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Biomedical subjects

M E Adams

Publications and source records attributed to M E Adams.

At least 73 records · Page 4Linked to original sources
PubMed1994

Neurotoxins: overview of an emerging research technology.

Neurotoxins have highly specific actions on molecular targets, and thus offer an effective means of characterizing the growing number of identified ion channels and receptors in the nervous system. This article and the Neurotoxins Supplement accompanying this issue of TINS provide a convenient reference source to facilitate the use of toxins as selective, diagnostic ligands in research. However, while many toxins exert potent actions on target receptors, it must be emphasized that their effects can be complex, and certain general pitfalls often become apparent. Some examples will be given illustrating these complexities and their impact on experimental interpretation. In addition, the potential for the purposeful creation of new 'designer' toxins using molecular cloning will also be addressed.

Amino Acid Sequence↗
PubMed1994

Changes in aggrecan populations in experimental osteoarthritis.

Adult articular cartilage contains at least two distinct populations of aggrecan: one is larger and richer in chondroitin sulfate (CS), while the other is smaller with less CS. The smaller form is thought to be derived from the larger. The amount of CS in cartilage decreases with maturation and aging, mainly because of a decrease in the proportion of the larger of these two proteoglycans. In early osteoarthritis (OA) the amount and concentration of CS in cartilage increases. To test the hypothesis that an increase in the more CS-rich form of aggrecan contributes to the increase in CS in cartilage in OA, experimental OA was induced in dogs by transection of the anterior cruciate ligament, with sacrifice at various times between 2 days and 64 weeks after the operation. Proteoglycans were extracted from the articular cartilage of eight areas of the joint, fractionated, and CS was quantified by measuring hexuronate. Aggrecan populations were assessed by composite agarose-polyacrylamide gel electrophoresis. The proportion of the more CS-rich form of aggrecan increased with time after operation in all areas of the joint. This increase correlated with increases in tissue mass and hexuronate, showing that the increase in the larger, CS-rich form of aggrecan contributes to the increase in CS in the tissue. It seems paradoxical that this form of aggrecan accumulates in the tissue despite the fact that increased protease activity has been demonstrated in experimental OA.

Aggrecans↗
PubMed1994

Antipsychotic drugs: is more worse? A meta-analysis of the published randomized control trials.

Effectiveness and side-effects of high- versus low-dose neuroleptic treatment of chronic psychosis have been assessed through a meta-analysis of 22 published randomized control trials comparing different neuroleptic doses. No incremental clinical improvement was found at doses above 375 mg equivalent of chlorpromazine, while a significant increase in adverse reactions was observed.

Antipsychotic Agents↗
PubMed1993

Toxityping rat brain calcium channels with omega-toxins from spider and cone snail venoms.

Different types of voltage-sensitive Ca2+ channels in the brain can be defined by specific ligands: L-type Ca2+ channels are uniquely sensitive to dihydropyridines, and N-type Ca2+ channels are selectively blocked by the Conus peptide omega-CTX-GVIA. Cloning data have revealed additional calcium channel types in mammalian brain for which selective ligands would be desirable. We describe binding experiments involving three newer ligands that block dihydropyridine- and omega-CTX-GVIA-resistant Ca channels: omega-Aga-IIIA and omega-Aga-IVA from venom of the spider Agelenopsis aperta and omega-CTX-MVIIC from Conus magus. [125I]omega-Aga-IVA binds with high affinity (IC50 = approximately 50 nM) to receptors in rat brain which may correspond to P-like calcium channels. A second high-affinity site (IC50 = approximately 1 nM) is defined by [125I]omega-CTX-MVIIC, proposed here to be on an "O"-type calcium channel. [125I]omega-Aga-IIIA targets homologous binding sites present on multiple Ca channel types. The IIIA sites overlap with the binding sites for [125I]omega-CTX-GVIA and [125I]omega-CTX-MVIIC. The IIIA sites do not overlap with the site defined by omega-Aga-IVA. Thus toxin ligands may be highly specific for a particular Ca channel (i.e., GVIA for the N-type channel) or exhibit broader specificity (i.e., omega-Aga-IIIA, which appears to bind L-, N-, P-, and O-type Ca2+ channels).

Agatoxins↗
PubMed1993

Multiple Ca2+ channel types coexist to regulate synaptosomal neurotransmitter release.

