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PubMed1999

Fast repair of hydroxy radical purine deoxynucleotide adducts by phenylpropanoid glycosides and their derivatives from Chinese herbs.

DNA damaged by oxygen radicals has been implicated as a causative event in a number of degenerative diseases, including cancer and aging. So it is very significant to look for ways in which either oxygen radicals are scavenged prior to DNA damage or damaged DNA is repaired to supplement the cells' inadequate repair capacity. The repair activities and reaction mechanism of phenylpropanoid glycosides (PPGs) and their derivatives, isolated from Chinese folk medicinal herbs, towards both dGMP-OH* adducts and dAMP-OH* adducts were studied with the pulse radiolytic technique. On pulse irradiation of nitrous oxide saturated 2 mM dGMP or dAMP aqueous solution containing one of the PPGs or their derivatives, the transient absorption spectra of the hydroxyl adduct of dGMP or dAMP decayed with the formation of that of phenoxyl radicals of PPGs or their derivatives within several decades of microseconds after electron pulse irradiation. The result indicated that dGMP or dAMP hydroxyl adducts can be repaired by PPGs or their derivatives. The rate constants of the repair reactions were deduced to be 0.641-1.28 x 10(9) M(-1) s(-1) for dGMP-OH* and 0.2-0.491 x 10(9) M(-1) s(-1) for dAMP-OH*, which positively correlated to the number of phenolic hydroxyl groups in the glycoside structure. A deeper understanding of this new repair mechanism may help researchers to design strategies to prevent and/or intervene more effectively in free radical related diseases.

DNA Adducts↗

PubMed2000

Pyrene nucleotide as a mechanistic probe: evidence for a transient abasic site-like intermediate in the bypass of dipyrimidine photoproducts by T7 DNA polymerase.

We recently proposed a mechanism for why dAMP is primarily inserted opposite both T's of photoproducts of TT sites by T7 DNA polymerase [Smith, C. A., Baeten, J., and Taylor, J.-S. (1998) J. Biol. Chem., 273, 21933-21940] that was based on analysis of a recent crystal structure of a complex of this enzyme with a template, a primer, and a dideoxynucleotide. We proposed that indiscriminate insertion of dAMP opposite the 3'-T of each photoproducts takes place via a transient abasic site-like intermediate, with the photoproduct outside the active site, whereas insertion of dAMP opposite the 5'-T takes place with the photoproduct inside the active site. To obtain further support for this mechanism, we have investigated the selectivity of dNMP and pyrene nucleotide (dPMP) insertion opposite each T of the cis,syn, trans,syn-I, trans,syn-II, (6-4), and Dewar photoproducts of TT and opposite a tetrahydrofuran abasic site analogue by the exonuclease-deficient T7 DNA polymerase, Sequenase Version 2.0. Selectivity was determined by a direct competition assay that makes use of a stacked gel to resolve the various extension products. Pyrene nucleotide was chosen for investigation because it has been previously shown to be selectively inserted opposite abasic sites and was therefore expected to probe whether the photoproducts were inside the active site during a particular insertion step. In accord with the proposed mechanism, dPMP was inserted in preference to dAMP opposite the 3'-T of all the photoproducts with the exception of the trans,syn-I product, whereas dAMP was inserted in preference to dPMP opposite the 5'-T of all the photoproducts. In addition to supporting the proposed mechanism, these results suggest that pyrene nucleotide may be a useful probe for investigating the mechanism of DNA damage bypass by polymerases and for characterizing their active sites.

Bacteriophage T7↗

PubMed1982

Coding properties of poly(deoxycytidylic acid) templates containing uracil or apyrimidinic sites: in vitro modulation of mutagenesis by deoxyribonucleic acid repair enzymes.

