Effects of angiotensin on the expression of fibrosis-associated cytokines, growth factors, and matrix proteins in human lung fibroblasts.

BACKGROUND AND OBJECTIVES: Angiotensin (Ang) II plays an important role in fibrogenesis in various organs, including the lung. The aim of this study is to elucidate (i) the effects of Ang II on the expression of cytokines, growth factors or matrix proteins in normal human lung fibroblasts, and (ii) the inhibitory effects of an Ang II type 1 (AT1) receptor blocker, candesartan. METHODS: Normal human adult lung fibroblasts were cultured. Candesartan was added and the cells were incubated. All the cells in culture dishes were collected at day 0 and 2, and the cell numbers were counted using a Neubauer haemocytometer (Clay-Adams, Parsippany, NJ, USA). The cell proliferation rates at day 2 were calculated in comparison to those at day 0. Total cellular RNA was extracted for real-time quantitative PCR, or the culture supernatant was collected for either a Sircol assay or enzyme-linked immunosorbent assay (ELISA). Laser scanning confocal microscopy was used for analyzing the cells with and without prior exposure to candesartan. Comparisons between the means of multiple groups were analyzed by one-way analysis of variance (ANOVA) followed by Tukey's test or Games-Howell's test. Values of P < 0*05 were considered to be statistically significant. RESULTS: Among the 12 fibrosis-associated cytokines and growth factors, mRNA expressions of interleukin (IL)-4, IL-7, and platelet-derived growth factor-D were significantly modulated by Ang II, and suppressed by candesartan. Soluble collagen and elastin levels were significantly elevated by Ang II, and suppressed by candesartan. Under confocal microscopy, the intracellular distribution of elastin was significantly increased by Ang II, and suppressed by candesartan. CONCLUSION: These data indicate that Ang II promotes lung fibrosis by increasing the matrix formation, which was suppressed by AT1 receptor blocker.

Clinical characteristics of patients with both anti-U1RNP and anti-centromere antibodies.

OBJECTIVE: To clarify the clinical characteristics of patients having both anti-U1RNP antibodies (anti-U1RNP) and anti-centromere antibodies (ACA) in comparison to subjects having either anti-U1RNP or ACA alone. SUBJECTS AND METHODS: One hundred and fifty-six subjects who had anti-U1RNP and/or ACA were enrolled. They were classified into three groups: anti-U1RNP alone group (n = 64); ACA alone group (n = 82); and anti-U1RNP+ACA group (n = 10). The anti-U1RNP alone and ACA alone groups were also divided into the low-titre and the high-titre subgroups, respectively. The frequencies of the specific clinical findings and laboratory data were compared among the groups or subgroups. RESULTS: The frequencies of persistent proteinuria or lupus nephritis (LN, 50.0%) and primary biliary cirrhosis (PBC, 30.0%) in the anti-U1RNP+ACA group were higher than that in the anti-U1RNP alone group (17.2%, p<0.01; 3.1%, p = 0.075; respectively). The frequencies of systemic lupus erythematosus (SLE, 60.0%), persistent proteinuria or LN (50.0%), anti-Ro (70.0%), and anti-La (30.0%) in the anti-U1RNP+ACA group were higher than those in the ACA alone group (11.0%, p<0.01; 4.9%, p<0.001; 23.2%, p<0.01; and 6.1%, p = 0.085; respectively). The frequency of systemic sclerosis (SSc) in the high-titre subgroup (30.0%) was higher than that in the low-titre subgroup (11.8%) in the anti-U1RNP alone group, without significance (p = 0.072). The frequency of interstitial pneumonia in the high-titre subgroup (26.8%) was higher than that in the low-titre subgroup (2.4%) in the ACA alone group (p<0.01). CONCLUSIONS: The clinical characteristics of patients with anti-U1RNP+ACA were clarified in comparison to subjects having either anti-U1RNP or ACA alone.

Salivary production rates fall with age in subjects having anti-centromere, anti-Ro, and/or anti-La antibodies.