The regulation of excitation-secretion coupling by Ca2+ channels is a fundamental property of the nerve terminal. Peptide toxins that block specific Ca2+ channel types have been used to identify which channels participate in neurotransmitter release. Subsecond measurements of [3H]-glutamate and [3H]dopamine release from rat striatal synaptosomes showed that P-type channels, which are sensitive to the Agelenopsis aperta venom peptide omega-Aga-IVA, trigger the release of both transmitters. Dopamine (but not glutamate) release was also controlled by N-type, omega-conotoxin-sensitive channels. With strong depolarizations, where neither toxin was very effective alone, a combination of omega-Aga-IVA and omega-conotoxin produced a synergistic inhibition of 60-80% of Ca(2+)-dependent dopamine release. The results suggest that multiple Ca2+ channel types coexist to regulate neurosecretion under normal physiological conditions in the majority of nerve terminals. P- and N-type channels coexist in dopaminergic terminals, while P-type and a omega-conotoxin- and omega-Aga-IVA-resistant channel coexist in glutamatergic terminals. Such an arrangement could lend a high degree of flexibility in the regulation of transmitter release under diverse conditions of stimulation and modulation.

Animals↗
PubMed1993

K(+)-stimulated 45Ca2+ flux into rat neocortical mini-slices is blocked by omega-Aga-IVA and the dual Na+/Ca2+ channel blockers lidoflazine and flunarizine.

High-threshold neuronal voltage-sensitive Ca2+ channels (VSCCs) have been classified into at least three subtypes, including L, N, and P, based on biophysical and pharmacological criteria. We examined K(+)-induced 45Ca2+ flux into rat neocortical mini-slices to determine which of these subtype(s) might be involved in this phenomenon. Neither the L-type Ca2+ channel antagonist isradipine at 10 microM nor the N-type antagonist omega-conotoxin GVIA at 1 microM were effective antagonists of 45Ca2+ flux in this model. However, the P-type Ca2+ channel antagonist, omega-Aga-IVA, blocked 70% of flux at 200 nM, with an IC50 of 17 nM, strongly implicating P-type Ca2+ channel involvement in K(+)-stimulated Ca2+ entry into mammalian nerve terminals. About 30% of the flux response was resistant to the action of omega-Aga-IVA, suggesting that a still uncharacterized subtype of VSCC is involved in Ca2+ entry into mammalian nerve terminals. Both the omega-Aga-IVA sensitive and insensitive components of 45Ca2+ flux were blocked by the diphenylalkylpiperazines, lidoflazine and flunarizine (IC50 = 6.4 microM and 11 microM, respectively), which have dual Na+/Ca2+ channel blocking actions.

Animals↗
PubMed1993

Inhibition of endogenous glutamate release from hippocampal tissue by Ca2+ channel toxins.

The pharmacology of voltage-dependent Ca2+ channels involved in the release of endogenous neurotransmitter amino acids was measured from small tissue slices of rat hippocampal CA1 region. Application of 50 mM KCl induced large increases in Ca(2+)-dependent overflow of endogenous glutamate, aspartate and gamma-aminobutyric acid (GABA). Pretreatment of tissues with the funnel-web spider toxin omega-Aga-IVA (200 nM) reduced KCl-induced overflow of all three amino acids. Pretreatment with the cone snail toxin omega-CgTx-GVIA (2 microM) caused similar but smaller reductions in amino acid overflow (aspartate overflow was not reduced significantly). These results indicate that P-type Ca2+ channels, and to a lesser extent, N-type Ca2+ channels, are involved in the release of transmitter amino acids under these conditions.

Animals↗
PubMed1993

Depressant insect selective neurotoxins from scorpion venom: chemistry, action, and gene cloning.

The present study examines the similarity in the symptoms and binding properties between the depressant and excitatory insect-selective neurotoxins, derived from scorpion venom. A comparison of their primary structures and neuromuscular effects is presented. A new depressant toxin (LqhIT2) was purified from the venom of the scorpion Leiurus quinquestriatus hebraeus. The effects of this toxin on a prepupal housefly neuromuscular preparation mimic its effects on the intact insect, i.e, a brief period of repetitive bursts of regular junction potentials (JPs) is followed by reduced amplitude JPs ending with a block of the neuromuscular transmission. "Loose" patch clamp recordings indicate that the repetitive activity has a presynaptic origin (the motor nerve) and resembles the effect of the excitatory toxin AaIT. The final synaptic block is supposed to be the end result of neuronal membrane depolarization. Such an effect is not caused by an excitatory toxin, which induces long "trains" of repetitive firing. The amino acid sequences of three depressant toxins were determined by automatic Edman degradation indicating a high degree of sequence homology. This conservation differs from those of other groups of scorpion toxins. The opposing pharmacological effects of depressant toxins are discussed in light of the above neuromuscular effects and sequence analysis. A genetic approach in the study of the structure-function relationships of the depressant toxins was initiated by isolating cDNA clones encoding the LqhIT2 and BjIT2 toxins. Their sequence analysis revealed the precursor form of these toxins: A 21 amino acid residue signal peptide followed by a 61 amino acid region of the mature toxin, and three additional amino acids at the carboxy terminus.

