Effects of the new potassium channel opener JTV-506 on coronary vessels in vitro and in vivo

The vascular effects of JTV-506 ((-)-(3S,4R)-2.2-bis(methoxymethyl)- 4-[(1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl)amino]-3-hydroxychroman+ ++-6- carbonitrile hemihydrate, CAS 170148-29-5), a new potassium channel opener, was evaluated in isolated coronary arteries and anesthetized dogs. JTV-506 (1 nmol/l-3 mumol/l) produced a concentration-dependent relaxation in porcine isolated epicardial large coronary arteries precontracted with KCl (30 mmol/l), phenylephrine (3 mumol/l), histamine (3 mumol/l), serotonin (5-HT; 300 nmol/l), prostaglandin F2 alpha (PGF2 alpha; 10 mumol/l), U-46619 (100 nmol/l), endothelin-1 (ET-1; 30 nmol/l) and Bay K-8644 (100 nmol/l). JTV-506 was 2.5-8.5 and 13.3-81.5 times more potent than levcromakalim (CAS 94535-50-9) and nicorandil (CAS 65141-46-0), respectively, but was less potent than nifedipine (CAS 21829-25-4). JTV-506 and levcromakalim produced almost a complete relaxation in arteries precontracted with various kinds of vasoconstrictor, except for KCl. In contrast, nifedipine produced about 80-90% relaxation in arteries, precontracted with PGF2 alpha, U-46619 and ET-1. Thus, this potassium channel opener can be characterized as an agonist-nonselective vasorelaxant. The relaxing effects of JTV-506 and levcromakalim on coronary arteries precontracted with 30 mmol/l KCl was competitively antagonized by 3 mumol/l glibenclamide, an ATP-sensitive potassium (KATP) channel blocker. In canine isolated epicardial large coronary arteries, 10 mumol/l JTV-506, 10 mumol/l levcromakalim, 100 mumol/l nicorandil and 0.1 mumol/l nifedipine eliminated 10 mmol/l 3,4-diaminopyridine-induced rhythmic contractions. In anesthetized dogs, when administered directly into the coronary artery, JTV-506 induced dose-dependent increases in coronary arterial diameter and coronary blood flow. These results suggest that JTV-506 elicits coronary vasorelaxation through activation of the KATP channel. It is expected that JTV-506 might be useful in the treatment of coronary vasospasm in angina pectoris.     

Epidermal growth factor receptor is indispensable for c-Fos expression and protein synthesis by angiotensin II.

We have reported that angiotensin II induces the epidermal growth factor (EGF) receptor transactivation leading to extracellular signal-regulated kinase (ERK) activation in rat vascular smooth muscle cells. Here, we report that the EGF receptor kinase inhibitor AG1478 and the ERK kinase inhibitor PD98059 markedly inhibited angiotensin II-induced c-Fos expression and protein synthesis but not c-Jun expression in these cells. These data suggest that the EGF receptor transactivation and subsequent ERK activation are indispensable for angiotensin II-mediated growth promotion of vascular smooth muscle cells providing a new mechanistic insight whereby angiotensin II contributes abnormal vascular remodeling.     

An immunohistochemical and immunoelectron microscopic study of adhesion molecules in synovial pannus formation in rheumatoid arthritis