OBJECTIVES: To clarify the relationship between a subject's sicca-associated autoantibodies type and changes in salivary production rate (SPR) with age in subjects having any of these antibodies. METHODS: One hundred and eighty-five subjects (female:male = 178:7), who had at least one of the three autoantibodies, anti-centromere (ACA), anti-Ro (SSA), and/or anti-La (SSB), and 65 healthy females were enrolled. The Saxon test was used to measure SPR. RESULTS: SPRs in the seven male subjects were significantly higher than those in the 178 females tested. Therefore, only female subjects were used for the following analyses. Subjects were classified into substantially four groups according to their seropositivities for ACA, anti-Ro, and/or anti-La: group A, subjects having ACA alone; group B, subjects having anti-Ro alone; group E, subjects having anti-Ro and anti-La; group DFG, subjects having ACA with anti-Ro and/or anti-La. The frequency of Sjögren's syndrome (SS) was 74.0-94.1% in these groups. SPR did not decrease with age in normal female controls. By contrast, SPR decreased significantly with age in the groups having sicca-associated antibodies. The degree of SPR decrease compared between groups was: group A group [symbol: see text] B > group E [symbol: see text] group DFG. In the analysis of the subgroup having any of the sicca-associated antibodies but not fulfilling the classification criteria of SS, SPR also decreased with age. CONCLUSION: SPR in subjects having any of the sicca-associated antibodies (ACA, anti-Ro, or anti-La) decreased with age.

Effect of betaxolol hydrochloride on heart rate variability indices during exercise stress testing in patients with hypertension.

Betaxolol hydrochloride is a beta1-selective antagonist that produces vasodilation in patients with hypertension and ischemic heart disease. The goal of the present study was to characterize the effect of betaxolol on heart rate variability indices (HRV), a well-established prognostic marker. Symptom limited-treadmill exercise testing was performed in 17 hypertensive patients (60.9 +/- 14.8 years-old) before and immediately a 3 weeks course of betaxolol hydrochloride (5 mg daily). Frequency domain HRV (high frequency spectra, HF; 0.15-0.40 Hz: low frequency spectra, LF; 0.04-0.15 Hz) was measured during exercise treadmill testing using MemCalc software. Betaxolol hydrochloride significantly decreased the maximal systolic blood pressure and heart rate (184 +/- 29 vs. 156 +/- 26 mmHg, P < 0.01; 132 +/- 21 vs. 113 +/- 15 bpm, P < 0.01) and significantly increased HF and LF during exercise treadmill testing (HF, 32 +/- 36 vs. 56 +/- 55 men/Hz, P < 0.01; LF, 64 +/- 58 vs. 95 +/- 86 men/Hz, P < 0.01). Thus, treatment with betaxolol hydrochloride resulted in a decrease in blood pressure during exercise treadmill testing and in an increase in HRV. This suggests that this agent could have beneficial effects on long-term prognosis in patients with hypertension.

Recombinant interferon alpha treatment decreases heart rate variability indices and impairs exercise tolerance in patients with chronic hepatitis.

Complications of interferon (IFN) therapy include cardiac arrhythmias, impaired cardiac function and myocardial ischemia. Decreased heart rate variability (HRV) indices, impaired exercise tolerance and decreased left ventricular (LV) function are related to unfavorable outcome of heart disease. To investigate the effect of IFN therapy on HRV, exercise tolerance and cardiac function, 24-h ambulatory electrocardiographic monitoring (AECG), two-dimensional echocardiography, and exercise treadmill testing (ETT) was performed in 9 patients (age 56 +/- 9 years-old) with chronic hepatitis and without underlying heart disease before and after treatment with IFN (recombinant alpha 2b; 10 x 10(6) U/day for 4 weeks). HRV parameters consisted of standard deviation of RR interval (sdNN, ms), SDANN (ms), S.D. index (ms), rMSSD (ms), pNN50 (%) and frequency analysis of heart rate spectrum resulted in low (ms, 0.04-0.15 Hz), high (ms, 0.15-0.40 Hz) and total (ms, 0.01-1.00 Hz) frequency components. Ischemia was not detected by AECG or ETT, and LV function was normal after INF treatment in all patients. However, INF treatment resulted in a decrease in exercise tolerance time (449 +/- 94 s vs. 329 +/- 67 s, P < 0.05) and a decrease in several HRV parameters (S.D. index, 42 +/- 5 ms vs. 37 +/- 9 ms; rMSSD, 22 +/- 5 ms vs. 19 +/- 4 ms; pNN50, 4 +/- 3% vs. 2 +/- 1%; P < 0.05). Further, patients treated with INF tended to have a lower sdNN and total frequency spectra, although this difference did not reach the level of statistical significance. These data suggest that the arrhythmogenic effect of INF may be mediated by decreases in HRV and impairment of exercise tolerance even in patients without overt heart diseases. Further, INF therapy may be contraindicated in patients with predisposing severe cardiac disorders, including arrhythmias, ischemia and decreased LV function.