Amino Acid Sequence↗
PubMed1993

Two forms of mouse syntrophin, a 58 kd dystrophin-associated protein, differ in primary structure and tissue distribution.

Syntrophin, a 58 kd extrinsic membrane protein, is concentrated at postsynaptic sites at the neuromuscular junction and may be involved in clustering acetylcholine receptors. In muscle and nonmuscle tissues, syntrophin is associated with dystrophin, utrophin, and two homologs of the dystrophin carboxy-terminal region. We have isolated three cDNAs encoding Torpedo and mouse syntrophins. The Torpedo cDNA encodes a full-length protein, and on Northern blots recognizes a 3.5 kb mRNA. The two mouse syntrophin cDNAs are products of separate genes but encode proteins that share 50% identity. Syntrophin-1 mRNA (2.2 kb) is expressed at highest levels in skeletal muscle. Syntrophin-2 mRNAs (2.2, 5.0, and 10 kb) are expressed in all mouse tissues examined. These patterns of expression suggest that syntrophin-1 and syntrophin-2 may associate with different members of the dystrophin family.

Amino Acid Sequence↗
PubMed1993

Distinctive biophysical and pharmacological properties of class A (BI) calcium channel alpha 1 subunits.

Transcripts for the class A Ca2+ channel alpha 1 subunit (also known as BI) are present at high levels in many parts of the mammalian CNS and are widely assumed to encode the P-type Ca2+ channel. To characterize the biophysical and pharmacological properties of alpha 1A channels, macroscopic and single-channel recordings were made in Xenopus oocytes injected with alpha 1A cRNA. alpha 1-specific properties were identified by making systematic comparisons with the more familiar class C alpha 1 subunit under the condition of a standard ancillary subunit (alpha 2/delta + beta) makeup. alpha 1A currents activate and inactivate more rapidly and display steeper voltage dependence of gating than alpha 1C currents. Unlike alpha 1C, alpha 1A channels are largely insensitive to dihydropyridines and FPL 64176, but respond to the cone snail peptide omega-CTx-MVIIC(SNX-230), a potent and fairly selective inhibitor. In comparison with P-type Ca2+ channels in rat cerebellar Purkinje cells, alpha 1A channels in oocytes are approximately 10(2)-fold less sensitive to omega-Aga-IVA and approximately 10-fold more sensitive to omega-CTx-MVIIC. alpha 1A channels are not inhibited by Bay K 8644 and inactivate much more rapidly than P-type Ca2+ channels. Thus, alpha 1A is capable of generating a Ca2+ channel phenotype quite different from P-type current.

Animals↗
PubMed1993

Differential activation of adenosine receptors decreases N-type but potentiates P-type Ca2+ current in hippocampal CA3 neurons.

Adenosine is released in the brain in significant quantities in response to increased cellular activity. Adenosine has been shown either to decrease synaptic transmission or to produce an excitatory response in hippocampal synapses, resulting in increased glutamate release. Previous reports have shown that adenosine or its analogs reduced Ca2+ current in dorsal root ganglion and hippocampal neurons. Here we show that the selective activation of adenosine receptor subtypes has different effects on Ca2+ channels from acutely isolated pyramidal neurons from the CA3 region of guinea pig hippocampus. Activation of A1 receptors inhibited primarily N-type Ca2+ current. In contrast, activation of A2b receptors resulted in significant potentiation of P-type but not N-type Ca2+ current. This potentiation could be inhibited by blocking the cAMP-dependent protein kinase. Because of the ubiquity of adenosine, the differential effects on Ca2+ channels of adenosine receptor subtype activation may have significant implications for neuronal excitability.

Adenosine↗
PubMed1993

Hindlimb loading, morphology and biochemistry of articular cartilage in the ACL-deficient cat knee.

