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Biomedical subjects

C R Jones

Publications and source records attributed to C R Jones.

162 records · Page 9Linked to original sources
PubMedDate not supplied

Effects of high intravenous doses of dynorphin A(1-13) on tail flick latency and central nervous system histology in rats.

Dynorphin A(1-13) blocks opiate withdrawal in rats without producing dependence, and enhances analgesia in morphine-tolerant animals. Its potential use in humans is therefore of interest. Dynorphin A(1-13) has little toxicity when administered at modest doses IV but has been reported to cause hindlimb paralysis and necrosis of the spinal cord in rats, at the catheter tip, when administered intrathecally. To further evaluate its potential neurotoxicity, we administered dynorphin A(1-13) to rats at very high doses IV. Rats (n = 6-10 per group) received dynorphin A(1-13) as bolus IV doses of 5 mg/kg, or as continuous IV infusions of 40 mg/kg/day for 1 day, with saline controls. The appearance and behavior of all animals was normal. Tail flick latencies remained unchanged (p > 0.5). There were no histologic abnormalities of the spinal cord or brain when examined by light microscopy. Two additional groups received bolus injections of dynorphin A(1-13) 50 or 100 mg/kg IV. Animals receiving 50 mg/kg showed cutaneous flushing, labored respirations, and decreased spontaneous movement, which resolved within 10 min. Histology at 1 week was normal. All six animals receiving 100 mg/kg convulsed and died within minutes. Three animals that received dynorphin A(1-13) 40 mg/kg/day for 7 days had normal behavior and histology. We conclude that the previously observed neurotoxicity of intrathecally administered dynorphin A(1-13) is a local effect that does not occur when dynorphin A(1-13) is administered IV, even at very high doses.

Analgesics, Opioid↗
PubMedDate not supplied

Effects of chronic beta-amyloid treatment on fatty acid incorporation into rat brain.

The present study evaluated the effects of chronic A beta administration on radio-labeled plasma fatty acid incorporation in rat brain. A beta was chronically infused intraventricularly via an osmotic minipump, for 1 week, at a concentration of 460 microM. After the infusion, fatty acid incorporation was quantified using an in vivo method developed in this laboratory. Three radiolabeled fatty acids were separately infused IV in awake animals. Biochemical analyses of fatty acid incorporation and histology for A beta showed no differences between control (vehicle infusion only) and experimental groups. However, in vitro tests on the cytotoxicity of A beta showed that it caused significant cell death relative to controls (PC-12 cells). The lack of effect of infused A beta on radiolabeled fatty acid incorporation is discussed.

Amyloid beta-Peptides↗
PubMedDate not supplied

Hepatic cytochrome P450 2B-type induction by ethyl/phenyl-substituted congeners of phenobarbital in the rat.

As part of an investigation of the structural requirements for the induction, by phenobarbital-type inducers, of a coordinate pleiotropic response consisting of increases in hepatic cytochrome P450 2B (P450 2B) activity, increases in other phase I and II enzyme activities, and liver hypertrophy, we have examined a series of analogues of phenobarbital in which the ethyl/phenyl substitution at the sp3 carbon of the parent molecule was kept constant while the heterocyclic portion of the molecule was modified. The induction of hepatic P450 2B protein and ethoxy-, pentoxy-, and (benzyloxy)resorufin O-dealkylation activities, and epoxide hydration activity and liver/body weight ratio increase were examined in male F344/NCr rats fed the various congeners for 14 days at doses equimolar to 500 ppm phenobarbital. Increases in the measured parameters were maximal in rats fed phenobarbital or 5-ethyl-5-phenylhydantoin. The responses to primidone or 2-ethyl-2-phenylsuccinimide were approximately 65% of maximal, while glutethimide yielded a response approximately 50% of maximal. Induction of this response in rats fed the ring-opened and decarboxylated analogues, (ethylphenylacetyl)urea and 2-ethyl-2-phenylmalonamide, were < 25% of maximal. 5-Ethyl-5-phenyloxazolidinedione caused minimal increases in the measured end points when administered at a dose equimolar to 500 ppm phenobarbital. The profound differences among the congeners in ability to induce P450 2B protein and associated catalytic activities were not due to differences in food consumption by the various groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Pharmacodynamics of cytochrome P450 2B induction by phenobarbital, 5-ethyl-5-phenylhydantoin, and 5-ethyl-5-phenyloxazolidinedione in the male rat liver or in cultured rat hepatocytes.

