22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis

22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis. BACKGROUND: 22-Oxacalcitriol (OCT) is a unique vitamin D analogue with less calcemic activity than calcitriol, and it effectively suppresses parathyroid hormone (PTH) secretion in uremic rats. This study was performed to examine the long-term effect of intravenously administered OCT on high-turnover bone disease in model rats of slowly progressive renal failure. METHODS: Slowly progressive renal failure rats were made by a single injection of glycopeptide isolated from rat renal cortical tissues. At 250 days, glycopeptide-induced nephritis (GN) rats were divided into three groups with the same levels of serum creatinine and PTH, and they received either OCT (0.03 or 0.15 microg/kg body wt) or vehicle given intravenously three times per week for 15 weeks. RESULTS: Renal function of GN rats deteriorated very slowly but progressively, as assessed by the increase of serum creatinine concentration. At sacrifice, serum PTH levels, bone formation markers, bone resorption markers, and fibrosis volume were significantly elevated in vehicle-treated GN rats compared with those of sham-operated rats, suggesting the development of high-turnover bone disease with osteitis fibrosa. In contrast, in the GN-OCT 0.15 microg/kg group, these high PTH levels and high-turnover bone and fibrosis were significantly decreased. Such amelioration of bone abnormalities by OCT was not accompanied by either hypercalcemia or further deterioration of renal function. CONCLUSIONS: These data indicate that OCT may be a useful and safe agent not only for the suppression of PTH, but also for the amelioration of osteitis fibrosa and high-turnover bone without causing hypercalcemia in chronic dialysis patients.     

Analysis of alpha1-adrenoceptor subtypes in rabbit aorta and arteries: regional difference and co-existence.

This study was done to determine the alpha1-adrenoceptor subtypes and to characterize the functional role of alpha1D-adrenoceptors in the following rabbit arteries: thoracic and abdominal aorta, mesenteric, renal and iliac arteries. In all arteries, selective alpha1D-adrenoceptor antagonist BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspirol(4,5) decane-7,9-dione dihydrochloride) dose dependently shifted the concentration-response curves for norepinephrine to the right. Schild plots of the results obtained from the inhibition by BMY 7378 for norepinephrine yielded a straight line with a slope of unity in thoracic (pA2 6.54+/-0.02) and abdominal (pA2 6.73+/-0.03) aorta. Slopes of Schild plots obtained from the inhibition by BMY 7378 for norepinephrine were significantly different from unity in mesenteric, renal and iliac arteries. Slopes of Schild plots for BMY 7378 were not different from unity in chloroethylclonidine-treated thoracic (pA2 6.49+/-0.14) and abdominal (pA2 6.61+/-0.11) aorta. Slopes of Schild plots for BMY 7378 were significantly different from unity in chloroethylclonidine-treated mesenteric, renal and iliac arteries. On the other hand, in Ca2+-free physiological saline solution (Ca2+-free PSS) slopes obtained from Schild plots for BMY 7378 were not different from unity in thoracic (pA2 6.41+/-0.09) and abdominal (pA2 6.28+/-0.07) aorta and mesenteric (pA2 6.55+/-0.06), renal (pA2 6.24+/-0.10) and iliac (pA2 6.64+/-0.13) arteries. BMY 7378 inhibited [3H]prazosin binding to thoracic (pKi 6.44+/-0.08) and abdominal (pKi 6.59+/-0.02) aorta with low potency, and mesenteric (pKi High 8.66+/-0.28, pKi Low 6.34+/-0.14), renal (pKi High 8.71+/-0.33, pKi Low 6.45+/-0.03) and iliac artery (pKi High 8.60+/-0.24, pKi Low 6.56+/-0.13). These results suggest that alpha1D-adrenoceptors play a significant role for contractile responses in renal and iliac artery, but play virtually no role in thoracic and abdominal aorta and that an alpha1-adrenoceptor subtype, which is pharmacologically distinguishable from the alpha1A-, alpha1B- and alpha1D-adrenoceptor subtype, may co-exist in mesenteric artery.     

