Search PubMed⌕ Search

Biomedical subjects

A G Karczmar

Publications and source records attributed to A G Karczmar.

At least 19 recordsLinked to original sources
PubMed1998

Common mechanism of toxicity: a case study of organophosphorus pesticides.

The Food Quality Protection Act of 1996 (FQPA) requires the EPA to consider "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity ... in establishing, modifying, leaving in effect, or revoking a tolerance for a pesticide chemical residue." This directive raises a number of scientific questions to be answered before the FQPA can be implemented. Among these questions is: What constitutes a common mechanism of toxicity? The ILSI Risk Science Institute (RSI) convened a group of experts to examine this and other scientific questions using the organophosphorus (OP) pesticides as the case study. OP pesticides share some characteristics attributed to compounds that act by a common mechanism, but produce a variety of clinical signs of toxicity not identical for all OP pesticides. The Working Group generated a testable hypothesis, anticholinesterase OP pesticides act by a common mechanism of toxicity, and generated alternative hypotheses that, if true, would cause rejection of the initial hypothesis and provide criteria for subgrouping OP compounds. Some of the alternative hypotheses were rejected outright and the rest were not supported by adequate data. The Working Group concluded that OP pesticides act by a common mechanism of toxicity if they inhibit acetylcholinesterase by phosphorylation and elicit any spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be used to determine if other classes or groups of pesticides that share structural and toxicological characteristics act by a common mechanism of toxicity or by distinct mechanisms.

Animals↗
PubMed1993

Brief presentation of the story and present status of studies of the vertebrate cholinergic system.

This year marks the seventieth anniversary of Otto Loewi's demonstration of chemical transmission generally and autonomic cholinergic transmission specifically and the fortieth anniversary of John Eccles's proof of the existence of central cholinergic transmission. Following these epochal findings, the subsequent studies of the cholinergic system led to discoveries of similarly important phenomena. This review concerns these phenomena, including chemical structure and molecular biology of cholinergic receptors; electrophysiologic and ionic aspects of pre- and postsynaptic cholinergic events; the quantal expression of cholinergic postsynaptic events and activities of their subunits, the elementary events; second messengers and G proteins; synthesis, storage and release of acetylcholine; cholinesterases, anticholinesterases, and war gases; central cholinergic pathways; central cholinergic functions, behaviors, cholinergic EEG and REM sleep; cholinergic ontogeny and teratology; trophic phenomena; and the clinical aspects of the cholinergic system. This review refers to the history as well as the present status of each of these phenomena; furthermore, it describes briefly the nineteenth-century work with calabar bean, pilocarpine, muscarine, and nicotine, that is, the work performed before the promulgation of the cholinergic era.

Animals↗
PubMed1993

Putative transmitter systems of mammalian sympathetic preganglionic neurons.

The sympathetic nervous system evokes complex effects at multiple target organs in response to external, internal as well as mental stimuli. This output involves an interplay between the actions of a number of transmitters and modulators and at the postsynaptic and presynaptic sites of the autonomic ganglia and the sympathetic preganglionic neurons (SPNs). This review concerns particularly the SPNs of the cat and neonatal rat, studied by means of electrophysiological and immunohistochemical methods. Four types of responses may be elicited, the fast EPSP and IPSP, and their currents, and the slow EPSPs and IPSPs, and their currents. Glutamate and glycine appear to mediate the fast excitatory and inhibitory responses, respectively; peptides and amines seem to be responsible for generating the slow excitatory response, while the slow inhibitory response, found so far only in the cat, appears to be mediated by norepinephrine. Finally, glutamate, enkephalin and GABA, but not glycine attenuate the release of the inhibitory and excitatory transmitters from the nerve terminals abutting on the SPNs. The supraspinal efferent and afferent projections which may release the transmitters and modulators in question are discussed, as well the mechanisms that ensure appropriate programming and moment-to-moment regulation of the autonomic output.

Animals↗
PubMed1986

Metabolism of choline in brain of the aged CBF-1 mouse.

In order to quantify the changes that occur in the cholinergic central nervous system with aging, we have compared acetylcholine (Ach) formation in brain cortex slice preparations from 2-year-old aged CBF-1 mouse brains and compared the findings with those in 2-4-month-old young adult mouse brain slices. Incorporation of exogenous radioactively labelled choline (31 nM [3H] choline) into acetyl choline in incubated brain slices was linear with time for 90 min. Percentage of total choline label distributed into Ach remained constant from 5 min after starting the incubation to 90 min. In contrast, distribution of label into intracellular free choline (Ch) and phosphorylcholine (Pch) changed continuously over this period suggesting that the Ch pool for Ach synthesis in brain cortex is different from that for Pch synthesis. Incorporation of radioactivity into Ach was not influenced by administration of 10 microM eserine, showing that the increment of radioactivity in Ach reflects rate of Ach formation, independently from degradation by acetylcholine esterases. Under our experimental conditions, slices from cortices of aged 24-month-old mouse brain showed a significantly greater (27%) incorporation of radioactivity into intracellular Ach than those from young, 2-4-month-old, brain cortices. Inhibitors of Ach release, 1 mM ATP or GABA, had no effect. Since concentration of radioactive precursor in the incubation medium was very low (31 nM), the Ch pool for Ach synthesis in slices was labelled without measurably changing the size of the endogenous pool. These data suggest a compensatory acceleration of Ach synthesis or else a smaller precursor pool specific for Ach synthesis into which labelled Ch migrated in aged brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1985

Facilitation and inhibition of nicotinic transmission by eserine in the sympathetic ganglia of the rabbit.