To investigate the mechanism of synovial pannus formation in rheumatoid arthritis, immunohistochemical and immunoelectron microscopic studies with monoclonal antibodies against the adhesion molecules, CD54 (ICAM-1), CD 11a (LFA-1), CDw49a (VLA-1), CDw49b (VLA-2), CDw49c (VLA-3), Cdw49d (VLA-4) and CDw49e (VLA-5), were carried out to determine the pattern of distribution of these molecules at the rheumatoid synovial cartilage junction. Treatment with anti-ICAM-1 resulted in membrane staining of most of the macrophages and fibroblasts infiltrating the synovial tissue and bordering the pannus-cartilage junction, suggesting the possibility that ICAM-1 may function to facilitate the adhesion of synovial type A cells bearing ICAM-1 to type B cells of the pannus. ICAM-1-positive macrophages and fibroblasts were often found to be in contact with lymphoid cells, suggesting also that a cellular immune reaction occurs in the formation of the pannus. In addition, VLA-3, VLA-4 and, particularly, VLA-5 were the predominant1 integrins expressed by rheumatoid synovial pannus. Since these three integrins all function as fibronectin receptors, it is possible that the fibronectin-rich environment of the rheumatoid cartilage surface effectively traps pannus cells expressing high levels of these molecules. The VLA-5 molecule was found in a pericellular and interterritorial matrix distribution in the present study, strongly suggesting that a recepfor-ligand interaction between VLA-5 and cartilage matrix may occur at the early stage of pannus formation. Furthermore, an increase in1 integrin may be necessary for the growth of the pannus and also for the upregulation of the VLA molecules, leading secondarily to increased attachment.     

Nicardipine inhibits acute rise of aqueous flare and intraocular pressure induced by argon laser photocoagulation

The purpose of this study was to examine the anti-inflammatory effect of the calcium channel blocker nicardipine. Intraocular inflammation was induced by argon laser photocoagulation of the iris of pigmented rabbits and was assessed by measuring aqueous flare and intraocular pressure. This resulted in a marked increase in the aqueous flare that peaked at approximately one hour following coagulation and returning to the original values after six hours. Intraocular pressure increased within 15 minutes following laser treatment and returned to baseline levels at 60 minutes. Pre-treatment of the rabbits with an intravenous injection of 2 mg/kg of nicardipine completely abolished both the increase in aqueous flare and intraocular pressure induced by laser photocoagulation as compared to the control experiment. Earlier work from the author's group has shown that nicardipine can also block aqueous flare and intraocular pressure increases induced by topical administration of prostaglandin E2. From these combined experiments they would like to draw the conclusion that the inflammatory reaction induced by photocoagulation of the iris is partly mediated by prostaglandins and that blockade of calcium channels by nicardipine can inhibit the effects induced by prostaglandin E2.     

More than 10 years of follow-up of two patients after total femur replacement for malignant bone tumor

One patient with osteosarcoma and one with Ewing’s sarcoma of the femur were in 1987 and 1988 treated with prosthetic replacement of the femur and chemotherapy. There has been no loosening of the prostheses and no recurrence of the tumor. The patients have maintained 60% and 63% limb function scores evaluated by ISOLS criteria.

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Résumé  Deux patients, l’un avec un ostéosarcome, l’autre avec un sarcome d’EWING, furent opérés en 1987–1988 avec remplacement prothétique du fémur, associéà une chimiothérapie. Ces patients ont été suivis sans qu’il soit noté de récidive. Il n’y a pas de descellement, ni de luxation de la prothèse. Un score fonctionnel évalué selon les critères de l’ISOLS, montre une conservation de 60% et 63% de la fonction du membre inférieur.

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Accepted: 17 March 2000     

Repair of nerve gap with the elongation of Wallerian degenerated nerve by tissue expansion

We have found previously that expansion of the Wallerian degenerated nerve was accompanied by accelerated Schwann cell proliferation. In this study, we investigated the usefulness of the elongation of Wallerian degenerated nerve for the repair of short nerve gap. Male Wistar rats were used. After the left sciatic nerve was transected the rats were divided into 4 groups. In the control group, nerve coaptation was not performed. In group 1, tensionless coaptation was performed immediately. In group 2, delayed tensionless coaptation was performed with the elongation of Wallerian degenerated nerve. In group 3, coaptation was performed immediately with autologous interposition nerve graft. The ideal tensionless nerve repair of group 1 was considered to produce the best result. Rats in group 2 showed functional recovery as good as rats in group 1. On histologic assessment, in group 2, a fibrous capsule that was very rich in vascularity was formed around the tissue expander. After 14 weeks, the capsule was diminished markedly in size, but the vascularity was rich around the sciatic nerve. We think that the excellent functional recovery seen in group 2 can be attributed to the increased activity of Schwann cell proliferation and increased vascularity.     

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.