Loss of p53 in stromal fibroblasts enhances tumor cell proliferation through nitric-oxide-mediated cyclooxygenase 2 activation.

Overexpression of cyclooxygenase 2 (COX-2) by stromal fibroblasts plays a critical role in the early stage of carcinogenesis. COX-2 expression is thought to be positively or negatively regulated by inflammatory chemical mediators or tumor suppressors. In this study, the contributions of inducible nitric oxide synthase (iNOS) and p53 to COX-2 expression were examined using mouse embryonic fibroblasts (MEFs) from wild-type, p53-deficient, iNOS-deficient, and p53/iNOS-deficient mice. These MEFs were treated with 1 µg/mL of lipopolysaccharide and 100 IU/mL of interferon gamma for up to 72 h. iNOS and COX-2 expression were analyzed by Western blotting. iNOS was induced earlier (16 h) in p53-deficient MEFs than in wild-type MEFs (48 h). Elevated expression of COX-2 was sustained for a longer duration in the p53-deficient MEFs. In contrast, COX-2 expression was reduced earlier in the iNOS-deficient MEFs. Addition of an exogenous NO donor (0.8 mM of S-nitroso-l-glutathione) to the iNOS-deficient MEFs augmented COX-2 expression. Co-culture with stimulated p53-deficient MEFs promoted cell proliferation of mouse rectal polyploid carcinoma CMT93 cells, but treatment with a COX-2-specific inhibitor counteracted this effect. These results suggest that loss of function of the p53 gene in stromal fibroblasts enhances COX-2 expression by enhancing iNOS expression and the resultant production of NO, contributing to the promotion of tumor growth.

Exercise-induced muscle damage impairs insulin signaling pathway associated with IRS-1 oxidative modification.

Strenuous exercise induces delayed-onset muscle damage including oxidative damage of cellular components. Oxidative stress to muscle cells impairs glucose uptake via disturbance of insulin signaling pathway. We investigated glucose uptake and insulin signaling in relation to oxidative protein modification in muscle after acute strenuous exercise. ICR mice were divided into sedentary and exercise groups. Mice in the exercise group performed downhill running exercise at 30 m/min for 30 min. At 24 hr after exercise, metabolic performance and insulin-signaling proteins in muscle tissues were examined. In whole body indirect calorimetry, carbohydrate utilization was decreased in the exercised mice along with reduction of the respiratory exchange ratio compared to the rested control mice. Insulin-stimulated uptake of 2-deoxy-[(3)H]glucose in damaged muscle was decreased after acute exercise. Tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and phosphatidyl-3-kinase/Akt signaling were impaired by exercise, leading to inhibition of the membrane translocation of glucose transporter 4. We also found that acute exercise caused 4-hydroxy-nonenal modification of IRS-1 along with elevation of oxidative stress in muscle tissue. Impairment of insulin-induced glucose uptake into damaged muscle after strenuous exercise would be related to disturbance of insulin signal transduction by oxidative modification of IRS-1.

Arterial stiffness acutely decreases after whole-body vibration in humans.

BACKGROUND: Increased arterial stiffness is a well-established cardiovascular risk factor. Mechanical stimuli to artery, such as compression, elicit vasodilation and acutely decrease arterial stiffness. As whole-body vibration (WBV)-induced oscillation is propagated at least to lumbar spine, WBV mechanically stimulates abdominal and leg arteries and may decrease arterial stiffness. WBV is feasible in vulnerable and immobilized humans. Therefore, it is worthwhile to explore the possibility of WBV as a valuable adjunct to exercise training. AIM: The aim of this study was to investigate the acute effects of WBV on arterial stiffness. METHODS: Ten healthy men performed WBV and control (CON) trials on separate days. The WBV session consisted of 10 sets of vibration (frequency, 26 Hz) for 60 s with an inter-set rest period of 60 s. Subjects maintained a static squat position with knees bent on a platform. In the CON trial, WBV stimulation was not imposed. Blood pressure, heart rate and brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, were measured before and 20, 40 and 60 min after both trials. RESULTS AND CONCLUSION: Heart rate and blood pressure did not change from baseline after both trials. Although baPWV did not change in the CON trial (baseline vs. after 20, 40 and 60 min; 1144 +/- 35 vs. 1164 +/- 41, 1142 +/- 39, and 1148 +/- 34 cm s(-1)), baPWV decreased 20 and 40 min after the WBV trial and recovered to baseline 60 min after the trial (1137 +/- 28 vs. 1107 +/- 30, 1108 +/- 28, and 1128 +/- 25 cm s(-1)). These results suggest that WBV acutely decreases arterial stiffness.