Heat treatment of poly(deoxycytidylic acid)-[poly(dC)] induces the formation of dUMP residues, which code for dAMP when replicated by Escherichia coli DNA polymerases I and III. The specificity of dUMP coding properties is indicated by the quantitative relation between the dAMP incorporated and the frequency of dUMP residues in the heat-treated poly(dC). The dAMP incorporation is prevented by preincubation of uracil containing poly(dC) with uracil-DNA glycosylase. The excision of uracil by uracil-DNA glycosylase leads to the formation of apyrimidinic sites (AP sites), which are barely replicated in vitro under physiological conditions. However, the alteration of E. coli DNA polymerase I fidelity of replication by Mn2+ greatly stimulates the replication of AP sites. There is a preferential incorporation of dAMP, as compared to dTMP, opposite the AP sites. The dAMP incorporation is prevented by preincubation of poly(dC) containing AP sites with Micrococcus luteus AP endonuclease B. The results show a close association between DNA repair by base excision and the prevention of mutagenic processes in vitro. Furthermore, since the alteration of DNA polymerase fidelity allows some replication of the noncoding DNA lesion (AP site), this could imply a role in SOS-induced mutagenesis in vivo.

DNA Ligases↗

PubMed2003

Yeast pol eta holds a cis-syn thymine dimer loosely in the active site during elongation opposite the 3'-T of the dimer, but tightly opposite the 5'-T.

Polymerase eta is a member of the Y family of DNA polymerases which is able to bypass thymine dimers efficiently and in a relatively error-free manner. To elucidate the mechanism of dimer bypass, the efficiency of dAMP and pyrene nucleotide insertion opposite the thymine dimer and its N3-methyl derivatives was determined. Pol eta inserts pyrene nucleotide with greater efficiency than dAMP opposite the 3'-T of an undimerized or dimerized T and is an effective inhibitor of DNA synthesis by pol eta. Substitution of the N3H of the 3'-T of an undimerized T or a dimerized T with a methyl group has little effect on the insertion efficiency of pyrene nucleotide but greatly inhibits the insertion of dAMP. Together, these results suggest that the error-free insertion of dAMP opposite the 3'-T of the cis-syn thymine dimer happens by way of a loosely held dimer in the active site which can be displaced from the active site by pyrene nucleotide. In contrast, pol eta cannot insert pyrene nucleotide opposite the 5'-T of the dimer, whereas it can insert dAMP with efficiency comparable to that opposite the 3'-T. The inability to insert pyrene nucleotide opposite the 5'-T of the dimer is consistent with the idea that while the polymerase binds loosely to a templating nucleotide, it binds tightly to the nucleotide to its 3'-side. Overall, the results show a marked difference from similar studies on pol I family polymerases, and suggest mechanisms by which this Y family polymerase can process damaged DNA efficiently.

Apurinic Acid↗

PubMed2005

The 2'-deoxyadenosine-5'-phosphate anion, the analogous radical, and the different hydrogen-abstracted radical anions: molecular structures and effects on DNA damage.

The 2'-deoxyadenosine-5'-phosphate (5'-dAMP) anion and its related radicals have been studied by reliably calibrated theoretical approaches. This study reveals important physical characteristics of 5'-dAMP radical related processes. One-electron oxidation of the 5'-dAMP anion is found on both the phosphoryl group and the adenine base with electron detachment energies close to that of phosphate. Partial removal of electron density from the adenine fragment leads to an extended pi system which includes the amine group of the adenine. Although the radical-centered carbon increases the extent of bonding with its adjacent atoms, it usually weakens the chemical bonds between the atoms at the alpha- and beta-positions. This tendency should be important in predicting the reactivity of the sugar-based radicals. The overall stability sequence of the H-abstracted 5'-dAMP anionic radicals is consistent with the analogous results for the H-abstracted neutral radicals of the adenosine nucleoside: aliphatic radicals > aromatic radicals. The negatively charged phosphoryl group attached to atom C(5)' of the ribose does not change this energetic sequence. All the H-abstraction produced 5'-dAMP radical anions are distonic radical anions. Studies have shown that the charge-radical-separating feature of the distonic radical anions is biologically relevant. This result should be important in understanding the reactive properties of these H-abstraction-produced anion radicals.

