The effect of furosemide on glucose oxidation of the cochlea and other tissues

We tested the hypothesis that furosemide interferes with energy generation in the cochlea, and determined its effect on CO2 formation from glucose and glyceroaldehyde-3-phosphate dehydrogenase (GAPDH) activity by examining biochemical and histochemical changes in the cochlea, the kidney, and the liver. We found that furosemide suppressed CO2 formation in vitro at relatively low concentrations in all tissues examined. GAPDH was inhibited as soon as 2 min after its administration (80 mg/kg, i.v.). Recovery of this enzyme activity was most rapid in the liver. We concluded that furosemide does interfere with energy generation in the cochlea, kidney, and liver as a result of its inhibition of GAPDH.     

Hemodynamic and hormonal effects of propranolol on patients with essential hypertension during head-up tilting: A comparison between normal and low cardiac index groups

Summary Twelve outpatients with essential hypertension who showed a normal cardiac index (CI) (between 2.5 and 3.6 1/min/m²) or low CI (2.5 and less 1/min/m²) were studied. Head-up tilting (70°) was performed for 15 min before and 2 weeks after treatment with propranolol (90 mg/day). Before treatment, the normal CI group showed a fall in systolic blood pressure (SBP) associated with a decrease in CI and an increase in the total peripheral resistance index (TPRI) during tilting. Conversely, the low CI group showed a rise in SBP associated with an increase in CI and a decrease in TPRI. There was a negative correlation (r=–0.69,P<0.05) between the basal CI and the change caused by the tilting. During treatment with propanolol, on the other hand, both groups showed decreases in CI.There was a greater increase in plasma renin activity (PRA) in the normal than in the low CI group before treatment with propranolol. The rise in PRA was significantly (P<0.05) suppressed by propranolol in the normal CI group only.It was demonstrated that the low CI group showed a different hemodynamic response to the tilting than the normal CI group. The lower rise in PRA may have partially contributed to the lack of increase in TPRI in the low CI group, compared with the normal CI group. Such hemodynamic differences may be abolished by propranolol which has a cardioinhibitory and/or renin-suppressive effect.     

Synthesis and antiarrhythmic activity of new 1-[1-[2-[3-(alkylamino)-2-hydroxypropoxy]phenyl]vinyl]-1 H-imidazoles and related compounds

Various 1-[1-[2-[3-(alkylamino)-2-hydroxypropoxy]phenyl]vinyl]-1 H-azoles were synthesized and investigated for beta-adrenoceptor-blocking and antiarrhythmic activities. Although no compounds showed more potent beta-blocking effects than propranolol in the isolated guinea pig right atria, many compounds exhibited significant antiarrhythmic effects against aconitine or ischemic arrhythmia in mice or dogs. 1-[2,5-Dichloro-6-[1-(1H-imidazol-1-yl)-ethenyl] phenoxy]-3-[(1-methylethyl)amino]-2-propanol hydrochloride (48) (711389-S) was selected as a candidate for clinical evaluation in man, since its antiarrhythmic effects were superior to those of quinidine, disopyramide, or propranolol. Asymmetric synthesis of (R)-(+)- and (S)-(-)-48 is described, and it is proven that there is no stereospecificity in the antiarrhythmic effect of 48.     

Synthesis,in vitro and in vivo pharmacology of a C-11 labeled analog of CP-101,606, (+/-)threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[11C]methoxyphenyl)piperidino]-1-propanol,as a PET tracer for NR2B subunit-containing NMDA receptors

A carbon-11 labeled methoxyl analog of CP-101,606, (+/-)threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[11C]methoxyphenyl)piperidino]-1-propanol [(+/-)[11C]1], was synthesized as a new subtype-selective PET radioligand for NMDA receptors. The in vitro binding studies using rat brain slices demonstrated that (+/-)[11C]1 shows an extremely high-specific binding to the NR2B subunit of NMDA receptors. In contrast to the in vitro binding, the in vivo binding to mouse and monkey brains showed no apparent specific localization of the radioactivity in any of the brain regions. Metabolism and physicochemical properties such as the lipophilicity of (+/-)[11C]1 seemed unlikely to affect the in vivo (+/-)[11C]1 binding. Among the various endogenous ligands acting at the NMDA receptors, polyamines (spermine and spermidine) and divalent cations (Mg(2+,) Zn(2+,) and Ca(2+)) strongly inhibited the in vitro (+/-)[11C]1 binding. Thus, the present studies point to the possibility that the polyamines and cations behave as endogenous inhibitors for (+/-)[11C]1 binding, leading to the loss of the specific binding in vivo.     

p38 MAPK phosphorylation and NF-kappa B activation in human crescentic glomerulonephritis.