Effect of antiarrhythmic agents on heart rate variability indices after myocardial infarction: comparative experimental study of aprindine and procainamide.

The cardiac arrhythmic suppression trial (CAST) reported that antiarrhythmic treatments in post-myocardial infarction (MI) patients resulted in poor outcome and decreased in heart rate variability indices (HRV). The goal of the present study was to determine whether aprindine and procainamide, antiarrhythmic agents that increase HRV, result in beneficial effects in post-MI rabbits. Four weeks before experiment, MI was induced in four rabbits by ligating the major branch of left coronary artery. A total of eight rabbits (four post-MI and four normal rabbits) were randomly assigned to treatment with either intravenous aprindine (1 mg/kg) or intravenous procainamide (15 mg/kg). Frequency domain HRV (low frequency spectra, LF, 0.04-0.15 Hz; high frequency spectra, HF, 0.15-0.40 Hz) were assessed by MemCalc software. Aprindine significantly increased HF and LF in both MI and normal rabbits, whereas procainamide tended to decrease HF and LF in MI and normal rabbits (in total rabbits; aprindine, LF, from 6.3 +/- 7.9 to 16.5 +/- 15.0 ms(2)/Hz, P < 0.05; HF, from 8.0 +/- 11.7 to 17.5 +/- 15.0 ms(2)/Hz, P < 0.05; procainamide, LF, from 4.9 +/- 7.4 to 4.8 +/- 8.5 ms(2)/Hz, NS; HF, from 11.1 +/- 23.0 to 5.1 +/- 10.6 ms(2)/Hz, NS). Under pharmacological denervation with propranolol (0.1 mg/kg) and atropine (0.04 mg/kg), aprindine increased LF and HF (LF, from 0.2 +/- 0.2 to 0.8 +/- 0.7 ms(2)/Hz, P < 0.05; HF, from 0.1 +/- 0.0 to 0.2 +/- 0.0 ms(2)/Hz, P < 0.05). These data suggest that aprindine can increase HRV in post-MI rabbits. Further experiments in human subjects would be of benefit.

Flow-mediated dilation in brachial artery in the second half of pregnancy and prediction of pre-eclampsia.

Endothelial injury and increased vascular reactivity are involved in the pathogenesis of pre-eclampsia (pregnancy-induced hypertension). To investigate whether flow-mediated dilation (endothelium-dependent dilation) and the reactive hyperemic response can predict pre-eclampsia, we prospectively measured flow-mediated dilation and the Doppler flow velocity pattern (V, cm/s) in the brachial artery using high-resolution ultrasound in 43 pregnant women (32+/-5 years old) in the second half of their pregnancy, and compared the findings with traditional risk factors. Regarding the Doppler flow velocity pattern, the pulsatility index (PI)=(systolic V-diastolic V)/mean V and resistance index (RI)=(systolic V-diastolic V)/systolic V were calculated. For the flow-mediated dilation, the per cent diameter changes were determined based on those from baseline to hyperemic conditions. Nine women suffered from pre-eclampsia and 34 women remained normotensive. Only flow-mediated dilation was found to be significantly lower in the subsequently developed pre-eclampsia patients (1.6+/-1.0% in subsequently developed pre-eclampsia patients vs 11.0+/-4.5% in normotensive patients, P<0.05). Neither the other traditional factors nor the Doppler flow velocity pattern were significantly different between the subsequently developed pre-eclampsia and normotensive patients. If a normal cutoff value of 3.0% obtained from age-matched 14 nonpregnant women (32+/-7 years old) in our laboratory was used, the positive predictive value of flow-mediated dilation (<3.0%) for subsequent pre-eclampsia is 90% and the negative predictive value is 100%. In conclusion, flow-mediated dilation in brachial artery can be a simple and noninvasive modality to predict pre-eclampsia.