Anions↗

PubMed2005

Viscoelasticity in carbon nanotube composites.

Polymer composites reinforced by carbon nanotubes have been extensively researched for their strength and stiffness properties. Unless the interface is carefully engineered, poor load transfer between nanotubes (in bundles) and between nanotubes and surrounding polymer chains may result in interfacial slippage and reduced performance. Interfacial shear, although detrimental to high stiffness and strength, could result in very high mechanical damping, which is an important attribute in many commercial applications. We previously reported evidence of damping in nanocomposites by measuring the modal response (at resonance) of cantilevered beams with embedded nanocomposite films. Here we carry out direct shear testing of epoxy thin films containing dense packing of multiwalled carbon nanotube fillers and report strong viscoelastic behaviour with up to 1,400% increase in loss factor (damping ratio) of the baseline epoxy. The great improvement in damping was achieved without sacrificing the mechanical strength and stiffness of the polymer, and with minimal weight penalty. Based on the interfacial shear stress (approximately 0.5 MPa) at which the loss modulus increases sharply for our system, we conclude that the damping is related to frictional energy dissipation during interfacial sliding at the large, spatially distributed, nanotube-nanotube interfaces.

Journal Article↗

PubMed2000

The role of M(2)-muscarinic receptors in mediating contraction of the pig urinary bladder in vitro.

1. In urinary bladder, M(2)-muscarinic receptors predominate, but it is the smaller population of M(3)-receptors which mediate detrusor contraction. This study examines the M(2) : M(3) ratio and the role of M(2)-receptors in contraction of pig urinary bladder. 2. Competition experiments with [(3)H]-QNB determined the ratio of M(2) : M(3). In functional studies, affinity values (pK(B)) for 4-DAMP, darifenacin and methoctramine were calculated. Similar experiments were performed on tissues following selective M(3)-inactivation (incubation with 40 nM 4-DAMP mustard in the presence of 1 microM methoctramine to protect M(2)-receptors), precontraction with 50 mM KCl and relaxation with isoprenaline (30 microM) or forskolin (1 microM). 3. In competition binding, displacement of [(3)H]-QNB by 4-DAMP, darifenacin and methoctramine best fitted a two-site model suggesting a predominant (70 - 80%) population of M(2)-receptors. 4. On normal detrusor in vitro, 4-DAMP and methoctramine caused surmountable antagonism of responses to carbachol with pK(B) values of 9.37+/-0.07 and 6.05+/-0.05 respectively. Darifenacin caused unsurmountable antagonism, the apparent pK(B) value being 8.61+/-0.10. 5. In tissues where the M(3)-receptors had been inactivated and cyclic AMP levels elevated, 4-DAMP and darifenacin were less potent, with apparent pK(B) values of 8.72+/-0.08 and 6.74+/-0.07. In contrast, methoctramine was more potent, the apparent pK(B) value increasing significantly to 6.86+/-0.06. 6. se data suggest that the pig bladder possesses a similar muscarinic receptor population to the human bladder and that the M(3)-receptor subtype mediates contraction of the normal detrusor muscle. However an involvement of M(2)-receptors in contraction can be observed following pharmacological manipulation of the receptor population.

Animals↗

PubMed1978

Partial purification and properties of an acid nucleotidase from the postmicrosomal supernatant of rat spleen.