Pharmacological evidence that tetraethylammonium-sensitive,iberiotoxin-insensitive K+ channels function as a negative feedback element for sympathetic neurotransmission by suppressing ω-conotoxin-GVIA-insensitive Ca2+ channels in the relaxation of rabbit facial vein

Naunyn-Schmiedeberg's Archives of Pharmacology -     

The effect of exogenous nitric oxide on endothelial dysfunction in two-kidney, one-clip renovascular hypertensive rats

Previous studies have shown that hypertension causes endothelial dysfunction. To study the influence of exogenous nitric oxide(NO) on endothelial dysfunction produced by hypertension, we administered a non-depressor dose of nipradilol to two-kidney, one-clip renovascular hypertensive rats(2K1C). Sprague-Dawley rats underwent either sham surgery(G-1) or clipping of the left renal artery. From day seven, 2K1C were randomized into 3 groups, placebo treatment(G-2), nipradilol treatment(G-3,) and propranolol treatment(G-4). Urinary NO2- + NO3-(NOx) excretion (UNOx V) was measured 4 weeks after clipping, and then, acetylcholine(Ach), A23187, or sodium nitroprusside(SNP)-induced relaxation were measured in the aorta. Blood pressure was increased in G-2, G-3, and G-4 compared to G-1. UNOx V was lower in G-2, G-3, and G-4 compared to G-1, but UNOx V was higher in G-3 compared to G-2 and G-4. Although Ach or A23187-induced relaxation was significantly decreased in isolated artery from G-2, G-3, and G-4 compared with those from G-1. Ach- or A23187-induced relaxation was improved in G-3. SNP-induced relaxation did not differ among the 4 groups. These results suggest that exogenous NO from nipradilol reduces the endothelial dysfunction caused by hypertension without changing the blood pressure.     

A cancer-prone case with a background of methylation of p16 tumor suppressor gene.

PURPOSE AND EXPERIMENTAL DESIGN: To date, the presence of p16 gene promoter methylation associated with loss of protein expression has been demonstrated frequently in digestive tract cancers. In this study, we tested for the methylation status of p16 promoter in normal tissue specimens using the methylation-specific PCR technique to examine whether p16 methylation already existed in the background of tumors. RESULTS: Aberrant promoter methylation of p16 gene was detected in 1 of 40 esophageal and 1 of 69 gastric and no colorectal epithelium specimens, and these 2 specimens were derived from the same patient. We also found the same methylation change in both tumor and blood cell DNA. CONCLUSION: These results suggested that the p16 gene was inactivated by methylation in normal background cells of this patient and that other additional factors may promote tumor development in his esophageal and gastric tissues.     

Nitric oxide and aneurysm formation in Kawasaki disease

The objective of this study is to show that nitric oxide plays a role in the development of coronary artery abnormalities in Kawasaki disease. We examined nitrite + nitrate, biopterin and neopterin in 316 urine samples of 34 patients with Kawasaki disease, those of 24 patients with other diseases, and those of 25 healthy children acting as a control group, because urinary nitrite + nitrate are reportedly useful as markers of nitric oxide generation in vivo , and pathways for neopterin-biopterin synthesis and nitric oxide generation are tightly coupled. In our study, the children with Kawasaki disease excreted more urinary nitrite + nitrate and neopterin than did the healthy control group children and excreted abnormally high quantities more often than did the patients with other diseases. Good relationships were found between the urinary nitrite + nitrate levels and the urinary biopterin levels, and between these biopterin levels and the urinary neopterin levels. Nitric oxide is therefore thought to be generated in abnormally high quantities, and to be closely related to the pathology of Kawasaki disease and to the development of coronary artery abnormalities. The role of nitric oxide in Kawasaki disease should be further studied to elucidate the pathophysiology of the disease and to aid in the development of new treatments.     

Role of Sialylglycoconjugate(s) in the Initial Phase of Metastasis of Liver-metastatic RAW117 Lymphoma Cells

