients’ sera. In the interference study, conjugated bile acids were added to normal serum, and their effects on the two assays were examined. The effects of lipoprotein-X (LP-X), intermediate-density lipoprotein (IDL), and apolipoprotein (apo) E-rich HDL on the LDL-C assays were also investigated by adding these lipoproteins to normal serum.Results: The LDL-C concentrations obtained with the D assay were higher than those obtained with the PC assay in the serum with high LP-X. The bias for LDL-C vs LP-X in cholestatic serum correlated with LP-X concentration (r = 0.582; P Conclusions: Although both homogeneous LDL-C assays are suitable for most cases, the present study showed that each homogeneous assay has a different limitation for cholestatic serum with gross alterations in lipoproteins.

Marked increases in metabolites of thel-tryptophan-kynurenine pathway, l-kynurenine and quinolinic acid (Quin), were observed in serum and cerebrospinal fluid (CSF) of both the rat and human with renal insufficiency. The mechanisms responsible for their accumulation after renal insufficiency were investigated. In patients with chronic renal insufficiency, elevated levels of serum l-kynurenine and Quin were reduced by hemodialysis. In renal-insufficient rats, Quin andl-kynurenine levels in serum, brain, and CSF were also increased parallel to the severity of renal insufficiency. Urinary excretion of Quin (3.5-fold) and l-kynurenine (2.8-fold) was also increased. Liver l-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of the kynurenine pathway, was increased in proportion to blood urea nitrogen and creatinine levels. Kynurenine 3-hydroxylase and quinolinic acid phosphoribosyltransferase were unchanged, but the activities of kynureninase, 3-hydroxyanthranilate dioxygenase, and aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) were significantly decreased. Systemic administrations of pyrazinamide (ACMSDase inhibitor) increased serum Quin concentrations in control rats, demonstrating that changes in body ACMSDase activities in response to renal insufficiency are important factors for the determination of serum Quin concentrations. We hypothesize the following ideas: that increased serum l-kynurenine concentrations are mainly due to the increased TDO and decreased kynureninase activities in the liver and increased serum Quin concentrations are due to the decreased ACMSDase activities in the body after renal insufficiency. The accumulation of CSFl-kynurenine is caused by the entry of increased seruml-kynurenine, and the accumulation of CSF Quin is secondary to Quin from plasma and/or Quin precursor into the brain.

Brain levels of TNF-alpha increase in many inflammatory conditions, including HIV-1 infection, and may contribute to neurodegenerative processes. The paucity of agents that can selectively and potently block TNF-alpha processing or its receptors has led us to investigate the role of TNF-alpha in chronic neurodegeneration associated with retroviral infection using mice with targeted deletions of the TNF-alpha gene. Infection of wild-type C57BL/6 mice with the LP-BM5 murine leukemia retrovirus mixture leads to the development of a severe immunodeficiency as well as cognitive deficits and neuronal damage. TNF-alpha-(-/-) mice infected with LP-BM5 developed a systemic immunopathology indistinguishable in severity from that observed in contemporaneously infected wild-type mice. In contrast, the performance of infected TNF-alpha-(-/-) mice in the Y-maze and Morris water maze was not different from that of uninfected TNF-alpha-(-/-) mice. The extent of glial activation in the striatum, as indicated by the increase in density of peripheral benzodiazepine receptors, was equivalent in both groups of LP-BM5-infected mice. However, the decrease in striatal MAP-2 expression, a marker of neurodegeneration observed in infected wild-type mice, was not found in infected TNF-alpha-(-/-) mice. While the loss of TNF-alpha appeared to have no effect on the course or severity of the central or peripheral immunopathology resulting from LP-BM5 infection, the behavioral and biochemical manifestations were substantially curtailed in the TNF-alpha-(-/-) mice. These findings directly support a role for TNF-alpha in the neurodegenerative processes associated with viral infections such as HIV-1.

This study examined whether cardiocyte load increases eIF-4F complex formation. To increase load in vitro, adult feline cardiocytes were electrically stimulated to contract (1 Hz, 5-ms pulses). eIF-4F complex formation, measured by eIF-4G association with eIF-4E, increased 57 ± 16% after 4 h of contraction compared with controls. eIF-4F complex formation did not increase on electrical stimulation with 2,3-butanedione monoxime (BDM), an inhibitor of active tension. Both insulin and phorbol ester increased eIF-4F complex formation, but these increases were unaffected by BDM. Insulin caused a shift of eIF-4E binding proteins (4E-BPs) into their hyperphosphorylated γ-isoforms and dissociation of 4E-BPs from eIF-4E. Rapamycin inhibited 4E-BP phosphorylation in response to insulin but had no effect on eIF-4F complex formation. Electrically stimulated contraction caused a partial shift of 4E-BP1 and 4E-BP2 into the γ-isoforms, but it had no effect on 4E-BP association with eIF-4E. Rapamycin blocked the increase in eIF-4F complex formation in electrically stimulated cardiocytes and depressed contractility. These data indicate that cardiocyte load causes a tension-dependent increase in eIF-4F complex formation that does not require dissociation of 4E-BPs from eIF-4E.