1. The dephosphorylation of 3'-AMP, 3'-dAMP, 3'-CMP and 3'-dCMP was studied in the postmicrosomal supernatant of rat spleen and liver. In both organs 3'-AMP and 3'-dAMP were dephosphorylated at an appreciable rate, in both the presence and the absence of Mg(2+). The pH optimum for this dephosphorylation was in the range 4.5-5.0. 3'-CMP and 3'-dCMP were very slowly degraded, though the activity towards 3'-dCMP increased somewhat in the presence of Mg(2+). The optimum pH for this Mg(2+)-dependent dephosphorylation was 5.5-6.0. 2. The rate of dephosphorylation of 3'-AMP and 3'-dAMP per mg of protein was about 5 times as high in spleen as in liver. 3. The dephosphorylation of 3'-AMP could be ascribed to a single enzyme with pH optimum about 4.5. The activity towards 3'-dAMP could be resolved into one component coinciding with the 3'-dAMP-degrading enzyme, and one Mg(2+)-requiring component probably identical with the soluble deoxyinosine-activated nucleotidase. The dephosphorylation of 3'-dCMP seemed to be performed only by the latter enzyme. 4. The enzyme dephosphorylating 3'-AMP was purified 200-fold from the postmicrosomal supernatant and its physical and catalytic properties were compared with those of acid nucleotidase (EC 3.1.3.31) purified from rat liver lysosomes. The two enzymes were identical in all properties tested (substrate specificity, K(m), molecular weight, response to phosphatase inhibitors), but some of the data differed from earlier reports on the acid nucleotidase. 5. The subcellular localization of the acid nucleotidase, its relationship to the acid phosphatase(s) and its role in the breakdown of nucleic acid constituents are discussed.

Adenosine Monophosphate↗

PubMed1984

Cleavage of single-stranded DNA by the varphiX174 A protein: The A-single-stranded DNA covalent linkage.

Phage varphiX174 A(*) protein cleaves single-stranded DNA and then binds to the 5'-phosphorylated terminus of the cleaved DNA fragment, forming a covalent protein-DNA complex. The bound A(*) protein can religate the termini to form covalently closed single-stranded circles. To determine the nature of the covalent linkage and the amino acid involved, we used A(*) protein to cleave DNA synthesized in vivo with [alpha-(32)P]dATP to form the A(*)-single-stranded DNA complex. The complex was then digested with DNase I and the (32)P-labeled A(*) protein was isolated by electrophoresis on polyacrylamide gels. The isolated complex was digested with either trypsin or Pronase. Incubation of the tryptic digest with snake venom phosphodiesterase gave (32)P-labeled products that migrated on electrophoresis on cellulose plates to the cathode, indicating covalent linkage of (32)P-labeled dAMP residues to a tryptic peptide. High concentrations of snake venom phosphodiesterase released all of the (32)P label as free dAMP. Formic acid/diphenylamine depurination (Burton reaction) of the [alpha-(32)P]dATP-labeled peptide-oligonucleotide complexes caused a transfer of the labeled phosphate from dAMP to the peptide. The phosphorylated peptides were isolated on cellulose plates and shown to be sensitive to bacterial alkaline phosphatase, indicating that a phosphodiester bond linked the peptides to the dAMP. The phosphorylated product of the Pronase digest was identified as free phosphotyrosine by its mobility in three different chromatography systems. Likewise, acid hydrolysis (5.6 M HCl, 110 degrees C, 2 hr) of the phosphorylated tryptic peptides revealed linkage of the phosphate to a tyrosine. Thus, A(*) protein cleaves single-stranded DNA and binds covalently to the 5'-phosphorylated terminus via a tyrosyl-dAMP phosphodiester bond.

Journal Article↗

PubMed1978

Comparison of the antitumor activity and toxicity of 2,4-diamino-5-(1-adamantyl)-6-methylpyrimidine and 2,4-diamino-5-(1-adamantyl)-6-ethylpyrimidine.

The effects of two new compounds, 2,4-diamino-5-(1-adamantyl)-6-methylpyrimidine (DAMP) and 2,4-diamino-5-(1-adamantyl)-6-ethylpyrimidine (DAEP), on the growth of Walker carcinoma 256 were studied. In Sprague-Dawley rats, both compounds inhibited the growth of the Walker tumor, which is naturally resistant to methotrexate. Murphy-Sturm lymphosarcoma, which is extremely sensitive to methotrexate, was not inhibited by DAMP. In contrast, 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (DDMP) inhibited the growth of the Murphy-Sturm and Walker tumors. The toxicity of DAMP and DAEP was charaxterized by convulsions followed by death; DDMP did not show such toxicity at median lethal doses. DAEP and DAMP reversibly reduced the number of polymorphonuclear leukocytes in the peripheral blood of rats, and DAMP also decreased the lymphocytes and platelets; DDMP markedly reduced all these cellular elements. Consistently, bone marrow was also markedly depressed by DDMP.