Remnant-like particles cholesterol is higher in diabetic patients with coronary artery disease.

Diabetes mellitus (DM) has been well known to be one of the risk factors of coronary artery disease (CAD). Recently, remnant-like particles cholesterol (RLP-C) has been reported to be associated with CAD. However, few studies reported the association of RLP-C level with CAD in subjects with DM. To investigate the effects of presence or absence of DM on the association between RLP-C and CAD, we compared the RLP-C level in 142 male patients with CAD and 123 male subjects without CAD (non-CAD), including 44 and 38 DM patients, respectively. RLP-C was significantly higher in CAD than non-CAD (P <.05). RLP-C and RLP-C/plasma-triglyceride (TG) ratio in CAD with DM were higher than CAD without DM (P <.01, P <.05), and non-CAD with DM (P <.001, P <.05). There was positive correlation between RLP-C and plasma-TG in non-CAD without DM (r =.44, P <.01), non-CAD with DM (r =.56, P <.001), CAD without DM (r =.81, P <.0001), and CAD with DM (r =.75, P <.001). After excluding the hypertriglyceridemic patients (>200mg/dL), RLP-C/plasma-TG ratio was significantly higher in CAD with DM than CAD without DM (P <.001) and non-CAD with DM (P <.05). These results suggest that increased RLP-C to plasma-TG may be associated with CAD in middle-aged diabetic male subjects.

Dynamic changes in cytokine levels in serum and synovial fluid following filtration leukocytapheresis therapy in patients with rheumatoid arthritis.

We attempted to determine whether various cytokine levels in the serum and synovial fluid (SF) of rheumatoid arthritis (RA) patients are influenced by the performance of filtration leukocytapheresis (LCP). The filtration LCP procedure that used a Cellsorba column (LCP group: n=22; responder subgroup: n=17, non-responder subgroup: n=5) or sham apheresis (control group; n=7) was repeated three times at 1-week intervals. Serum (LCP group, n=22; control group, n=7) and SF (LCP group, n=6; control group, n=3) samples were collected before and after LCP. Levels of tumor necrosis factor alpha (TNFalpha), interleukins (IL-1 beta, IL-2, IL-6, IL-8, IL-10, and IL-15), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), RANTES were measured by an enzyme-linked immunosorbent assay. Serum TNF alpha, IL-15, and RANTES were significantly reduced only in the LCP group. Serum IL-10 significantly increased only in the LCP group. In the LCP subgroup, serum IL-15, GM-CSF, and RANTES levels were reduced significantly, while serum IL-10 levels increased significantly only in the responder group after treatment. Serum TNF alpha levels were reduced significantly in both subgroups. Changes in serum IL-10 correlated positively with the improvement of patient's assessment of pain and global severity, and physician's assessment of global severity. These results indicate that the removal of leukocytes from the peripheral blood of RA patients provokes dynamic changes in some cytokine levels in the serum and/or synovial fluid. These changes may explain some of the mechanisms by which the articular symptoms are improved by filtration LCP.

Immediate remission obtained by minocycline in a patient with histiocytic necrotizing lymphadenitis.

