Partially modified retro-inverso-enkephalinamides: topochemical long-acting analogs in vitro and in vivo.

The synthesis of four enkephalinamide analogs is described in which the peptide bond between residues 4 and 5 is reversed with or without simultaneous reversal of the carboxyl-terminal amide bond. These so-called partially modified retro-inverso-isomers are new, potent, topochemical analogs of the enkephalins. Tests, both in vitro and in vivo, have shown that these analogs are considerably longer acting than any previously studied enkephalins. Thus, partial reversal of the peptide bonds of the backbone can result in peptides with enhanced activity compared to a parent compound, provide that the structural complementarity of both the side chains and end groups are conserved.

beta-Endorphin and adrenocorticotropin are selected concomitantly by the pituitary gland.

The opiate-like peptide beta-endorphin and adrenocorticotropin are concomitantly secreted in increased amounts by the adenohypophysis in response to acute stress or long-term adrenalectomy as well as in vitro in response to purified corticotropin releasing factor and other secretagogues. Conversely, administration of the synthetic glucocorticoid dexamethasone inhibits the secretion of both adrenocorticotropin and beta-endorphin. Thus, both hormones possess common and identical regulatory mechanisms and there may be a functional role for circulating beta-endorphin.

beta-Endorphin secretion of arginine vasopressin in vivo.

The effect of beta-endorphin upon plasma arg8-vasopressin release was studied in vivo in rabbits and in vitro in rat neural lobes. Following intravenous administration of 200 mug/kg synthetic beta-endorphin plasma AVP rose significantly by five minutes after injection and remained elevated for twenty-five minutes compared to controls. In contrast beta-endorphin had no significant effect on AVP release from isolated rat neural lobes in vitro. beta-Endorphin stimulates AVP secretion in vivo, but this is not due to a direct action upon the neural lobe.

Regional dissociation of beta-endorphin and enkephalin contents in rat brain and pituitary.

beta-Endorphin and enkephalin in extracts of whole brain, various brain regions, adenohypophysis, and combined pars intermedia and neurohypophysis of the rat were measured by radioimmunoassay. In brain extracts, the immunoreactive substances were further separated according to molecular size by gel filtration. beta-Endorphin was found in the diencephalon but not in the hippocampus, cerebral cortex, cerebellum, and striatum. Enkephalin was found predominantly in the striatum and diencephalon. Attention is called to possible artifactual interference by myelin basic protein in the immunoassays for beta-endorphin in some regions of the brain. In the pituitary, enkephalin was mainly restricted to the pars intermedia-neurohypophysis. Neither adrenalectomy nor hypophysectomy significantly altered levels of beta-endorphin in brain extracts. Adrenalectomy increased the levels of beta-endorphin in adenohypophysis and pars intermedia-neurohypophysis; after adrenalectomy, enkephalin was also increased in the adenohypophysis but less so in the pars intermedia-neurohypophysis. These results show that brain endorphin levels are independent of pituitary endorphin levels; they suggest that beta-endorphin-containing neurons and those containing enkephalin constitute two separate groups of brain cells.

Acute respiratory effects on workers exposed to metalworking fluid aerosols in an automotive transmission plant.

Exposure to metalworking fluids has been linked to modest cross-shift reductions in FEV1 and occupational asthma. To identify responsible agents, we measured personal exposures to thoracic particulate (TP), viable plus nonviable thoracic bacteria (BAC), and vapor phase nicotine (VPN) (as a surrogate for tobacco particulate) among 83 machinists exposed to soluble oils and 46 dry assemblers working in an automotive transmission machining plant using biocides infrequently. The participants completed interviews and performed pre- and postshift spirometry on Monday and Thursday of the same week in each of three rounds of data collection (June 1992, January 1993, June 1993). Generalized estimating equations were used to combine information across rounds in multiple regression models of cross-shift and cross-week changes in forced expiratory volume, I second (FEV1) and forced vital capacity (FVC). Mean seniority was 19 years among machinists. Mean personal TP levels were 0.41 mg/m3 in machinists and 0.13 mg/m3 in assemblers. Six of the 83 machinists and none of the 46 assemblers experienced a greater than 19% cross-shift decrement in FEV1 or FVC at least once (p = .07). In regression models using either TP or BAC, among subjects with lower baseline (Monday preshift) FEV1/FVC ratios, increasing exposure was significantly associated with increasing cross-shift decrements in FEV1 and FVC in linear models, and with increased likelihood of a 10% or greater cross-shift decrement in FEV1 or FVC in logistic models. Adjustment of TP for VPN did not affect models significantly. We conclude that clinically important cross-shift decrements in pulmonary function are associated with exposure to metalworking fluid aerosols within a high-seniority population.