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Biomedical subjects

A R Martin

Publications and source records attributed to A R Martin.

At least 19 recordsLinked to original sources
PubMed1992

The dependence of calcium-activated potassium currents on membrane potential.

Previous experiments on cholinergic synapses in chick cochlear hair cells have shown that calcium entering through acetylcholine-activated synaptic channels in turn activates calcium-dependent potassium currents, resulting in synaptic inhibition. In voltage-clamp experiments such currents would be expected to increase with depolarization (as the driving force for potassium entry is increased) and then decrease towards zero as the membrane approaches the calcium equilibrium potential (when calcium entry is suppressed). In the hair cells, however, such currents approached zero at about +20 mV, more than 170 mV negative to the calcium equilibrium potential. Another feature of the synapse is its post-junctional morphology: a uniform 20 nm cleft is formed between the postsynaptic membrane and the outermost membrane of an underlying cisterna. Here we present a model in which synaptic activation results in calcium influx into the subsynaptic cleft and thence into the bulk of the cytoplasm. The model suggests that the voltage dependence of the calcium-activated potassium current can be accounted for by only two basic assumptions: (i) entry of calcium through the activated synaptic channels by simple diffusion; and (ii) activation of the potassium channels by the cooperative action of four calcium ions. In addition, the model suggests that during activation the calcium concentration in the restricted subsynaptic space can reach levels adequate to activate the potassium channels, without requiring additional, more complicated, considerations (for example, secondary calcium release from the cisterna).

Animals↗
PubMed1992

Principles of neuromuscular transmission.

Activation of skeletal muscles, small and large alike, occurs when spinal cord neurons send action potentials to groups of fibers. The central role of acetylcholine and its receptors in this activation is well established. The mechanisms involved and the implications for understanding neuromuscular disorders and for rationalizing and improving therapy are discussed.

Acetylcholine↗
PubMed1992

Causes of mortality and parasites and incidental lesions in harbour porpoises (Phocoena phocoena) from British waters.

Detailed post mortem examinations were carried out on 41 harbour porpoises (Phocoena phocoena) found dead on the coast of the United Kingdom. The commonest causes of death were entanglement in fishing gear, and parasitic and bacterial pneumonia. Among the non-fatal conditions parasitoses of various organs were common and there was a very wide variety of other conditions. In total 295 diseases and other lesions were found, an average of 7.2 per animal.

Animals↗
PubMed1992

Flow cytometric DNA analysis of ovarian Brenner tumors and transitional cell carcinomas.

Flow cytometry has been previously used as a method of obtaining prognostic information about ovarian carcinomas using ploidy, DNA index, and S-phase fraction. DNA content has also been assessed in ovarian tumors of low malignant potential. Brenner tumor variants such as metaplastic, proliferating, and low malignant potential, recently designated as intermediate Brenner tumors, and malignant Brenner tumors are unusual tumors that present classification problems. Their histological appearance may not accurately reflect biological activity. We used flow cytometry to analyze paraffin-embedded tissue for DNA content and S-phase in 34 Brenner tumors, three ovarian transitional cell (urothelial) carcinomas (TCCs), and nine normal control ovaries. We correlated histological and clinical features with DNA analysis. Twenty-five Brenner tumors and three ovarian TCCs were acceptable for histogram analysis (coefficient of variation less than 7.0). Thirteen typical, three metaplastic (extensive mucinous or glandular metaplasia), and two proliferating (papillary formation with increased cellularity) Brenner tumors were diploid. One proliferating tumor was tetraploid. The single Brenner tumor of low malignant potential was diploid but had an increased S-phase. Four of five malignant Brenner tumors were aneuploid, and one was diploid. All the TCCs were aneuploid. S-phase was elevated in intermediate and malignant Brenner tumors and TCC. Limited numbers of cases available preclude prognostic prediction based on ploidy in malignant Brenner tumors or primary ovarian TCCs. DNA ploidy and S-phase reflect the intermediate status of metaplastic, proliferating, and low malignant potential Brenner tumors.