Sustained swimming increases erythrocyte MCT1 during erythropoiesis and ability to regulate pH homeostasis in rat.

We investigated the effect of sustained swimming exercise on the increase in monocarboxylate transporter 1 (MCT1) concentration and its ability to regulate pH homeostasis in rat erythrocytes. Male Sprague-Dawley rats aged 9 weeks were divided into sedentary and swimming groups for both 1- and 3-week experiments. The exercise group swam for 30 - 60 min/day, 5 days/week. Before and 1 and 3 weeks after initiation of the exercise, blood was collected for lactate concentration measurement during pre-exercise rest and post-exercise recovery periods. On the last day of each experiment, venous blood and erythroid cells in bone marrow were collected to assay the capacity for erythropoiesis and MCT1 concentration. In the swimming group at 0 weeks (p < 0.05), 1 week (p < 0.01) and 3 weeks (p < 0.001), the blood lactate concentration post-exercise was significantly higher than at rest. The ratio of young erythrocytes to total erythrocytes was significantly higher in the 3-week swimming group than in the sedentary group (p < 0.05). The MCT1 concentration in erythrocytes was higher in the 3-week swimming group than in the sedentary group (18 %, p < 0.05), which was found in young erythrocytes (22 %, p < 0.05) when total erythrocytes were separated into young and old fractions. The MCT1 concentration in erythroid cells was higher in both the 1-week and 3-week swimming groups than in either of the sedentary groups (27 and 28 %, respectively, p < 0.05). The pH recovery of erythrocyte suspensions at 10, 15 and 20 seconds after addition of lactate to the suspension medium was significantly faster in the 3-week swimming group than in the sedentary group (p < 0.001). These findings suggest that erythrocyte MCT1 is increased during erythropoiesis in bone marrow and that the increase of the transporter facilitates, at least partly, lactate/proton co-transport due to sustained swimming exercise in rats.

Von Hippel-Lindau disease with multiple spinal cord hemangioblastomas, syringomyelia and pheochromocytoma.

A 31-year-old blind man presented with numbness and weakness in the left hand, and elevated blood pressure. Multiple hemangioblastomas in the spinal cord associated with syringomyelia were well demonstrated by gadolinium-enhanced magnetic resonance imaging (MRI). He also had pheochromocytoma in the right adrenal gland, which was disclosed by abdominal computed tomography, MRI and 131I-metaiodobenzylguanidine scintigraphy. MRI screening should be considered for patients with von Hippel-Lindau gene to detect the multiple lesions in this disease.

Circadian rhythms of blood pressure and heart rate in patients with human T-lymphotropic virus type-I-associated myelopathy.

Noninvasive ambulatory blood pressure and heart rate monitoring were used to investigate cardiovascular dysfunction in patients with human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy (HAM). The subjects were 23 patients with HAM, and 23 sex- and age-matched normotensive healthy volunteers (controls). Circadian rhythms of blood pressure and heart rate were present in both the HAM patients and controls. Amplitudes and the 24-hr mean systolic and diastolic blood pressures were significantly lower in the patients than in the controls. The 24 hr mean heart rate was significantly higher in the patients, the difference being particularly marked during the night. Differences in the acrophases of the systolic and diastolic blood pressures and heart rate between patients and controls were small but still significant. These results suggest that subclinical cardiovascular autonomic dysfunction is present in HAM patients.