Adamantane↗

PubMed1999

M2 muscarinic receptor subtype in the feline medial pontine reticular formation modulates the amount of rapid eye movement sleep.

Rapid eye movement (REM) sleep is generated, in part, by activating muscarinic cholinergic receptors (mAChRs) in the medial pontine reticular formation (mPRF). Molecular cloning has identified five mAChR subtypes, and this study tested the hypothesis that the M2 subtype in the mPRF modulates the amount of REM sleep. This hypothesis cannot be tested directly, due to lack of subtype selective muscarinic agonists. However, the amount of REM sleep can be enhanced by mPRF microinjection of a muscarinic agonist, and the relative potencies of muscarinic antagonists to block the REM sleep enhancement can be determined. Two muscarinic antagonists, methoctramine and 4-DAMP, were studied. Six concentrations of each antagonist were microinjected into the mPRF of conscious cat 15 min prior to the agonist bethanechol. Nonlinear regression analysis was used to calculate the dose of antagonist that caused a 50% inhibition (ID50) of bethanechol-induced REM sleep. Bethanechol significantly increased (442%) the amount of time spent in REM sleep. Both methoctramine and 4-DAMP significantly blocked the bethanechol-induced REM sleep increase, with an ID50 of 1.8 microM and 0.6 microM, respectively. The ID50 ratio for methoctramine-to-4-DAMP (3.0) was similar to the affinity ratio of methoctramine-to-4-DAMP only at the M2 subtype (3.5), suggesting that the M2 subtype in the mPRF modulates the amount of REM sleep. This study also tested the null hypothesis that sleep-dependent respiratory depression evoked by mPRF cholinomimetics would not be antagonized by pretreatment of the mPRF with muscarinic antagonists. Neither methoctramine nor 4-DAMP antagonized the bethanechol-induced decrease in respiratory rate.

Animals↗

PubMed1991

Dynamics of swaying of Picea sitchensis.

Six 26-year-old Sitka spruce (Picea sitchensis (Bong.) Carr.) trees growing in a Scottish plantation were swayed manually to determine their mechanical dynamics. The natural frequency of sway of the intact trees (mean height 14.2 m and mean stem diameter 14.5 cm at 1.3 m) was on average 0.35 Hz. The variation of this frequency with tree size was found to be well described by engineering mechanics theory. In particular, shape parameters could be defined for both intact and branchless trees, which, along with stem size, density and elasticity, could predict the natural sway frequency using a simple formula. The damping of sway was found to consist of three components, (1) interference of branches with those of neighbors, (2) aerodynamic drag on foliage, and (3) damping in the stem. For the sample of six trees, which spanned the diameter range at the experimental site, the importance of these three components to overall damping was in the ratio 5/4/1 for the median sized tree. Interference between neighbors depended on the distance to neighbors, as well as on the sizes of the chosen tree and its neighbors. Aerodynamic damping was larger for larger trees and the energy lost to this force was similar in magnitude to that calculated to be lost using drag coefficients from published wind tunnel and other studies. The amount of damping from the stem was linearly related to stem diameter.

Journal Article↗

PubMed2004

Energy loss of ions and ion clusters in a disordered electron gas.