Anthranilic acid (AA) has been attracted considerable attention as one of the L-tryptophan-kynurenine pathway metabolites in the central nervous system. In this study, the concentration of L-kynurenine (L-KYN) and AA in serum and CSF, and its related enzyme activities were determined in several species. In rabbits, CSF AA concentrations were lower and serum AA concentrations were slightly higher than those in other species. However, the concentrations of L-KYN were substantially higher in rabbits in both serum and CSF compared with other species. Tissue enzyme activities varied among species. In rabbits, lung IDO activities were higher, but liver kynurenine 3-hydroxylase activities were lower than those of the other species tested. Furthermore, brain kynurenine 3-hydroxylase activities were higher in gerbils than those in other species. These results clearly demonstrated that kynurenine pathway enzyme activities and metabolite concentrations vary with species.

Accumulation of L-kynurenine and 3-hydroxyanthranilic acid (3HAA) occurs in the monocyte-derived cells following immune stimulation, and may derive from L-tryptophan following induction of indoleamine-2,3-dioxygenase. In the present study, we evaluate the possibility that 3HAA acts as an endogenous inducer of monocyte/macrophage apoptosis. Supplementation with 200 μM of 3HAA, but not other L-tryptophan metabolites tested, significantly increased the number of apoptotic cells in both THP-1 and U937 cells. Catalase, superoxide dismutase and manganese ions markedly enhanced apoptosis in the presence of 3HAA in these cells. The present results suggest that 3HAA induces the macrophage/monocyte apoptosis under certain conditions, which may be relevant to patho-physiology of inflammatory conditions.

Anthranilic acid (AA) has attracted considerable attention as one of the l -tryptophan–kynurenine pathway metabolites in the central nervous system. In this study, a highly sensitive and accurate method for the quantification of AA has been developed using reversed-phase high-performance liquid chromatography with electrochemical detection. Serum and cerebrospinal fluid (CSF) AA concentrations in different animal species were measured. CSF AA concentrations in rabbits were 1.1 ± 0.1 nmol/liter, which were 5.7–33.0 times lower than those in other species studied. Serum AA concentrations, however, were slightly higher in rabbits than in other species. In contrast, the concentrations of l -kynurenine (L-KYN) in both serum and CSF were substantially higher in rabbits than in other species. Tissue kynurenine pathway enzymes, indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase, kynurenine 3-hydroxylase, and kynureninase were determined in rabbits, rats, gerbils, and mice. These enzymes varied among species, especially lung IDO activities in rabbits were 146–516 times higher than those found in other species, but rabbit liver kynurenine 3-hydroxylase activities were lower by one order of magnitude than those of the other species tested. Furthermore, brain kynurenine 3-hydroxylasae activities were 12.3–23.2 times higher in gerbils than those in the other species tested. In addition, AA concentrations in serum following intravenous administration of L-KYN (5 mg/kg) were also measured in rabbits. AA levels peaked sharply within 5 min after administration and decreased in a time-dependent manner. At 5 min after administration, CSF L-KYN and AA concentrations were also increased by 1.76- and 2.56-fold, respectively, compared with basal levels. Increased AA concentrations in CSF following L-KYN administration may reflect the entry of AA into the CSF after conversion to AA in systemic tissue and/or the local synthesis of AA from L-KYN in the CNS.

SUMMARY 1. We investigated the role of vascular smooth muscle α-adrenoceptor subtypes in the vasoconstrictor response of femoral arteries and veins to dopamine and whether the vasoconstriction is modified by endothelium-dependent relaxation mediated via the activation of α2-adrenoceptors in ring preparations of femoral arteries and veins from mongrel dogs. 2. Dopamine contracted both arteries and veins in a dose-dependent manner and this contraction was inhibited by pre-treatment with phentolamine or prazosin. Pretreatment with yohimbine shifted the dose-response curve for dopamine to the right in femoral veins, but not in arteries. 3. Phenylephrine contracted femoral arteries and veins in a dose-dependent manner and this contraction was inhibited by pretreatment with prazosin. 4. Clonidine produced a bell-shaped dose-response curve in femoral veins and this curve was shifted upwards by pretreatment with NG-nitro-l-arginine (l-NNA). In contrast, femoral arteries were not affected by clonidine. NG-Nitro-l -arginine potentiated contractile responses to dopamine in both veins and arteries. This potentiation was inhibited by yohimbine or by the removal of the endothelium in both arteries and veins. 5. These results suggest that dopamine contracts femoral arteries via stimulation of α1-adrenoceptors and contracts femoral veins via stimulation of both α1- and α2-adrenoceptors and that these contractions are attenuated by the vasodilator action of dopamine via α2-adrenoceptor-mediated release of endothelium-derived relaxing factor.