Loss of nocturnal decline in blood pressure in diabetic patients with autonomic neuropathy.

We investigated loss of the nocturnal decline in blood pressure (BP) and its mechanism in diabetes mellitus with autonomic neuropathy (ANP). BP was measured every 30 min using ambulatory BP recorders in 52 diabetic patients and 11 nondiabetic controls. As an index of autonomic nervous dysfunction, CVRR (the coefficient of variation of the R-R interval on ECGs) and diastolic blood pressure response on standing were measured. Plasma volume (PV) was measured with RISA. The difference between daytime mean BP (09:00 to 13:00) and nighttime mean BP (01:00 to 05:00) was analyzed. The normal control group showed a significant reduction in mean BP during the nighttime (-12.8 +/- 7.5 mmHg) as compared with the DM group (-3.3 +/- 8.6 mmHg, p < 0.001). The diabetic patients with loss of the nocturnal decline in blood pressure showed autonomic nervous dysfunction and increased PV. In conclusion, the nocturnal elevation of blood pressure might result from an imbalance between reduced tone of sympathetic and parasympathetic functions in addition to the postural effect and increased plasma volume present in diabetic patients.

[Effect of weight loss on the reduction of blood pressure in obesity hypertension--hyperinsulinemia and renal sodium retention].

The role of insulin and dopamine on blood pressure and renal sodium excretion was evaluated in 10 obese hypertensive patients. Essential hypertensive subjects (age 49.7 +/- 7.7) with at least 26.0kg/m2 obesity were hospitalized and a 2000k cal diet for 7 days (control periods) followed by a 800 k cal for 21 days were given. Salt intake was maintained at 10 g/day throughout this study. Mean blood pressure (MBP), plasma insulin (IRI), urinary dopamine and fractional excretion of sodium (FENa) were measured in both diet periods. Body mass index significantly decreased from 31.6 +/- 4.6kg/m2 to 28.6 +/- 4.1 kg/m2 after weight reduction (P < 0.001). MBP significantly lowered from 112.8 +/- 14.1 mmHg to 100.4 +/- 12.4 mmHg (P < 0.01) and IRI from 9.11 +/- 5.0 microU/ml to 6.3 +/- 5.5 microU/ml (P < 0.001) after weight loss. We observed a significant correlationship between delta MBP and delta IRI (r = 0.754, P < 0.01). Also, we observed a significant correlationship between delta MBP and delta FENa (r = -0.835, P < 0.01). A significant relationship was observed between urinary excretion of sodium and urinary excretion of dopamine (r = 0.507, P < 0.05). We concluded that sodium retention and increase of sympathetic nervous activity by hyperinsulinemia might play an important role of hypertension, and blood pressure reduction by weight loss resulted from decreased insulin and increased excretion of sodium in obesity hypertension.

[A case of sarcoidosis with hypercalcemia, urolithiasis, nephrocalcinosis and renal insufficiency].

A sixty nine-year-old woman was admitted to the hospital because of further examination of hypercalcemia. On July 1990, she complained of general fatigue and loss of appetite. She was pointed out to have hypercalcemia (15.1mg/dl), urolithiasis, and renal insufficiency. CT films of the chest showed swelling of the mediastinal lymphnodes and CT of the abdomen nephrocalcinosis. Ga-scintigraphy demonstrated an abnormal accumulation of gallium in the mediastinum. Levels of the parathyroid hormone was normal. Levels of the serum calcium (13.7mg/dl), angiotensin converting enzyme (30.4IU/L) and 1.25 (OH)2D (87PG/ml) were elevated. Giant cells were found in the biopsy specimen of the lung. A significant relationship between the serum calcium and creatinine were observed (r = 0.76, p < 0.02). Proximal fractional reabsorption of sodium showed to be suppressed (47.7%), and distal fractional reabsorption of sodium showed to be normal (88.4%). From these findings hypercalcemia and urolithiasis was suggested to result from sarcoidosis. The hypercalcemia and renal insufficiency improved with corticosteroid therapy.