To elucidate the early events of blood-borne metastasis under actual blood flow, real-time trafficking of RAW117 large cell lymphoma cells, namely parental RAW117-P and liver-metastatic RAW117-H10 cells, was investigated using positron emission tomography (PET). Both types of cells accumulated in the liver immediately after injection via the portal vein, and were eliminated from the liver time-dependently. The elimination rate of RAW117-H10 cells, however, was slower than that of RAW117-P cells, suggesting that RAW117-H10 cells interact more strongly with hepatic sinusoidal endothelium than the parental cells. This result correlated with the metastatic potential of these cells: RAW117-H10 cells metastasized in the liver to a greater extent than RAW117-P cells after injection via this route. To investigate the role of sialylglycoconjugates in the interaction of RAW117-H10 cells with the hepatic endothelium after injection via the portal vein, the trafficking of RAW117-H10 cells was examined after the cells had been treated with sialidase. The elimination rate of RAW117-H10 cells from liver was observed to be greatly accelerated by sialidase treatment. To elucidate what kind of sialylglycoconjugates is related to this phenomenon, we analyzed the distribution of sialyl Lewis A and sialyl Lewis X antigens of both sublines of RAW117 by using flow cytometry. RAW117-H10 cells were found to express a much higher level of sialyl Lewis A than RAW117-P cells, whereas the amount of sialyl Lewis X did not differ significantly. These findings suggest that some sialylglycoconjugates, perhaps sialyl Lewis A in particular, play an important role in the initial interaction of RAW117-H10 cells with the hepatic endothelium, leading to metastasis.     

Role of sialylglycoconjugate(s) in the initial phase of metastasis of liver-metastatic RAW117 lymphoma cells.

To elucidate the early events of blood-borne metastasis under actual blood flow, real-time trafficking of RAW117 large cell lymphoma cells, namely parental RAW117-P and liver-metastatic RAW117-H10 cells, was investigated using positron emission tomography (PET). Both types of cells accumulated in the liver immediately after injection via the portal vein, and were eliminated from the liver time-dependently. The elimination rate of RAW117-H10 cells, however, was slower than that of RAW117-P cells, suggesting that RAW117-H10 cells interact more strongly with hepatic sinusoidal endothelium than the parental cells. This result correlated with the metastatic potential of these cells: RAW117-H10 cells metastasized in the liver to a greater extent than RAW117-P cells after injection via this route. To investigate the role of sialylglycoconjugates in the interaction of RAW117-H10 cells with the hepatic endothelium after injection via the portal vein, the trafficking of RAW117-H10 cells was examined after the cells had been treated with sialidase. The elimination rate of RAW117-H10 cells from liver was observed to be greatly accelerated by sialidase treatment. To elucidate what kind of sialylglycoconjugates is related to this phenomenon, we analyzed the distribution of sialyl Lewis A and sialyl Lewis X antigens of both sublines of RAW117 by using flow cytometry. RAW117-H10 cells were found to express a much higher level of sialyl Lewis A than RAW117-P cells, whereas the amount of sialyl Lewis X did not differ significantly. These findings suggest that some sialylglycoconjugates, perhaps sialyl Lewis A in particular, play an important role in the initial interaction of RAW117-H10 cells with the hepatic endothelium, leading to metastasis.     

Glomerular size in renal dysplasia secondary to obstructive uropathy: a further exploration of the fetal lamb model

BACKGROUND/PURPOSE: Creating an obstructive uropathy early in glomerulogenesis would produce multicystic dysplastic kidneys (MCDK). Measuring the mean planar area of the glomeruli (GMPA) may clarify the pathogenesis of MCDK. METHODS: Fetal lambs at 60 days' gestation had their left ureter ligated and were delivered by cesarian section at 145 days' gestation. Kidney weight and length were recorded. GMPA in 3 zones (outer, middle, inner) of the sectioned kidney was measured using a computerized planimeter. The obstructed kidneys were compared with contralateral unobstructed kidneys. The unpaired Student's t test was used to determine significance. RESULTS: One ewe miscarried. Four of 5 (80%) 60-day lambs survived. All had dysplastic kidneys. Mean kidney weights were 4.3 +/- 0.84 g in MCDK and 16.8 +/- 3.6 g in controls (P< .05). The GMPA of the outer, middle, and inner zones of the MCDK were 2.7 x 10(-3) mm2, 3.2 x 10(-3) mm2, and 4.0 x 10(-3) mm2, respectively. Controls were 2.8 x 10(-3) mm2, 4.4 x 10(-3) mm2, and 6.0 x 10(-3) mm2. The glomeruli of 60-day fetal kidneys were 3.0 x 10(-3) mm2, 6.1 x 10(-3) mm2, and 11.0 x 10(-3) mm2. MCDK had smaller glomeruli in the inner and middle zones than controls. CONCLUSION: Fetal glomeruli appear to grow from the inner zone of the kidney. Early urinary tract obstruction stops this growth.