Binding, degradation and pressor activity of angiotensins II and III after aminopeptidase inhibition with amastatin and bestatin

In the metabolism of angiotensin peptides by tissue angiotensinases, aminopeptidases A, B, M and leucine aminopeptidase have been identified as being particularly effective. Because the inhibitory actions of amastatin (AM) and bestatin (BE) are relatively specific for these aminopeptidases, we have examined the effects of these inhibitors on the binding, degradation and pressor activity of angiotensin II (AII) and angiotensin III (AIII). Within 30 min at 37 degrees C, significant metabolism of 125I-AII and 125I-AIII by homogenates of a block of tissue containing hypothalamus, thalamus, septum and anteroventral third ventricle regions of the brain was observed. A majority of 125I-AIII metabolism was due to soluble peptidases, whereas that of 125I-AII primarily resulted from membrane-bound peptidases. AM, BE and reduced incubation temperatures significantly decreased the metabolism of 125I-AII and 125I-AIII. After appropriate adjustments to reflect the proportion of intact radioligand bound, temperature- or inhibitor-induced decreases in metabolism were matched by corresponding increases in specific binding. Heat-treated bovine serum albumin, as a nonspecific peptidase inhibitor, had no effect on either the metabolism or binding of the ligands used. In accordance with their actions in vitro, i.c.v. administration of AM and BE prolonged the pressor activity of subsequently applied AII and AIII. Unexpectedly, the amplitude of the pressor response to AIII was increased by BE, whereas that to AII was decreased by AM. The results of this study indicate that the metabolism of AII and AIII by aminopeptidases is relatively specific and acts to modulate the actions of these peptides.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exposure to pesticides in ambient air

Abstract: Ambient air was monitored for pesticides at four sites in Coffs Harbour, a coastal town (population about 50 000) surrounded by banana plantations. Air was sampled continuously for five consecutive months during the peak agricultural spraying period using vacuum pumps set to sample one litre per minute through ORBO-42 adsorption tubes. Six pesticides were detected: three organochlorines and three organophosphates. The most commonly detected pesticide (14 per cent of all samples) was chlor-pyrifos (maximum detected level 208.0 ng/m³, mean 3.6 ng/m³). Heptachlor was detected in 7.1 per cent of all samples (maximum detected level 133 ng/m³, mean 2.7 ng/m³). Other pesticides were only rarely detected. The only pesticide applied by air in the district (propiconazole) was not detected. If international health guidelines are used as a yardstick, these levels of exposure appear unlikely to present an appreciable health risk. Chlorpyrifos detection was associated with low wind speed (P = 0.012) and high temperature (P = 0.015), and detection at one site was associated with detection at another (P < 0.001). Chlorpyrifos detection was also associated with domestic applications within the town area as reported by pesticide applicators (P = 0.045). Peak agricultural use of chlorpyrifos did not coincide with peak detection periods. None of the detected organochlorines is registered for agricultural use, although at the time, heptachlor was permitted for use as a domestic termiticide. Even in a semirural town with nearby widespread use of agricultural chemicals, community exposures to pesticides in ambient air may largely relate to their nonagricultural use.     

Wallerian degeneration in the optic nerve of the wabbler-lethal (wl/wl) mouse.

Optic nerve pathology was studied in C57BL/6J wabbler-lethal (wl/wl) and control (+/+) mice at postnatal age of 4 weeks (P28). Qualitative light and ultrastructural pathology in wl/wl animals conformed to the criteria of primary axonal (Wallerian) degeneration. Most optic nerve axons in mutant animals appeared normal, as did oligodendroglia, the degree of myelination, the integrity and maturity of vascular elements, astroglia, and most myelin. Still, degenerating axons surrounded by somewhat normal myelin and axons with thickened myelin sheaths were prevalent in wl/wl mice. Dysmyelination or hypomyelination was not evident. At P28, pathology appeared more prominent in large diameter fibers. In the optic nerve of wl/wl mice, axonal degeneration preceded myelin disruption, adding this nerve to other previously reported systems undergoing Wallerian degeneration in this mutant.     

Comparative investigation of the influence of nizatidine, ranitidine, and cimetidine on the steady-state pharmacokinetics of theophylline in COPD patients.

The influence of usual regimens of the H2 blocking drugs, cimetidine, ranitidine, and nizatidine on the steady-state plasma concentrations and pharmacokinetic characteristics of theophylline was studied in seventeen patients with chronic obstructive pulmonary disease (COPD). Patients were dosed to steady-state with an oral, sustained-release formulation of theophylline given in therapeutic doses twice daily for 2 weeks. Over the next 4 weeks, each patient received a week-long regimen of each H2 blocker concomitantly with theophylline, and a week-long regimen of theophylline alone (control). At the end of each of the latter 4 weeks the steady-state pharmacokinetics of theophylline were assessed. Neither ranitidine nor nizatidine treatment altered the steady-state pharmacokinetics of theophylline relative to the control phase (i.e. no H2 blocker treatment). Values for theophylline C(ave), Cssmax, AUC0-12, and CLoral were significantly different during cimetidine treatment compared with all other treatments (ranitidine, nizatidine, and control). Cimetidine increased theophylline Cssmax, AUC0-12 and Cave by approximately 32%, and decreased theophylline oral clearance by approximately 23%. The authors conclude that cimetidine alters the steady-state pharmacokinetics of theophylline in COPD patients, whereas ranitidine and nizatidine are without effect.     