A 29-year-old man was admitted because of fever, arthralgia and swelling of the cervical lymph nodes. A diagnosis of histiocytic necrotizing lymphadenitis (HNL) was made based on the findings of a lymph node biopsy. At first, piperacillin sodium (PIPC) was started, but a spiking fever persisted. We therefore changed the PIPC treatment to minocycline. On the following day, his clinical and laboratory findings were dramatically improved. After administering minocycline for 10 days, the HNL symptoms completely disappeared. He has been in good health for 3 years since undergoing treatment. This case strongly indicates that minocycline-sensitive microorganism(s) may be related, at least in part, to the etiology of HNL.

Assessment of left ventricular volume by an ambulatory radionuclide monitoring system during head-up tilt in patients with unexplained syncope: relation to autonomic activity assessed by heart rate variability.

BACKGROUND: Decreased left ventricular volume during head-up tilt plays an important role in triggering syncope in patients with neurally mediated syncope. However, precise changes in left ventricular volume during head-up tilt have not been well investigated. This study was conducted to test the hypothesis that the decline in left ventricular volume during tilt could trigger ventricular mechanoreceptor activation. METHODS AND RESULTS: To investigate the mechanisms of tilt-induced syncope, we measured the temporal changes in left ventricular volume, ejection fraction, cardiac output, and heart rate variability indices during head-up tilt in 25 patients with syncope of undetermined etiology. Eleven patients had a cardioinhibitory response (CI group), 7 patients showed a vasodepressor response (VD group), and 7 patients demonstrated a negative response (NG group). Before syncope, ejection fraction increased most in the CI group, the left ventricular end-diastolic volume declined most in the VD group (VD group, -11.0% +/- 3.3%; CI group, -2.8% +/- 4.8%; NG group, -3.4% +/- 2.2%; P <.005), and the high-frequency spectra increased most in the CI group (CI group, 25.0% +/- 21.0%; VD group, -4.1% +/- 11.7%; NG group, -5.3% +/- 12.7%; P <.01). The vasodepressor response was dependent on left ventricular volume, whereas the cardioinhibitory response was related to the vagal activity reflected by high-frequency spectra. CONCLUSIONS: The precise evaluation of left ventricular volume by an ambulatory radionuclide monitoring system combined with a heart rate variability analysis is considered useful for clarifying the pathophysiology of neurally mediated syncope.

Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection.

OBJECTIVES: This study was done to elucidate the effects of interleukin (IL)-1 gene polymorphisms on coronary artery disease (CAD) associated with Chlamydia pneumoniae (CP) infection. BACKGROUND: It was suggested that CP was associated with CAD. However, genetic factors involved in CAD associated with CP infection are unknown. METHODS: We evaluated CP immunoglobulin G (IgG) seropositivity and IL-1 beta (a C/T transition at -511) and IL-1 receptor antagonist (IL-1Ra) (a variable-number repeat in intron 2) gene polymorphisms in 292 patients undergoing coronary angiography. RESULTS: Seropositivity for CP was present in 61% of patients with CAD versus 51% without CAD (p = NS). The percentage of patients having IL-1 beta (-511) C/C genotype and/or IL-1Ra (intron 2) 2- or 3-repeat allele was higher in patients with CAD than without CAD (29 vs. 16%, p < 0.025). To clarify the effects of these CAD-associated variants (IL-1 beta C/C and/or IL-1Ra 2- or 3-repeat), patients were divided into four groups. A stepwise increase in CAD prevalence was observed depending on CP seropositivity and the variants. Odds ratios (ORs) for CAD were 1.4 in the group with seropositivity alone, 1.7 with the variants alone and 3.8 with seropositivity and the variants. Such variants were associated with CAD in both patients with and without seropositivity. Interestingly, high prevalence of myocardial infarction (MI) was confined to the group with seropositivity and the variants (OR, 2.8). The variants were associated with MI only in patients with CP seropositivity. CONCLUSIONS: The IL-1 gene polymorphisms were found to play a role in the development of CAD, especially MI, in patients with CP infection.

Rapid improvement of osteomalacia by treatment in a case with Sjögren's syndrome, rheumatoid arthritis and renal tubular acidosis type 1.