We examined whether the vasodilating effect of vasodilators on systemic capacitance vessels is modified by the baroreflex when a fall in arterial blood pressure was induced by the vasodilators in dogs. We estimated the dilation of the systemic capacitance vessels from the fall in mean circulatory pressure (MCP), proposed by Guyton et al. and the dilation of the systemic capacitance vessels from the fall in the total peripheral resistance (TPR). The dose-response curve for percent change in TPR to graded doses of nitroglycerin (NG, 0.8–200 µg/kg) in the untreated group was not different from that in the total spinal anesthesia (TSA) group in which the baroreflex was eliminated. The TSA group gave a dose-response curve for percent change in MCP to NG on the low dose side of NG as compared with the untreated group. NG increased both plasma levels of nor-epinephrine (NA) and epinephrine (A) in the untreated group. However, NG hardly affected plasma levels of NA or A in the TSA group. Milrinone significantly decreased the TPR and there was no significant difference in the percent change in TPR between the untreated and TSA groups. Milrinone did not change the MCP in the untreated group, but decreased it in both TSA group and the group pretreated with α-blocker, suggesting that baroreflex-mediated vasoconstriction is mediated through α-adrenoceptors in the capacitance vessels. Milrinone also increased plasma levels of NA and A in the untreated group but not in the TSA group.

We estimated the effects of intravenous injection of endothelin-1 (ET-1; 400 pmol/kg) on the systemic capacitance and resistance vessels in anesthetized mongrel dogs by measuring changes in the mean circulatory pressure (MCP) and total peripheral resistance (TPR), respectively. In addition, the present study investigated the inhibiting action of nicardipine (NIC; 10 micrograms/kg bolus injection followed by 1.0-2.0 micrograms/kg/min continuous infusion) against the vasoconstrictor action of ET-1. We examined the effects of ET-1 (30 to 1,000 pmol/0.1 ml) on the femoral arterial system by measuring the percent changes in the perfusion pressure (% delta PP) of the femoral artery perfused with a constant flow, and investigated the effect of NIC on the vasoconstrictor action of ET-1 in this preparation. We obtained the following results: (a) Intravenous injection of ET-1 raised both TPR and MCP. However, in the presence of NIC, ET-1 raised TPR without influencing MCP. (b) Intra-arterial injection of ET-1 caused a dose-dependent increase in % delta PP. NIC shifted the dose-response curve of ET-1 for % delta PP to the right in a parallel fashion.

ミオグロビン尿症は骨格筋細胞の急速な崩壊により, 大量のミオグロビンが血中に放出されて発症する. その原因にはtraumaticなものとnontraumaticなものがあり, 近年ミオグロビンの測定がRIA法により容易になったこともあり, nontraumatic rhabdomyolysisと, それに伴う急性腎不全の報告も増加してきた. 今回, nontraumatic rhabdomyolysisにより急性腎不全を併発した1例を報告するとともに, これに類似した本邦報告例を検討し, さらに本症の発生機序ならびに臨床像の特徴について考察した.症例は51歳の男性である. 1歳時に脳炎に罹患した. 昭和60年7月30日炎天下に約15km歩行し, 意識消失し, 某病院へ入院した. その後無尿が出現し, 発病3日目に当科へ転院した. 入院時, 体温37.5℃, 脈拍70/分, 血圧130/70mmHg, 胸・腹部に異常所見なく, 大腿部に腫脹と圧痛が認められた. 尿ミオグロビン190ng/ml, 血清Na 157mEq/l, K 5.1mEq/l, Pi 6.0mg/dl, クレアチニン9.5mg/dl, UN 125mg/dl, GOT 596IU/l, GPT 225IU/l, LDH 2,782IU/l, CPK 40,800IU/l, アルドラーゼ27.9IU/lと上昇し, Caは6.3mg/dlと低下した. 阻血下前腕運動負荷試験により, 遺伝性解糖系酵素欠損症は考えにくく, nontraumatic rhabdomyolysisによる急性腎不全と診断した. ただちに血液透析を開始し第2週より利尿をみて, 約2ヵ月後, 症状ならびに臨床検査値が改善し退院した.

We measured mean circulatory pressure (MCP) in anesthetized, open-chest dogs before and after intravenous administration of Ca++-antagonists to estimate the effects on systemic capacitance vessels and on venous return (VR) curves both with and without continuous intravenous infusion of norepinephrine (NE). Diltiazem (300 micrograms/kg) decreased total peripheral resistance (TPR) and MCP significantly. Nifedipine (5 micrograms/kg), nicardipine (30 micrograms/kg) and verapamil (200 micrograms/kg) decreased TPR significantly without any change in MCP in the absence of NE, but with the exception of verapamil, they decreased MCP in the presence of NE. This indicates that diltiazem relaxed the systemic capacitance vessels, and nifedipine and nicardipine significantly decreased the tone of the systemic capacitance vessels that had been previously elevated by NE, but this action was very slight with verapamil. These Ca++-antagonists rotated VR curves clockwise, decreased resistance to VR (RVR) and increased VR both in the presence and absence of NE. It was suggested that the decrease in the RVR would be at least partially responsible for the increase in the VR.