DIFFERENCES IN ENDOTHELIUM-DEPENDENT RELAXATION IN VARIOUS ARTERIES FROM WATANABE HERITABLE HYPERLIPIDAEMIC RABBITS WITH INCREASING AGE

1. Endothelium-dependent relaxation in response to acetylcholine (ACh) and the calcium ionophore A 23187 was examined in aorta, coronary, basilar and renal arteries isolated from Watanabe heritable hyperlipidaemic (WHHL) rabbits of 2, 6 and 12 months of age, with normolipidaemic heterozygous WHHL rabbits as controls. 2. In the rings of WHHL rabbit aortae and coronary arteries preconstricted with vasoconstrictors, endothelium-dependent relaxation in response to ACh was attenuated with age compared to the heterozygous WHHL rabbits. A significant negative correlation was found between the total cholesterol content and the relaxation response to ACh in the aortae or coronary arteries from 6 and 12 month old WHHL rabbits. 3. In the rings of basilar arteries, endothelium-dependent relaxations to ACh were not modified with age. Similarly, in the rings of renal arteries, the relaxation response to ACh was not changed with age, but in the 6 and 12 month preparations, after the age of 6 months, a contraction following the relaxation appeared at higher concentrations of ACh (10^?7 to 10^?6 mol/L). The contraction was endothelium-dependent and inhibited by indomethacin. 4. A 23187-induced endothelium-dependent relaxations were also markedly attenuated in the aorta and significantly in the coronary artery with age. 5. Endothelium-independent relaxation to sodium nitroprusside was not changed in all arteries from WHHL rabbits of different ages. 6. These findings indicate that in the aorta and coronary artery of the WHHL rabbit, the endothelium-dependent relaxation to ACh and A 23187 becomes impaired with increasing age (i.e., with the progression of cholesterol deposition in the arterial wall) but is preserved in the basilar and renal artery.     

Aggressive resection for advanced pancreatic carcinoma

An aggressive pancreatectomy was performed on a 53 year old Japanese man with advanced cancer of the pancreas. The tumor originated from the body of the pancreas and invaded the stomach, duodenum, left kidney, transverse colon and common hepatic artery. An unexpected cancer was also found in the head of the pancreas during the operation. Therefore, total pancreatectomy, total gastrectomy, left adrenonephrectomy, resection of the left transverse colon and dissection of the regional lymph nodes were performed. Resection of the common hepatic artery was also performed, followed by an end-to-end anastomosis between the common hepatic artery and celiac trunk. The postoperative course was uneventful and the patient was doing well until nine months after the operation when multiple metastatic lesions were noted in the liver. He died 391 days after the operation from hepatic failure.     

Effects of elevated d-alpha(RRR)-tocopherol dosage in man

A study was conducted to investigate the effects of a megadosage of free RRR-alpha-tocopherol in healthy college student volunteers. Of 19 volunteers, 14 were given daily doses of 600 mg (900 IU) of RRR-alpha-tocopherol for 12 weeks, and the remaining 5 were given identical placebo capsules. The investigation was performed by the single-blind method. Alpha-tocopherol levels were measured in plasma, red blood cells (RBCs), platelets, leucocytes (WBCs), and buccal mucosal cells. Alpha-tocopherol in plasma, RBCs, and WBCs rose, reached a maximum level 4 weeks after commencement of administration, and then remained at a plateau, while platelet and buccal cell levels reached a maximum level after 12 weeks of administration. The maximum levels in all the subjects were 2.5 to 3 times the baseline values. During the study, there were no changes in laboratory values for thyroid, liver, or kidney functions, and coagulation activity (including the vitamin K-dependent Hepaplastin test and PIVKA-II) or immunoglobulin levels. Healthy status continued without any abnormal symptoms, and without any subjective complaints on the questionnaire. In the control group also, no changes occurred during the investigation. Gamma-tocopherol changes were measured in plasma and RBCs. As plasma and RBC tocopherol levels rose after administration, the isomer levels were suppressed in both plasma and RBCs.     

Effects of total parenteral nutrition with nucleoside and nucleotide mixture on D-galactosamine-induced liver injury in rats

The effect of a nucleoside-nucleotide mixture on liver injury of rats induced by D-galactosamine was studied by examining changes in function and histopathology of the liver. Animals with liver damage received total parenteral nutrition with glucose and amino acids supplemented with a nucleoside-nucleotide mixture containing inosine, cytidine, GMP, uridine and thymidine, or with uridine which inhibits galactosamine injury, or with liver cell extract containing flavin adenine dinucleotide and nucleic acid derivatives. As control, animals with liver damage received total parenteral nutrition with glucose and amino acids only. The serum GOT and GPT concentrations were significantly lower in the group supplemented with nucleoside-nucleotide mixture than those in other groups. A large dose (1.2 g/kg) of uridine inhibited liver injury, but a lower dose (0.14 g/kg) did not have any effect, whereas nucleoside-nucleotide mixture containing the same amount of uridine inhibited the injury. Liver cell extract also did not improve liver function. Thus infusion of a physiological and balanced mixture of nucleosides or nucleotides may improve liver function in rats with liver injury.     