Adult↗
PubMed1990

Comparison of two different arterial tissues suggests possible 5-hydroxytryptamine2 receptor heterogeneity.

A comparison of activities and affinities of several known and novel compounds in the isolated rat thoracic aorta (RA) and the rabbit femoral artery (RFA) was undertaken to evaluate these two tissues for use in screening for functional 5-hydroxytryptamine2 (5-HT2) receptor activity. Affinities for 5-HT and for ketanserin against 5-HT-elicited contractions in both vascular tissues suggested the presence of homogeneous 5-HT2 receptors with values consistent with other reported 5-HT2 receptor preparations. However, further studies showed compounds which exhibited either partial agonism in the RFA and competitive antagonism of 5-HT in the RA, or antagonism of 5-HT in both arteries with different affinities. Affinity constants calculated from the isolated vascular tissue studies were compared with affinity constants calculated for inhibition of [3H]ketanserin binding in the frontal cortices of both the rat and the rabbit. There were no significant differences between the pKi values in the rat and the rabbit cortical membranes or between these pKi's in either species and the pA2 values in the RA. Several of the affinities for both the partial agonists and the antagonists in the RFA were significantly different from the binding pKi and the pA2 values in the RA. These findings suggest identity between the [3H]ketanserin binding site in the cortices of both species and the 5-HT2 receptor in the RA; however, the contractile 5-HT receptor in the RFA, although showing some characteristics of a 5-HT2 receptor, is significantly different. We suggest that there may be functional subtypes of the vascular 5-HT receptor.

Animals↗
PubMed1989

MDL 73005EF: partial agonist at the 5-HT1A receptor negatively linked to adenylate cyclase.

MDL 73005EF has been recently described as a potent, highly selective 5-HT1A ligand. Although proposed to act predominantly as an antagonist (M. Hibert, A.K. Mir, G. Maghioros, P. Moser, D.N. Middlemiss, M.D. Trickleband and J.R. Fozard, 1988, The Pharmacological properties of MDL 73005EF: a potent and selective ligant at 5-HT1A receptors, Br. J. Pharmacol. 93, 2P), we have demonstrated that MDL 73005EF also acts as a highly efficacious partial agonist at the 5HT1A receptor, based on its ability to inhibit forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Compared with two structurally related 5-HT1A partial agonists, the rank order of potency of MDL 73005EF in the FSC assay was comparable to affinity calculated by radioligand binding.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Presynaptic calcium currents recorded from calyciform nerve terminals in the lizard ciliary ganglion.

Electron microscopic examination of ciliary ganglion from Anolis carolinensis shows large calyciform presynaptic nerve terminals ending on ganglion cells. Intracellular records were obtained from the terminals, and membrane currents were recorded with the single-electrode voltage clamp technique. After block of Na+ currents with tetrodotoxin, depolarization of the terminals produced inward currents that disappeared when extracellular Ca2+ was removed, and increased in magnitude and duration when competing outward currents were blocked by intracellular Cs+. Thus it is possible, with this preparation, to record and characterize Ca2+ currents presumably associated with neurotransmitter release.

Animals↗
PubMed1989

3-(1-Methyl-1,2,3,6-tetrahydropyrid-4-yl)indole.

C14H16N2, Mr = 212.3, orthorhombic, Pca2(1), a = 19.424 (3), b = 6.770 (1), c = 8.899 (1) A, V = 1170.2 (3) A3, Z = 4, Dx = 1.20 g cm-3, Mo K alpha, lambda = 0.71073 A, mu = 0.7 cm-1, F(000) = 456, T = 296 K, final R = 0.043 for 1162 observed reflections. The pi systems in the title compound (1), a serotonin mimic, are in a 'near-planar' conformation (actually twisted 21 degrees from the transoid conformation) as has been postulated to be essential for activity. Molecular-mechanics calculations indicate that the inactive 2-methyl derivative of (1) has near-planar forms of much higher energy in accordance with expectation.

Carbolines↗
PubMed1989

Potassium channels activated by sodium.