We present here a case of Sjögren's syndrome (SjS) with osteomalacia based on renal tubular acidosis type 1 (RTA-1). A 53-year-old woman, diagnosed as having rheumatoid arthritis (RA) at the age of 33, was admitted to our hospital because of sicca complex, fatigability and worsening general aching. The activity of RA had been low, but it was complicated by SjS, RTA-1 and remarkable osteomalacia. Acidosis was corrected by alkali supplement therapy. By treatment with a regimen consisting of alfacalcidol, calcium L-aspartate, elcatonin and ipriflavone, her bone mineral density (BMD) was remarkably improved within months and the generalized aching gradually diminished.

Different mechanisms of isoproterenol-induced and nitroglycerin-induced syncope during head-up tilt in patients with unexplained syncope: important role of epinephrine in nitroglycerin-induced syncope.

INTRODUCTION: A reduction in left ventricular volume and an increase in epinephrine levels have been reported in tilt-induced neurally mediated syncope. To compare the mechanisms of isoproterenol-induced and nitroglycerin-induced syncope during head-up tilt and to investigate the role of catecholamines, the temporal changes in plasma levels of norepinephrine and epinephrine and in left ventricular volume were measured. METHODS AND RESULTS: The first study population consisted of 90 patients with syncope of unknown etiology and 12 control subjects. The second study population consisted of 43 patients with unexplained syncope. In the first study, head-up tilt (80 degree angle) was conducted for 40 minutes, and norepinephrine and epinephrine levels were measured. In the second study, all patients were randomly allocated to either isoproterenol test (20 patients) or nitroglycerin test (23 patients) for 20-minute head-up tilt. Isoproterenol infusion was given at a rate of 1 to 3 microg/min. Intravenous infusion of nitroglycerin was started at 250 microg/hour with increasing dosages up to 1,500 microg/hour. Norepinephrine and epinephrine were measured in peripheral venous blood. Left ventricular volumes were measured by echocardiography with patients in the supine position and during head-up tilt every 1 minute. End-diastolic volume and end-systolic volume were calculated. In the first study, 61 patients demonstrated a positive response and 29 patients demonstrated a negative response. Plasma norepinephrine changes during head-up tilt were not significantly different, whereas epinephrine levels were significantly higher in the positive patients than in the negative and control subjects (148 +/- 118 pg/mL vs 66 +/- 31 pg/mL and 55 +/- 27 pg/mL). Thirteen of the 20 patients given isoproterenol and 15 of the 23 patients given nitroglycerin showed a positive head-up tilt (65.0% vs 65.2%; P = NS). During isoproterenol and nitroglycerin infusion head-up tilt, epinephrine in the positive group determined by the nitroglycerin test was significantly higher than that in the other three groups (103 +/- 38 pg/mL vs 60 +/- 33 pg/mL, 31 +/- 21 pg/mL, and 50 +/- 52 pg/mL). In contrast, end-systolic volume was significantly smaller in the positive group than in the other three groups based on findings of the isoproterenol test. CONCLUSION: The findings suggest that nitroglycerin triggers head-up tilt-induced syncope by increasing epinephrine levels, whereas isoproterenol induces syncope by decreasing left ventricular volume.

Three-year follow-up of an atrial septal aneurysm.

This is a 3-year follow-up of a gradually ballooning atrial septal aneurysm (ASA) which developed a spontaneous echo contrast and later a mobile thrombus in the aneurysm. This clearly demonstrates one of the pathogenetic mechanisms of systemic thromboembolism associated with ASA. In view of the risk of systemic thromboembolism or the need for lifelong anticoagulation treatment, the aneurysm was excised and an atrial septal patch was fashioned to close the resultant defect.

Effect of coronary risk factors on arterial compensatory enlargement in japanese middle-aged patients with de novo single-vessel disease--an intravascular ultrasound study.