Relationship between blood pressure and left ventricular mass in male patients with essential hypertension.

We performed retrospective study of the relationship between the severity and duration of hypertension and echocardiographically-detected left ventricular hypertrophy (echo-LVH) in patients with untreated essential hypertension. The subjects consisted of 92 untreated essential hypertensives who were observed for more than 5 years from the onset of diastolic hypertension (greater than or equal to 95 mmHg), and whose left ventricular (LV) mass index was measured at the end of the observation period. On the basis of the frequency of diastolic hypertension during the observation period, the population was categorized in 3 groups. In Group I (32 cases), diastolic hypertension was observed in more than 80% of blood pressures obtained throughout the entire observation period. In Group II (38 cases), diastolic hypertension was observed in 33 to 80% of the observation period. In Group III (22 cases), diastolic hypertension was observed in less than 33% of the observation period. The average diastolic blood pressure during the entire observation period in each group were 101.0, 96.0, and 90.7 mmHg in groups I, II, and III, respectively. The LV mass index was significantly higher in groups I (114.6 g/m2) and II (105.3 g/m2) than in group III (90.7 g/m2) (p less than 0.01). The prevalence of echo-LVH (more than 121 g/m2) was 34.4%, 18.4%, and 4.8% in groups I, II, and III, respectively. The average diastolic blood pressure in patients with echo-LVH (99.3 +/- 5.1 mmHg) was significantly higher than in patients without echo-LVH (95.7 +/- 4.7 mmHg). We concluded that the degree and duration of diastolic pressure elevation are closely correlated to the LV mass index.

[Paradoxical response of blood pressure to salt loading in renovascular hypertension].

We studied the effect of high salt intake on blood pressure in two cases with renovascular hypertension. They had hypertension with hyperreninemia and marked difference in plasma renin activity between both renal veins. Blood pressure significantly decreased after single oral administration of captopril. Renal arteriogram revealed significant stenosis in the main artery to the left (case 1) and right (case 2) kidney. Blood pressure response was evaluated after seven (case 1) and five (case 2) days of low salt and seven days (both cases) of high salt intake. Mean blood pressure in two patients was significantly decreased (case 1; 118 +/- 5.5 to 108 +/- 6.1 mmHg and case 2; 150 +/- 3.8 to 138 +/- 3.1 mmHg). Plasma renin activity was also decreased (case 1; 6.25 to 0.77 ng/ml/hr and case 2; 22.8 to 6.3 ng/ml/hr). In case 2, blood pressure elevated markedly during low salt intake, compared with blood pressure level during normal salt intake. The results suggest that excessive salt intake in patients with unilateral renovascular hypertension produces blood pressure reduction because of suppression of renin-angiotensin system. We concluded that in patients with unilateral renovascular hypertension dietary sodium depletion may be harmful, whereas salt supplement may have a beneficial effect.

Beneficial effects of angiotensin-converting enzyme inhibitor on renal function and glucose homeostasis in diabetics with hypertension.

The antihypertensive efficacy of enalapril and its effects on renal function and glucose homeostasis were investigated in 9 hypertensive patients with non-insulin-dependent diabetes mellitus. Enalapril therapy produced a significant fall in blood pressure (BP) (p less than 0.05) and a significant increase in renal blood flow (p less than 0.05) without a change in glomerular filtration rate. Furthermore, fasting plasma glucose was significantly reduced (p less than 0.01). Similarly, M value, as an index of plasma glucose control in diabetes, was significantly reduced from 19.6 to 10.1 (p less than 0.01). These findings suggested that the angiotensin-converting enzyme inhibitor enalapril was effective in reducing BP and improving renal function, and might improve glucose homeostasis in hypertensive diabetics.