Na+-activated K+ currents have been reported in snail neurones, crayfish giant motoneurones, cardiac myocytes, and in ganglion cells and brain stem cells from chick embryos. Such currents are seen in voltage-clamp experiments, following depolarization-induced Na+ influx. A variety of experiments have shown that the currents through the conductance pathways are indeed carried by K+ ions and that they are quantitatively dependent upon Na+ influx into the cells. Theoretical calculations indicate that such currents must make a substantial contribution to action potential repolarization. The conductances are activated by Li+ in invertebrate neurones, but not in the embryonic vertebrate neurones. Single-channel recordings from vertebrate brain stem cells reveal channels with conductances of about 50 pS, activated by Na+ concentrations in the 10-100 mM range.

Animals↗
PubMed1989

A Na+-activated K+ current in cultured brain stem neurones from chicks.

1. Patch-clamp techniques were used to study the properties of a Na+-activated K+ current (IK(Na) in neurones cultured from embryonic chick brain stem. 2. With whole-cell clamp, a depolarizing voltage command evoked an inward current that was followed by an outward current with two components, the first transient, the second sustained. 3. Tetrodotoxin (TTX, 1 microM) eliminated the inward current and the transient component of the outward current, without affecting the sustained outward current. In addition, the transient outward current was attenuated when all external Na+ was replaced by Li+, suggesting that it was activated specifically by Na+ entry into the cell. 4. The time course of the transient outward current was obtained by subtracting records obtained in Li+ solution from those obtained in Na+ solution. There was significant overlap between the decay of the inward current and the onset of the transient outward current. 5. When just after the peak of the transient outward current, the membrane was stepped to progressively more hyperpolarized levels, the tail currents associated with the current reversed polarity near the calculated K+ equilibrium potential. 6. 4-Aminopyridine (4-AP, 4 mM) abolished the transient outward current and approximately half of the sustained late current. Tetraethylammonium (TEA, 2 mM) had no effect on the transient current, but reduced the sustained current slightly. 7. Inside-out patches, made in LiCl bathing solutions, contained channels that were activated by exposing the cytoplasmic face of the patch to Na+. Channel activity continued as long as Na+ was present. 8. The single-channel currents reversed at the K+ equilibrium potential, and were associated with a main conductance that depended upon K+ concentration (about 50 pS with [K+]o = 15 mM, [K+]i = 5 mM, and 100 pS when [K+]i was increased to 75 mM). 9. The open probability of the channels increased with increasing cytoplasmic Na+ concentration. At [Na+]i = 150 mM (the maximum concentration tested), channels were open almost continuously. Open probability was considerably less at 50 mM, and still measureable at 20 mM. 10. The magnitude of IK(Na) and its overlap with the inward Na+ current indicate that these channels contribute significantly to the repolarizing phase of the action potential. In addition, the relation between channel activity and Na+ concentration suggests that the channels may make a measurable contribution to membrane conductance at resting intracellular Na+ concentrations.

Animals↗
PubMed1988

Serotonergic properties of spiroxatrine enantiomers.

The neuroleptic drug spiperone (1) has proven very useful in the characterization of putative serotonin (5-hydroxytryptamine, 5-HT) receptors. Thus, 5-HT1 receptors have been divided into subtypes based on their affinities for 1: 5-HT1A sites have high affinity, while 5-HT1B sites have low affinity. However, the usefulness of 1 for the pharmacological characterization of 5-HT1A sites is limited because of its high affinity for 5-HT2 (as well as D2-dopaminergic) receptors. A close analogue of 1, (+/-)-spiroxatrine (2), has much higher affinity for 5-HT1A receptors and much lower affinity for 5-HT2 receptors. We report here the stereospecific synthesis of (R)-(+)- and (S)-(-)-spiroxatrine enantiomers and their evaluation at several 5-HT receptors and D2-dopaminergic and alpha 1-adrenergic receptors.

Animals↗
PubMed1988

Molecular determinants for recognition of RU 24969 analogs at central 5-hydroxytryptamine recognition sites: use of a bilinear function and substituent volumes to describe steric fit.