The various aspects of the correlated stopping power of pointlike and extended ions moving in a disordered degenerate electron gas have been analytically and numerically studied. Within the linear response theory we have made a systematic and comprehensive investigation of correlated stopping power, vicinage function, and related quantities for protons and extended ions, as well as for their clusters. The disorder, which leads to a damping of plasmons and quasiparticles in the electron gas, is taken into account through a relaxation time approximation in the linear response function. The stopping power for an arbitrary extended ion with a single bound electron is calculated in both the low- and high velocity limits. Our analytical results show that in a high velocity limit the main logarithmic contribution to the stopping power for an extended ion is significantly modified and for instance, in the case of He+, Li2+, and Be3+ ions must behave as ln ( A v(5) ), ln ( A v(3.25) ), and ln ( A v(2.77) ), respectively where v is the ion velocity. This behavior may be contrasted with the usual ln ( v(2) ) dependence for a point ion projectile. It is shown that the factor A which depends on the damping can be significantly reduced by increasing the latter. In order to highlight the effects of damping we present a comparison of our analytical and numerical results, in the case of both pointlike and extended ions, obtained for a nonzero damping with those for a vanishing damping.

Journal Article↗

PubMed2004

Integration of the Lorentz-Dirac equation: Interaction of an intense laser pulse with high-energy electrons.

Usually the motion of an electron under the influence of electromagnetic fields is influenced to a small extent by radiation damping. With the advent of high power high irradiance lasers it has become possible to generate focused laser irradiances where electrons interacting with the laser become highly relativistic over very short time and spatial scales. By focusing petawatt class lasers to very small spot sizes the amount of radiation emitted by electrons can become very large. Resultingly, the damping of the electron motion by the emission of this radiation can become large. In order to study this problem a code is written to solve a set of equations describing the evolution of a strong electromagnetic wave interacting with a single electron. Usually the equation of motion of an electron including radiation damping under the influence of electromagnetic fields is derived from the Lorentz-Dirac equation treating the damping as a perturbation. We use this equation to integrate forward in time and use the Lorentz-Dirac equation to integrate backward in time. We show that for very short wavelength electromagnetic radiation deep in the quantum regime at high irradiances differences between the perturbation equation and Lorentz-Dirac can be seen. However, for electron motion in the classical regime the differences are negligible. For electron motion in the classical regime the first order damping equation is found to be very adequate.

Journal Article↗

PubMed2006

Theoretical limit of the minimal magnetization switching field and the optimal field pulse for Stoner particles.

The theoretical limit of the minimal magnetization switching field and the optimal field pulse design for uniaxial Stoner particles are investigated. Two results are obtained. One is the existence of a theoretical limit of the smallest magnetic field out of all possible designs. It is shown that the limit is proportional to the damping constant in the weak damping regime and approaches the Stoner-Wohlfarth (SW) limit at large damping. For a realistic damping constant, this limit is more than 10 times smaller than that of so-called precessional magnetization reversal under a noncollinear static field. The other is on the optimal field pulse design: if the magnitude of a magnetic field does not change, but its direction can vary during a reversal process, there is an optimal design that gives the shortest switching time. The switching time depends on the field magnitude, damping constant, and magnetic anisotropy.

Journal Article↗

PubMed1999

Multineuronal spike classification based on multisite electrode recording, whole-waveform analysis, and hierarchical clustering.

We proposed here a method of multineuronal spike classification based on multisite electrode recording, whole-waveform analysis, and hierarchical clustering for studying correlated activities of adjacent neurons in nervous systems. Multineuronal spikes were recorded with a multisite electrode placed in the hippocampal pyramidal cell layer of anesthetized rats. If the impedance of each electrode site is relatively low and the distance between electrode sites is sufficiently small, a spike generated by a neuron is simultaneously recorded at multielectrode sites with different amplitudes. The covariance between the spike waveform at each electrode site and a template was calculated as a damping factor due to the volume conduction of the spike from the neuron to the electrode site. Calculated damping factors were vectorized and analyzed by hierarchical clustering using a multidimensional statistical test. Since a cluster of damping vectors was shown to correspond to an antidromically identified neuron, spikes of different neurons are classified by referring to the distributions of damping vectors. Errors in damping vector calculation due to partially overlapping spikes were minimized by successively subtracting preceding spikes from raw data. Clustering errors due to complex spike bursts (i.e., spikes with variable amplitudes) were avoided by detecting such bursts and then using only the first spike of a burst for clustering. These special procedures produced better cluster separation than conventional methods, and enabled multiple neuronal spikes to be classified automatically. Waveforms of classified spikes were well superimposed. We concluded that this method is particularly useful for separating the activities of adjacent neurons that fire partially overlapping spikes and/or complex spike bursts.