The cat hindlimb is the best studied animal model of neuromuscular control, muscle mechanics/muscle morphology, and locomotor kinematics. Therefore, this model offers itself for intervention studies, where a musculoskeletal parameter is perturbed and the effects of this perturbation are compared with normal function. The objective of this study was to describe the effects of anterior cruciate ligament (ACL) transection in the cat knee and to correlate hindlimb loading with morphological and biochemical changes of articular cartilage. A distinct unloading of the deficient hindlimb was found when compared with the nonoperated hindlimb immediately after ACL transection, and persisted for about 16-18 weeks. Beyond about 18 weeks post-ACL transection, hindlimb loading returned to the symmetric pattern observed before surgery. In accordance with the expectations from the force-platform results, a decrease in muscle mass was found from muscles of the experimental hindlimb when compared to the mass of muscles from the contralateral hindlimb. This decrease of muscle mass was largest at 4 weeks and smallest at 35 weeks post-ACL transection. At 12 and 35 weeks post-ACL transection, cell density was increased and absolute amounts of hexuronic acid were elevated in the articular cartilage of the experimental knee compared with the corresponding values of the contralateral knee. Progressive changes of the articular cartilage towards osteoarthritis (OA) were not observed in the time frame of this experiment. The results suggest that anterior cruciate ligament transection in the cat produces initial changes in the knee that are similar to those observed previously in the dog and rabbit.

Animals↗
PubMed1993

Assessing the effectiveness of ambulatory cardiac monitoring for specific clinical indications. Introduction.

This introduction and the three essays that follow examine ambulatory cardiac monitoring for specific clinical indications. They also examine the ways in which evidence from the literature may be synthesized through the framework of decision analysis to guide its appropriate use and identify areas in which more research is needed. The essays discuss ambulatory cardiac monitoring for evaluation of syncope in the elderly; detection of silent ischemia after a myocardial infarction; and selection of antiarrhythmic drugs for malignant ventricular arrhythmias.

Aged↗
PubMed1993

Noninvasive testing of asymptomatic patients for the detection of silent ischemia after an infarction. A decision analysis.

This decision analysis estimates the overall gain in life expectancy and the relative efficacy of predischarge submaximal exercise electrocardiography, ambulatory cardiac monitoring, and thallium-201 scintigraphy for the identification of silent ischemia in asymptomatic postinfarct patients. A small, virtually equal increase in life expectancy can be obtained from any of the noninvasive tests (as compared to no testing). Large differences in life expectancy may result only when the prevalence of residual coronary artery disease and the probability of left-main and three-vessel lesions are high.

Aged↗
PubMed1993

Ambulatory cardiac monitoring for the evaluation of antiarrhythmic agents.

This decision-analysis model assesses ambulatory cardiac monitoring (ACM), ACM followed by exercise testing, and electrophysiologic studies (EPS) in the evaluation and selection of antiarrhythmic agents in postinfarct patients with malignant arrhythmias. With existing data, we find no consistent advantage for one method of drug testing over another, although ACM appears to require fewer resources than does EPS. More patients qualify for EPS, but this fact does not increase the proportion of patients for whom a drug can be identified. These methods may test different aspects of arrhythmia activity and drug response, and sequential use may provide additional benefits. Such benefits must be determined empirically.

Anti-Arrhythmia Agents↗
PubMed1993

Structure and properties of omega-agatoxin IVB, a new antagonist of P-type calcium channels.

A new peptide antagonist of voltage-activated calcium channels was purified from venom of the funnel web spider, Agelenopsis aperta. This 48-amino acid peptide, omega-agatoxin (omega-Aga)-IVB, was found to be a potent (Kd, approximately 3 nM) blocker of P-type calcium channels in rat cerebellar Purkinje neurons but had no activity against T-type, L-type, or N-type calcium channels in a variety of neurons. The calcium channel-blocking properties of omega-Aga-IVB were similar to those of another toxin, omega-Aga-IVA, which has 71% amino acid identity with omega-Aga-IVB. The 10-fold greater abundance of omega-Aga-IVB in venom allowed structural studies using NMR spectroscopy. The three-dimensional structure derived from NMR data resulted in a proposed disulfide bond configuration for the peptide. Although omega-Aga-IVB has fewer basic and more acidic residues than does omega-Aga-IVA, the two toxins show conservation of positively charged residues in a mid-peptide region that is predicted to form one face of the omega-Aga-IVB molecule. This region may be crucial for high affinity binding to the P-type calcium channel. In contrast, the amino termini of the two toxins have different charges and seem unlikely to be involved in binding to the channel.

Agatoxins↗