The inhibitory effect of KT3-671, a nonpeptide angiotensin-receptor antagonist, on rabbit and rat isolate vascular smooth muscles: a possible involvement of K(ATP) channels

The vasoinhibitory effect of KT3-671, a recently synthesized nonpeptide angiotensin II (Ang II), AT1-receptor antagonist, and the factors affecting insurmountable antagonism of Ang II were examined in rabbit and rat isolated vascular smooth muscle preparations. In rabbit and rat aortic rings, KT3-671 caused insurmountable antagonism of Ang II. In addition, KT3-671 inhibited contractile responses to angiotensin III (Ang III). In rabbit isolated smooth muscles, KT3-671 was most effective in reducing the maximal contraction induced by Ang II in the renal artery followed by the basilar artery and the aorta. In rat renal arterial rings, KT3-671 (10(-5) M) inhibited the concentration-response curves of prostaglandin F2alpha and STA2. In rabbit and rat aortic rings without endothelium, the insurmountable antagonisms of Ang II by KT3-671 and EXP 3174 were changed to surmountable antagonism by pretreatment with DuP 753 and KT3-671, respectively. In addition, KT3-671 abolished the inhibitory effect of CV- 11974 in the rat aorta but not in the rabbit aorta. Indomethacin (10(-5) M) or the removal of endothelium did not affect the inhibitory effect of Ang II by CV-11974 or EXP 3174 but enhanced the insurmountable antagonism by KT3-671. ODQ (3 x 10(-6) M), N(G)-nitro-L-arginine (3 x 10(-4) M), 4-aminopyridine (3 x 10(-3) M), tetraethylammonium (TEA; 10(-3) M), or iberiotoxin (10(-7) M) did not affect the inhibitory action of KT3-671 or CV-11974. Methylene blue (3 x 10(-6) M), KCl (10(2) M), TEA (10(-2) M), or BaC12 (10(-4) M) changed the insurmountable antagonism by KT3-671 to surmountable antagonism and abolished the inhibitory effect of CV-11974. However, glibenclamide (3 x 10(-6) M) did not affect the inhibitory action of KT3-671 but reduced the insurmountable antagonism by CV- 11974. These results indicate that KT3-671 is an insurmountable antagonist of Ang II in the rabbit and rat aorta. The results in the rat aorta also suggest that K(ATP) channels may be involved in insurmountable antagonism of Ang II by KT3-671 and CV-11974. Key Words: KT3-671-Rabbit-Rat-Vascular smooth muscle-Angiotensin II-Insurmountable antagonist-K(TP)channels.     

Serum Lipid and Lipoprotein Levels in School Age Population of a Middle-class Urvan Town in Japan

In a study of risk factors for coronary heart disease (CHD) in Japanese schoolchildren, serum cholesterol and triglyceride were measured in 3813 fasting schoolchildren ages 6 to 18 years, and simultaneously serum high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were measured in a randomly selected subsample of 2579 children. Mean and standard deviations as well as the fifth, 50th and 95th percentiles for serum cholesterol, triglyceride, HDLC and LDL-C for males and females were summarized by the age groups. The percentage of serum cholesterol levels higher than 200 mg/dl and triglyceride levels higher than 140 mg/dl by sex and age were also shown. In the light of the present results, it is concluded that the serum cholesterol, triglyceride, HDL-C and LDL-C levels are suggested to be on the same level with those in the United States. Accordingly, the present results also appear to emphasize the importance of further studies on the serum lipid and lipoprotein levels in Japanese children, as they are emphasized in the Western countries with high CHD mortality rates.     

The effects of delayed treatment with sialyl Lewis X against lipopolysaccharide-induced acute lung injury in rabbits

The therapeutic effects of a selectin inhibitor against lipopolysaccharide-induced acute lung injury were studied in rabbits by using sialyl Lewis X-oligosaccharide. Lipopolysaccharide-induced acute lung injury, as characterized by an impairment of pulmonary gas exchange, clinically resembles that of the acute respiratory distress syndrome. Delayed treatments with sialyl Lewis X-oligosaccharide (55 mg kg(-1) i.v. bolus injection 0.5, 1 or 2 h after lipopolysaccharide administration+36 mg kg(-1) h(-1) i.v. infusion for 5.5, 5 or 4 h, respectively) prevented the lipopolysaccharide-induced impairments in pulmonary gas exchange, as well as the accumulation of polymorphonuclear leukocytes in the lung tissue. In contrast, this agent had no significant effects on lipopolysaccharide-induced systemic hypotension, the decrease in the number of circulating white blood cells and platelets or the decline in blood pH.This is the first demonstration that sialyl Lewis X-oligosaccharide is effective against the impairments in pulmonary gas exchange even if administered 0.5, 1 or 2 h following the lipopolysaccharide injection.     