BACKGROUND: Compensatory enlargement (CE) of atherosclerotic human arteries has been reported; however, the pattern of arterial remodeling in response to plaque formation is not unique. HYPOTHESIS: The study was undertaken to determine the extent of coronary artery compensatory enlargement at stenotic lesions and to correlate the arterial compensatory enlargement with risk factors. METHODS: We studied 62 patients with stable angina and de novo single-vessel disease using intravascular ultrasound and obtained good images in 42 patients (68%). The vessel cross-sectional area (VA), lumen cross-sectional area (LA), and plaque cross-sectional area (PA) were measured at the lesion site and at proximal and distal reference sites. Positive CE was defined as increase in VA of lesion site > 10% compared with that of proximal reference site (CE group, n = 15); shrinkage was defined as reduction in VA of lesion site > 10% compared with that of proximal reference site (S group, n = 14); inadequate CE was defined as intermediate between CE and S (IE group, n = 13). All subjects had coronary risk factors measured before this study. RESULTS: There was no difference in VA, LA, or PA among the three groups at the proximal and distal reference sites, nor in LA at the lesion site; however, VA and PA were significantly smaller in the S group than in the other groups (p < 0.01). Of coronary risk factors, increased systolic blood pressure (SBP), increased diastolic blood pressure (DBP), and decreased high-density lipoprotein cholesterol (HDL-c) levels had the strongest association with shrinkage (p < 0.05). CONCLUSION: Hypertension and decreased HDL level may contribute to the shrinkage response in middle-aged patients with stable angina.

Impaired endothelium-dependent vasodilation in the brachial artery in variant angina pectoris and the effect of intravenous administration of vitamin C.

UNLABELLED: Endothelial dysfunction in the coronary artery contributes to the pathogenesis of variant angina, and endothelial dysfunction in variant angina may be associated with increased oxidant stress in the systemic arteries. We investigated whether endothelial dysfunction exists in the peripheral artery in patients with variant angina, and also examined the effect of vitamin C, an antioxidant, on endothelium-dependent vasodilation. Using high-resolution ultrasound, both the flow-mediated vasodilation (FMD, endothelium-dependent vasodilation) and sublingual nitroglycerin-induced vasodilation (NTG-D, endothelium-independent vasodilation) in the brachial artery were measured in 28 patients with variant angina and 24 control subjects who had normal coronary arteries. FMD was significantly impaired in patients with variant angina compared with control subjects (1.8 +/- 2.2% vs 6.4 +/- 4.9%, p <0.001). FMD and NTG-D before and after intravenous administration of either vitamin C or placebo were measured in 17 patients with variant angina. FMD significantly improved after the administration of vitamin C (from 2.2 +/- 2.4% to 4.5 +/- 1.6%, p <0.01), but not after administration of the placebo (from 2.0 +/- 2.6% to 1.7 +/- 1.9%). The improved FMD due to vitamin C in patients with variant angina, however, was not significantly different from that in the control subjects. NTG-D was not significantly different between patients with variant angina and control subjects (14.0 +/- 7.8% vs 13.6 +/- 5.0%) and it was also not affected by vitamin C. IN CONCLUSION: (1) FMD in the brachial artery is impaired in patients with variant angina, and (2) the acute administration of the antioxidant, vitamin C, was observed to reverse this endothelial dysfunction. These findings support the theory that the systemic inactivation of nitric oxide due to oxidative stress might exist in patients with variant angina.

Lipid microspheres incorporated by U937 cells via their specific receptors.

Lipid microspheres (LM), currently in clinical use as drug carriers, mainly consist of soybean oil as a core and lecithin as a surfactant. The purpose of our study wass to determine whether or not LM incorporation is receptor-mediated. U937 cells resuspended in a serum-free medium abundantly took up unmodulated LM. A binding study showed that U937 cells had a single binding site for LM (410 sites/cell at 24 degrees C; 100 sites/cell at 4 degrees C). Inhibition assays revealed that lecithin liposome, lysophosphatidylcholines, activated alpha2-macroglobulin, and HDL did not affect the binding of LM to U937 cells. VLDL strongly, and LDL and AcLDL moderately, inhibited the binding of LM to U937 cells. Ligand blotting analysis revealed that unmodulated LM in an apoprotein-free buffer directly bound to a 40 kDa protein in the cell membrane fraction. These results suggest that LM that is not modulated by any protein is incorporated by specific cells via receptor-mediated processes.