The effects of eserine on neurons and on ganglionic transmission of the isolated superior cervical ganglia of the rabbit were investigated by means of intracellular recording techniques. At the concentration of 10 microM or less, eserine reversibly increased the amplitude and duration of the fast excitatory postsynaptic potential (f-epsp) induced by preganglionic nerve stimulation and of the membrane depolarization evoked by iontophoretically-applied acetylcholine (ACh), but not carbachol. At the concentration of 50 microM or more, eserine consistently and reversibly depressed the fast excitatory postsynaptic potential as well as the depolarization induced by iontophoretic application of either ACh or carbachol. Furthermore, depolarization by ACh evoked in a low Ca/high Mg solution, which blocked the liberation of transmitter was similarly reduced by eserine in greater concentrations. The passive membrane properties of the sympathetic neurons were not significantly altered by eserine in the majority of neurons studied. The results indicate that the facilitatory action of eserine on ganglionic transmission may be explained by its anticholinesterase activity, whereas eserine-induced block of transmission appears to be related to a direct interaction between the compound and the postsynaptic ACh receptor-channel complex.

Acetylcholine↗
PubMed1983

Effects of serotonin (5-hydroxytryptamine) on amphibian neuromuscular junction.

A study of the effects of serotonin transmission was carried out on the frog neuromuscular junction by means of microelectrode methods. Serotonin was employed in concentrations of 5-100 microM. Serotonin did not affect membrane characteristics or the resting potential whether at non-neuronal (muscular fiber) or endplate segments of the junction. While serotonin did not affect the frequency of the miniature endplate potentials (MEPPs), it significantly decreased evoked release of acetylcholine. Serotonin significantly decreased, in a dose-dependent fashion, the amplitude of acetylcholine potentials, endplate currents (EPCs), endplate potentials (EPPs) and MEPPs. Also, serotonin shortened significantly the EPC time course and half-decay time, and caused loss of membrane voltage sensitivity of the half-decay time. While it did not affect the null potential, serotonin changed the voltage-EPC relationship from linear to non-linear, and markedly attenuated the dependence of EPC amplitude on membrane potential. These results demonstrate that serotonin induces depressant effects at both pre- and post-synaptic sites of amphibian neuromuscular junction and that its post-synaptic action is directed at the receptor-channel macromolecule rather than at either the channel or the receptor alone.

Acetylcholine↗
PubMed1983

Inhibition of bradykinin-induced contraction of isolated smooth muscle tissue preparations by oligopeptide thiobenzyl ester substrates for serine proteases.

Synthetic peptide substrates containing various chromophores and fluorophores have been utilized in the quantitation of serine protease activities. Recently, amino acid thiobenzyl esters containing arginine and lysine have also been used to evaluate the serine proteases. In an attempt to develop specific peptide thiobenzyl substrates, we have screened D-Pro-Phe-Arg-S-CH2-C6H5, D-Phe-Phe-Arg-S-CH2-C6H5, D-Gly-Pro-Arg-S-CH2-C6H5, and D-Val-Leu-Lys-S-CH2-C6H5 to determine the enzymatic activity of serine proteases. Since we found that D-Pro-Phe-Arg-pNA is a potent inhibitor of the bradykinin induced contractile action of isolated smooth muscle preparations such as the guinea pig ileum and rat uterus, we screened D-Pro-Phe-Arg-S-CH2-C6H5 at a 5 X 10(-5) M and found that it completely blocked the bradykinin (1 ng) induced contraction of the isolated rat uterus preparation. Other peptide thiobenzyl esters produced somewhat weaker effects, however, none of the free peptides not C6H5CH2SH, at concentrations of up to 10 microns, produced any significant contraction or inhibition of the isolated smooth muscle preparation. These observations suggest that peptide thiobenzyl esters are effective blockers of bradykinin induced contraction of the isolated smooth muscle preparations and the amino acid sequence of the peptides plays an important role in the determination of relative potency of each of these peptide derivatives. Moreover, the result of this investigation provides the basis for a new approach to further design specific inhibitors of the pharmacologic actions of biologically active peptides.

Animals↗
PubMed1982

Substance P: a putative sensory transmitter in mammalian autonomic ganglia.

Repetitive presynaptic stimulation elicited slow membrane depolarization in neurons of inferior mesenteric ganglia from guinea pigs. This response was not blocked by cholinergic antagonists but was specifically and reversibly inhibited by a substance P analog, (D-Pro2, D-Phe7, D-Trp9)-substance P, which also depressed the depolarization induced by exogenously applied substance P. The atropine-sensitive slow excitatory and slow inhibitory postsynaptic potentials evoked in neurons of rabbit superior cervical ganglia were not affected by the substance P analog. These and previous results provide strong support for the hypothesis that substance P or a closely related peptide is the transmitter mediating the slow depolarization. The latter may represent a sensory input from the gastrointestinal tract to neurons of the prevertebral ganglia.

Action Potentials↗