The putative serotonin (5-HT) agonist RU 24969 [5-methoxy-3-1,2,3,6-tetrahydropyridin-4-yl)indole; 5-MeO-THPI] has been extensively used in the study and classification of 5-HT receptors. In order to study molecular determinants for recognition of THPIs at central 5-HT recognition sites, about 25 additional THPI derivatives were synthesized, incorporating, among others, 16 different indole-5-substituents and three different pyridine-N substituents in various combinations. Two saturated derivatives (piperidin-4-ylindoles) and two 2-methyl analogs were also included. Binding affinities at 5-HT1A, 5-HT2, and total 5-HT1 sites were obtained and the data were incorporated in quantitative structure-activity relationships (QSARs) using a combined linear free energy/molecular modeling approach. The QSAR analyses suggest distinct differences in the structural features that determine optimal potency at 5-HT1A sites versus those directing optimal potency for 5-HT2 sites. The parameter of the indole-5 substituent that almost exclusively determines potency for 5-HT1A sites is volume, the optimal size being about 24 cubic angstroms (calculated by fitting the activity versus volume data to a bilinear function). This is approximately the size of a carboxamide group. In contrast, at the 5-HT2 site both volume and hydrophobicity play major but opposing roles for the 5-substituent. A balance between the smallest possible volume and the greatest possible hydrophobicity is required for maximal 5-HT2 potency. Benzyl groups on the indole-1 or pyridyl-1 positions also favor potency at the 5-HT2 site (probably largely due to increased hydrophobic binding) while decreasing potency at the 5-HT1A site. A minor electronic contribution to the QSARs involving the charge on the indole 5-carbon is of opposite sign for 5-HT1A versus 5-HT2 sites and thus may also be useful for selective drug design. The data are consistent with the possibility that the indole and pyridyl rings are in a coplanar configuration when binding at both 5-HT1A and 5-HT2 sites, because the indole-2-methyl substituent, which provides a large energy barrier to the coplanar configuration, greatly reduces the potency of THPIs at both binding sites. Similarities in analog selectivity patterns suggest that the indolic portion of these compounds binds similarly to that of other indole derivatives such as tryptamines; thus, it is possible that optimally selective substituents predicted by these QSARs may be extrapolated to tryptamines and other indoles.

Animals↗
PubMed1987

Structure-anticonvulsant activity relationships of cannabidiol analogs.

Cannabidiol (CBD) exhibits anticonvulsant activity in experimental animals and in man. As part of a structure-activity study, analogs were prepared wherein the terpene unit, the aryl unit, and/or the side chain were modified. Thus, several pinenyl and carenyl derivatives, aryl ethers and acetates, and a variety of 1",1"-dialkylhexyl and 1",1"-dialkylheptyl analogs were synthesized. The compounds were evaluated for anti-convulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rat rotorod (ROT) test. Comparisons of stereoisomers of CBD and several analogs revealed a general lack of stereoselectivity for anticonvulsant and other CNS properties of this class of compounds.

Animals↗
PubMed1978

Substituted tetralins VI: Tentative assignment of absolute stereochemistry of 1-methyl-1-phenyl-1,2,3,4-tetrahydro-3-naphthoic acid and N,N,1-trimethyl-1-phenyl-1,2,3,4-tetrahydro-3-naphthylamine isomers.

The absolute configurations of the enantiomers of N,N,1-trimethyl-cis- and trans-1-phenyl-1,2,3,4-tetrahydro-3-naphthylamines (Ia and Ib) were assigned tentatively from the circular dichroism spectrum of a bridged ketone derived by cyclization of optically active 1-methyl-cis-1-phenyl-1,2,3,4-tetrahydro-3-naphthoic acid (IIa). Thus, (--)-IIa and the corresponding amine, (--)-Ia, were assigned the (2S, 4R)-configuration. Epimerization of (--)-IIa through its methyl ester yielded the trans-acid, (--)-IIb, which established the absolute configuration of (--)-IIb and the corresponding amine, (--)-Ib, as (2R, 4R).

Circular Dichroism↗