Action Potentials↗

PubMed2004

The Leg Drop Pendulum Test performed under general anesthesia in spastic cerebral palsy.

The general aim of this study was to examine the stiffness and damping characteristics (rate at which oscillations diminish) of limbs of a small population of patients with spastic cerebral palsy (CP) during the Leg Drop Pendulum Test while under general anesthesia and to compare them with patients without CP, both awake and under similar anesthetized conditions. To facilitate a quantitative comparison the authors defined a set of parameters that reflect the stiffness and damping of limbs with spasticity under general anesthesia. To give these parameters more meaning a similar set was constructed for children without disabilities under conditions of normal wakefulness and under anesthesia. The test population of 10 patients with spasticity ranged in age from 4 to 19 years and had a mean age of 10 years 9 months (SD 5 years 10 months); there were four females and six males. The control population consisted of eight patients without disabilities who ranged in age from 7 to 19 years with mean age of 13 years 9 months (SD 3 years 3 months); there were six females and two males. To even out the populations, two limbs from the non-affected sides of two patients with hemiplegic spasticity (both female) were used in the control group. The Leg Drop Pendulum Test was administered to 10 limbs with spastic CP and 10 control limbs under general anesthesia. The two test populations were chosen from patients who were previously scheduled to undergo surgery. Two measures compared limbs of those under anesthetic with those under alert conditions: the damped natural frequency and the damping ratio. The natural frequency is the frequency at which a pendulum oscillates as it comes to rest; the damping ratio is a measure of how quickly the oscillations diminish. In spasticity, active muscle tone disappeared under anesthesia. In both groups the underlying biomechanics of the limb varied considerably. In controls the variation seemed to be growth related.

Adolescent↗

PubMed1994

Antimuscarinic action of liriodenine, isolated from Fissistigma glaucescens, in canine tracheal smooth muscle.

1. The antimuscarinic properties of liriodenine, isolated from Fissistigma glaucescens, were compared with methoctramine (cardioselective M2 antagonist) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, smooth muscle selective M3 antagonist) by radioligand binding tests, functional tests and measurements of second messenger generation in canine cultured tracheal smooth muscle cells. 2. Liriodenine, pirenzepine, methoctramine and 4-DAMP displaced [3H]-N-methyl scopolamine ([3H]-NMS) binding in a concentration-dependent manner with Ki values of 2.2 +/- 0.4 x 10(-6), 3.3 +/- 0.7 x 10(-7), 8.9 +/- 2.3 x 10(-8) and 2.3 +/- 0.6 x 10(-9) M, respectively. The curves for competitive inhibition of [3H]-NMS with liriodenine, methoctramine and 4-DAMP were best fitted according to a two site model of binding, but pirenzepine was best fitted according to a model with one site. 3. Liriodenine and 4-DAMP displayed a high affinity for blocking tracheal contraction (pKB = 5.9 and 9.1, respectively) and inositol phosphate formation (pKB = 6.0 and 8.9, respectively), but a low affinity for antagonism of cyclic AMP inhibition (pKB = 4.7 and 7.8, respectively). 4. Methoctramine blocked cyclic AMP inhibition with a high affinity (pKB = 7.4), but it antagonized tracheal contraction and inositol phosphate formation with a low affinity (pKB = 6.1 and 6.0, respectively). 5. In conclusion, both M2 and M3 muscarinic receptor subtypes coexist in canine tracheal smooth muscle and are coupled to the inhibition of cyclic AMP formation and phosphoinositide breakdown, respectively. The antimuscarinic characteristics of liriodenine are similar to those of 4-DAMP. It may act as a selective M3 receptor antagonist in canine tracheal smooth muscle.

Adenylyl Cyclase Inhibitors↗