Distal interphalangeal joint abnormalities in children with polyarticular juvenile rheumatoid arthritis

Involvement of the distal interphalangeal (DIP) joints was noted radiographically in 24 (43.6%) of 55 patients with polyarticular juvenile rheumatoid arthritis. DIP changes were apparent later in the course of the disease and were less severe than in other affected joints. Soft tissue swelling and joint space narrowing were the most frequent abnormalities in the DIP joints. Erosive changes and angular deformities were uncommon. There was no significant correlation between DIP joint involvement and sex, age at presentation, involvement of the hands and wrists at presentation, or positivity of either rheumatoid factor or antinuclear antibody. There was a strong correlation between the presence of extraarticular signs and symptoms and involvement of the DIP joints; however, this may reflect the greater severity of the disease in these patients generally.     

Surface-coil MR imaging of orbital neoplasms

Fifteen patients with orbital neoplasms demonstrated by CT were studied with magnetic resonance (MR) using a 13 cm surface coil and a 0.6 T superconducting magnet. The use of a surface coil allowed for a reduction in slice thickness and a significant improvement in spatial resolution resulting in better demonstration and improved characterization of orbital lesions. All neoplasms (15/15) were demonstrated by MR. The lesions were grouped into four main categories on the basis of signal intensities on T1- and T2-weighted images. CT was superior to MR in displaying densely calcified or bony lesions (two of 15 cases). MR was at least equal or superior to CT in demonstrating the other lesions (13 of 15 cases) and had the added advantage of improved tissue characterization in some cases. With the use of surface coils, MR could become the primary imaging technique for evaluation of orbital neoplasms.     

Corticosterone controls the developmental emergence of fear and amygdala function to predator odors in infant rat pups

In many altricial species, fear responses such as freezing do not emerge until sometime later in development. In infant rats, fear to natural predator odors emerges around postnatal day (PN) 10 when infant rats begin walking. The behavioral emergence of fear is correlated with two physiological events: functional emergence of the amygdala and increasing corticosterone (CORT) levels. Here, we hypothesize that increasing corticosterone levels influence amygdala activity to permit the emergence of fear expression. We assessed the relationship between fear expression (immobility similar to freezing), amygdala function (c-fos) and the level of corticosterone in pups in response to presentation of novel male odor (predator), littermate odor and no odor. CORT levels were increased in PN8 pups (no fear, normally low CORT) by exogenous CORT (3 mg/kg) and decreased in PN12 pups (express fear, CORT levels higher) through adrenalectomy and CORT replacement. Results showed that PN8 expression of fear to a predator odor and basolateral/lateral amygdala activity could be prematurely evoked with exogenous CORT, while adrenalectomy in PN12 pups prevented both fear expression and amygdala activation. These results suggest that low neonatal CORT level serves to protect pups from responding to fear inducing stimuli and attenuate amygdala activation. This suggests that alteration of the neonatal CORT system by environmental insults such as alcohol, stress and illegal drugs, may also alter the neonatal fear system and its underlying neural control.     

Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation

The receptor tyrosine kinase (RTK) Ret is activated by the formation of a complex consisting of ligands such as glial cell line-derived neurotrophic factor (GDNF) and glycerophosphatidylinositol-anchored coreceptors termed GFRalphas. During activation, Ret translocates into lipid rafts, which is critical for functional responses to GDNF. We found that Ret was rapidly ubiquitinated and degraded in sympathetic neurons when activated with GDNF, but, unlike other RTKs that are trafficked to lysosomes for degradation, Ret was degraded predominantly by the proteasome. After GDNF stimulation, the majority of ubiquitinated Ret was located outside of lipid rafts and Ret was lost predominantly from nonraft membrane domains. Consistent with the predominance of Ret degradation outside of rafts, disruption of lipid rafts in neurons did not alter either the GDNF-dependent ubiquitination or degradation of Ret. GDNF-mediated survival of sympathetic neurons was inhibited by lipid raft depletion, and this inhibitory effect of raft disruption on GDNF-mediated survival was reversed if Ret degradation was blocked via proteasome inhibition. Therefore, lipid rafts sequester Ret away from the degradation machinery located in nonraft membrane domains, such as Cbl family E3 ligases, thereby sustaining Ret signaling.