Methods of sleep induction for EEG recordings: comparison between three hypnotics and natural sleep

We compared the effects of three oral hypnotics, monosodium trichloroethyl phosphate (MTP), chloral hydrate (CH), and pentobarbital calcium (PTB), to those of non-medication on wake-sleep states and sleep activation of epileptic seizure discharges. The subjects consisted of 410 epileptics and 171 non-epileptic outpatients (mean age: 12.5 years) of the Department of Pediatrics, Nagoya City University Hospital. Complete EEG records including awake and sleep states were obtained in 230/241 (95%) of patients with MTP, 20/22 (91%) of those with CH, 72/85 (85%) of those with PTB, and 225/233 (97%) of those without any hypnotics. There were no statistically significant differences in the effect of sleep induction among the four groups. Sleep activation effects were observed in 25% of patients with natural sleep and 35% of those with induced sleep. There was no statistical difference (p > 0.05). These results suggested MTP, CH, and PTB are useful hypnotics for sleep EEG recordings.     

Activation of matrix metalloproteinase-2 in head and neck squamous cell carcinoma: studies of clinical samples and in vitro cell lines co-cultured with fibroblasts

We undertook this present study to investigate the activation of matrix metalloproteinase-2 (MMP-2) in human head and neck squamous cell carcinomas (HNSCC) tissues and cell lines. Gelatinolytic activities of active MMP-2 were significantly higher in carcinoma samples than in normal portions. Furthermore, the activation ratio of proMMP-2 significantly correlated with cervical lymph node metastasis. In vitro studies revealed an HNSCC cell line, HEp-2, to produce neither the pro form nor the active form of MMP-2, but human fibroblasts were found to produce proMMP-2. However, coculture of HEp-2 cells with fibroblasts resulted in the production of not only proMMP-2 but also activeMMP-2 in the culture medium. Northern blot analysis revealed a stronger expression of membrane-type 1 matrix metalloproteinase (MT1-MMP),which is a specific activator of MMP-2, mRNA in HEp-2 cells than in fibroblasts. These results suggest the activation of proMMP-2 as an important event in the process of HNSCC metastasis. They also suggest MMP-2 is secreted in its pro form by stromal fibroblasts surrounding the cancer cells and activated by MT1-MMP localized on the cancer cells.     

A case of biloma caused by early complications of hepatic artery infusion chemotherapy

We report a 70-year-old male who had biloma as an early complication of hepatic artery infusion chemotherapy. The patient had a history of subtotal gastrectomy for a advanced gastric cancer. Two years after the primary operation on the stomach, a solitary metastatic liver tumor was indicated by follow-up abdominal CT, and a segmental hepatectomy was performed. Soon after the hepatectomy, intraarterial catheter placement was performed via the left subclavian artery for preventive chemotherapy. Infusion chemotherapy of 10.5 g 5-FU and 75 mg CDDP was administered for a month, during which time the patient had liver dysfunction, fever, tenderness, and abdominal fullness. Abdominal CT revealed a large low density mass at a lateral segment of the liver which could not be seen on the previous CT image. Also, extravasation of contrast media was identified by angiography via the reservoir catheter. Using an interventional technique, percutaneous transhepatic drainage for biloma and extubation of the reservoir catheter were performed. The present case is thought to be of an early and rare complication of hepatic artery infusion chemotherapy. The etiology is discussed herein.     

Differential profiling analysis of proteins involved in anti-proliferative effect of interferon-alpha on renal cell carcinoma cell lines by protein biochip technology

Interferon-alpha (IFN) is widely used for the treatment of progressive renal cell carcinoma (RCC), but its effective response rate is only about 15%. New biomarkers of RCC contributing to the effective IFN treatment are needed to establish a sensitivity test for evaluating if the IFN is effective or not against RCC. All the proteins expressed in the IFN-susceptible and -resistant RCC cell lysates were analyzed by surface enhanced laser desorption ionization (SELDI) mass spectrometry using ProteinChip technology and their different protein expression were detected by the comparison of the profiles between them. We detected the following candidate markers that exhibited peak shifts: a) in the IFN-susceptible cell lines, a candidate marker with a molecular weight of 5,688 Da was detected on a hydrophobic (H4) chip: b) in the IFN-resistant cell lines, candidate markers each with a molecular weight of 8,049, 3,157, 3,993, and 8,959 Da were detected on strong anion exchange (SAX2, pH 9.0, two types) chips, H4 chip, and weak cation exchange (WCX, pH 9.0) chips, respectively. IFN treatment produced no weight increase in these four proteins, and c) candidate marker with a molecular weight of 1,623 Da that was expressed in both cell lines after the IFN treatment was detected on the H4 chip. These data suggest that the ProteinChip system is very useful in identifying proteins showing unique peaks in the RCC cell lines with different IFN susceptibility, and the comparison of these proteins measured in RCC cell lysates may help to identify the IFN sensitivity. Furthermore, the discovery of a susceptibility and or a inhibitory factor may eventually lead to the development of a novel drug targeting the respective factor for the improvement of anticancer chemotherapy.