The pharmacodynamics of rat hepatic cytochrome P450 2B (P450 2B) induction by phenobarbital (PB) and two structural congeners, dl-5-ethyl-5-phenylhydantoin (EPH) and dl-5-ethyl-5-phenyloxazolidinedione (EPO), were investigated. The in vivo induction of P450 2B was probed in F344/NCr rats by measuring immunoreactive hepatic P450 2B1 protein and by assaying the hepatic 16 beta-hydroxylation of testosterone and O-dealkylation of (benzyloxy)- and pentoxyresorufin. The induction of (benzyloxy)resorufin O-dealkylation activity was also measured in adult rat hepatocyte cultures exposed to the three xenobiotics. The concentration of xenobiotic at the putative active site in the in vivo studies was approximated by measuring serum total xenobiotic levels, while in the hepatocyte culture studies, the nominal xenobiotic concentration in the culture medium was used. Concentration-dependent induction of P450 2B activities was observed in the in vivo and hepatocyte culture studies. The in vivo ED50 values for P450 2B induction were approximately 110, approximately 100, and approximately 3000 dietary ppm (14 days administration) for PB, EPH, and EPO, respectively. The in vivo EC50 values for P450 2B induction were approximately 9, approximately 6, and approximately 130 microM (total serum) for PB, EPH, and EPO, respectively. In cultured rat hepatocytes, the ED50 values for induction of (benzyloxy)resorufin O-dealkylation activity were 14.5, 14.2, and 108 microM for PB, EPH, and EPO, respectively. These data indicate that pharmacodynamic results obtained with cultured hepatocytes represent a good qualitative and quantitative approximation of the in vivo hepatic responses in male rats caused by PB-type inducers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Urinary metabolites of workers exposed to nitrotoluenes.

Nitrotoluenes are important intermediates in the chemical industry. 2,6-Dinitrotoluene (26DNT), 2,4-dinitrotoluene (24DNT) and 2-nitrotoluene (2NT) are carcinogenic in animals and possibly carcinogenic in humans. Thus, it is important to develop methods to biomonitor workers exposed to such chemicals. The authors have monitored the air and urine metabolite levels for a group of workers in China exposed to 24DNT, 26DNT, 2NT and 4-nitrotoluene (4NT). The metabolites 2,4-dinitrobenzylalcohol (24DNBAlc), 2-amino-4-nitrobenzoic acid (2A4NBA), 4-amino-2-nitrobenzoic acid (4A2NBA) and 2,4-dinitrobenzoic acid (24DNBA) resulting from exposure to 24DNT were found in 89, 88, 91 and 78% of the exposed workers, respectively. The metabolites 2,6-dinitrobenzylalcohol (26DNBAlc) and 2,6-dinitrobenzoic acid resulting from 26DNT exposure were found in 99 and 86% of the exposed workers, respectively. Quantitatively, 2A4NBA, 4A2NBA and 26DNBAlc were the major metabolites. The nitrobenzoic acids were the major metabolites resulting from exposure to 2NT and 4NT and were present in 96 and 73% of the exposed workers, respectively. Air concentrations of DNT and 2NT did not correlate with the levels of metabolites in the urine. In conclusion, the dinitrobenzyl alcohols and aminonitrobenzoic acids determined in the urine provided a good marker for recently absorbed dose and were intrinsically related to the bioactivation and detoxification pathways of DNT. Air measurements were not a good measure to predict internal exposure.

Adult↗
PubMedDate not supplied

Cardiac and lymphocyte beta-adrenoceptors in perinephritis hypertension in the rabbit.

The effects of perinephritis hypertension on lymphocyte and cardiac beta-adrenoceptors in the rabbit were examined. Hypertensive animals 8-12 weeks after surgery had an increase in cardiac weight consistent with hypertrophy compared with sham-operated age-matched controls. Specific binding of [I125] iodocyanopindolol (ICYP) to cardiac ventricular membranes was reduced in the hypertensive animals (Bmax44 +/- 14 in hypertensives and 30 +/- 15 fmoles/mg protein in controls; p less than 0.01). However, weight-matched ventricles from a group of older sham-operated normotensive rabbits showed a similar cardiac beta-receptor number to that found in the hypertensive animals. There were no changes in affinity of the ligand for the binding site. The reduction in cardiac beta-receptor density was not accompanied by changes in the chronotropic or blood pressure responses to isoprenaline in the conscious animal. Specific ICYP binding to lymphocyte beta-receptors did not differ significantly between the hypertensive and age-matched normotensive animals. Lymphocyte beta-adrenoceptors thus may not always reflect changes in heart beta-adrenoceptors, and changes in receptor density may not be directly related to blood pressure or have identifiable functional significance.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

The effect of aging on alpha-adrenoceptors and their responses in rabbits.

The effects of age on alpha-adrenoceptor responses, sensitivity and number were studied in rabbits aged from 1 to 36 months. Three types of investigation were carried out: conscious animal studies, isolated tissue studies and radioligand binding studies. Specific [3H]-prazosin binding decreased with age in both spleen and heart suggesting that the number of alpha 1-receptors declined at least in the tissues studied. The specific binding of [3H]-clonidine to spleen membranes and [3H]-yohimbine to platelets was not affected by age. In vitro responsiveness to alpha-adrenoceptor agonists decreased with age in abdominal aorta and renal artery, while the affinity of adrenoceptors for prazosin (pA2) was not altered. The decrease may be non-specific as responses to potassium were also altered. No change in alpha 2-adrenoceptor mediated platelet aggregation was observed. No change in pressor or depressor responses to full adrenoceptor agonists or to antagonists was observed in vivo. However, responses to clonidine, which is a partial agonist at alpha 1-adrenoceptors, were decreased. While aging influenced alpha-adrenoceptor subtypes differently, there was no direct relation between functional changes and number of receptors.

Aging↗