BACKGROUND: p38 mitogen-activated protein kinase (p38 MAPK) followed by the activation of NF-kappa B participates in the intracellular signal transduction and production of cytokines and chemokines. The pathophysiological roles of p38 MAPK and NF-kappa B in human glomerulonephritis, however, remain to be investigated. METHODS: We investigated the phosphorylated p38 MAPK (p-p38 MAPK) and activated NF-kappa B immunohistochemically in the kidneys of 34 patients with crescentic glomerulonephritis and 26 control patients with thin basement membrane disease and minimal change nephrotic syndrome. We also explored the co-localization of p-p38 MAPK with CCR5, the signal of which leads to p38 MAPK activation. Furthermore, urinary levels of MIP-1 alpha, the cognate ligand for CCR5, were determined by enzyme-linked immunosorbent assay. RESULTS: p-p38 MAPK-positive cells and activated NF-kappa B-positive cells were mainly detected in crescentic lesions, tubular epithelial cells, and interstitial mononuclear infiltrates. The number of p-p38 MAPK-positive cells in patients with crescentic glomerulonephritis was higher than that in control patients. The number of p-p38 MAPK-positive cells in glomeruli was well correlated with the percentage of cellular crescents, the number of CD68-positive cells, and urinary MIP-1 alpha levels. In addition, the number of activated NF-kappa B-positive cells was well correlated with the number of p-p38 MAPK-positive cells in glomeruli. Dual staining revealed that most of CCR5-positive cells were positive for p-p38 MAPK. Finally, p-p38 MAPK-positive cells and activated NF-kappa B-positive cells decreased during glucocorticoid therapy-induced convalescence. CONCLUSIONS: We conclude that the phosphorylation of p38 MAPK associated with the activation of NF-kappa B may be involved in the upregulation of intrarenal MIP-1 alpha and the utilization of CCR5 signalling, which may result in human crescentic glomerulonephritis.     

Pseudomyxoma peritonei of appendiceal cancer with metastasis to the stomach: report of a case

Appendiceal cancer associated with pseudomyxoma peritonei is a relatively low-grade malignancy rarely associated with extraperitoneal metastasis. We report herein the case of a 71-year-old man in whom a metastasis was found in the stomach 2 years after he underwent surgery for pseudomyxoma peritonei of appendiceal cancer. He was referred to our hospital after presenting with anorexia and vomiting. Gastrofiberscopy, abdominal computed tomography, and ultrasound examination all revealed a mass 4 × 4 cm in size, containing a small ulcer, in the antrum of the greater curvature of the stomach. The histopathological diagnosis made from a biopsy of the tumor was mucinous cystadenocarcinoma. A distal partial gastrectomy was performed and the resected specimens from the appendiceal cancer resected 2 years earlier showed the same histological pattern as that of the gastric lesion. To the best of our knowledge, this is only the second report of pseudomyxoma peritonei secondary to mucinous cystadenocarcinoma of the appendix that metastasized to the stomach. Received: September 12, 2001 / Accepted: January 8, 2002     

Effect of lumbar disc herniation on clinical symptoms in lateral recess syndrome

This study investigated the differences in the clinical features of lateral recess syndrome attributable to the bony entrapment of the spinal nerve root under the superior articular facet, and lateral recess syndrome and associated lumbar disc herniation. Ninety patients with pure bony entrapment (47 men, 43 women) ranging in age from 19 to 83 years (mean age, 63 years) and 59 patients with lumbar disc herniation in the lateral recess (43 men, 16 women) 19 to 85 years of age (mean age, 49 years) were included in this study. All patients had L5 root radiculopathies and were treated surgically. Although the early symptoms of patients with lateral recess syndrome often were in the lower extremities, many of the patients with associated lumbar disc herniation had a transition initially experiencing low back pain and subsequently having lower extremity symptoms. Flexion and extension of the lumbar spine exacerbated symptoms, particularly in patients with lumbar disc herniation. The results of the current study show that the clinical presentation of lateral recess syndrome differs depending on the cause of the compression in the lateral recess.