Determination of beta-adrenoceptor subtype on rat isolated ventricular myocytes by use of highly selective beta-antagonists.

1. The relative proportions of beta 1- and beta 2-adrenoceptors were determined by radioligand binding studies in three different rat myocardial preparations: membranes prepared from rat ventricle (ventricular membranes), membranes prepared from rat isolated ventricular myocytes (myocyte membranes), and myocytes isolated from rat ventricle (myocytes). 2. Competition experiments using CGP 20712A or ICI 118,551 with [125I]-iodocyanopindolol ([125I]-ICYP) revealed high- and low-affinity binding sites in ventricular membranes. The concentration at which each beta-antagonist occupied 100% of its high-affinity binding sites was 300 nM for CGP 20712A (beta 1-adrenoceptor) and 50 nM for ICI 118,551 (beta 2-adrenoceptor). 3. The density of high-affinity (beta 1-adrenoceptor) and low-affinity (beta 2-adrenoceptor) binding sites for CGP 20712A was measured by a saturation experiment using [125I]-ICYP in the presence and absence of 300 nM CGP 20712A. In ventricular membranes, the proportions of high-affinity and low-affinity binding sites for CGP 20712A were 73% and 27%, respectively, whereas in myocyte membranes, the corresponding figures were 90% and 10%, respectively. The density of low-affinity binding sites for CGP 20712A in ventricular membranes, defined as [125I]-ICYP-specific binding in the presence of 300 nM CGP 20712A, was decreased by addition of 50 nM ICI 118,551, whereas that in myocyte membranes was not affected. 4. In myocytes, specific binding of [125I]-ICYP and [3H]-CGP 12177 was not detected by saturation experiments performed in the presence of 300 nM CGP 20712A.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rupture of flexor tendons due to pisotriquetral osteoarthritis

We are reporting a case of a flexor profundus tendon rupture of the little finger due to pisotriquetral osteoarthrosis. Resection of the pisiform bone and resurfacing of the carpal tunnel with the joint capsule was performed for the osteoarthrosis and free tendon grafting for the tendon rupture. The tendon grafting and a subsquent tenolysis restored the function of the little finger. Other than radiological changes in the pisotriquetral joint, the diagnostic value of preoperative radiocarpal arthrography was emphasized in this rare complication of pisotriquetral arthrosis.     

Clonal growth of hepatitis B virus-integrated hepatocytes in cirrhotic liver nodules.

A total of 83 cirrhotic nodules (pseudolobules) individually collected from 11 cirrhotic livers of hepatitis B virus carrier patient were analyzed for the frequency and mode of hepatitis B virus integration as well as histological features. Southern blot analysis disclosed discrete bands at higher molecular weight region in 26 of 83 nodules (31.3%), indicating a clonal growth of hepatocytes with viral integration. Considerable variation (0-75%) existed in the positive rates for discrete bands in nodules among livers. Molecular cloning revealed the sequence flanking an integrated viral sequence to be host DNA and thus confirmed true integration. Histological analysis, however, did not reveal any neoplastic-appearing foci of growth within nodules, despite the fact that the detection sensitivity would predict clones of more than 10(5) cells to give rise to clonal integration patterns on Southern blot analysis. The question of whether clonal expansion of hepatocytes reflects any viral integration-associated growth advantage and/or a preneoplastic condition awaits future studies.     

Effects of ONO-3708, an antagonist of the thromboxane A2/prostaglandin endoperoxide receptor, on platelet aggregation and thrombosis

The beneficial effects of an antagonist of the thromboxane A2/prostaglandin endoperoxide receptor, 7-[2 alpha,4 alpha-(dimethylmethano)-6 beta-(2-cyclopentyl-2 beta- hydroxyacetamido)-1 alpha-cyclohexyl]-5(Z)-heptenoic acid (ONO-3708) on thrombosis were examined. ONO-3708 at 0.1-3 microM inhibited the human platelet aggregation induced by thromboxane A2, prostaglandin H2, collagen, ADP (secondary phase) and epinephrine (secondary phase) without affecting prostanoid synthesis and the content of cyclic AMP in platelets. The in vivo effects, on coronary thrombosis in this case, were examined in two canine models. ONO-3708, 3 to 300 micrograms/kg i.v., prevented dose dependently the coronary thrombosis induced by partial obstruction of the coronary artery. ONO-3708, 3 micrograms/kg per min i.v., significantly prevented electrically stimulated coronary thrombosis without affecting systemic blood pressure and heart rate. These results indicate that the thromboxane A2/prostaglandin endoperoxide receptor could play an important role in the pathogenesis of thrombosis and that ONO-3708 may have therapeutic advantages in preventing thrombosis.