bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacology of systemically administered domoic acid in mice
Authors: Tasker R. A. R. , Connell B. J. , Strain S. M.
Published: April 2011

Domoic acid, a structural analogue of kainic acid, has been identified as the toxin that poisoned people who consumed contaminated blue mussels harvested from eastern Prince Edward Island in December of 1987. To investigate the pharmacology of domoic acid in vivo we injected groups of mice with serial dilutions of extracts of contaminated mussels and verified domoic acid concentrations using high performance liquid chromatography. Mice progressed through a series of behavioural changes that were both reproducible and dose-dependent. These behaviours formed the basis of a rating scale that was used to reliably quantitate domoic acid concentrations as low as 20 μg/mL. This scale was then used to compare the relative toxicity of domoic acid contained in four formulations: namely, (1) extracts of contaminated mussels, (2) pure domoic acid, (3) extracts of noncontaminated mussels that were "spiked" with pure domoate, and (4) extracts of the algal source of domoic acid. Interpolation of the resulting dose–response curves produced median toxic dose (TD50) values of 2.9, 3.9, 4.9, and 4.2 mg/kg for the four formulations, respectively. Statistical analysis of these data revealed that curves for all formulations of domoic acid were parallel, but that extracts of contaminated mussels were significantly more potent than any of the other formulations at low and intermediate doses of domoic acid. We further compared domoic acid toxicity with that produced by kainic acid. Dose–response curves for both compounds were statistically parallel and both toxins were equally efficacious. The TD50 values were 3.9 and 31.9 mg/kg for pure domoic acid and kainic acid, respectively. We conclude that this method can be effectively applied to studies of domoic acid pharmacology in vivo and that domoic acid is 8 – 11 times more potent than kainic acid following systemic administration.Key words: domoic acid, domoate, kainic acid, excitatory amino acid, amnesic shellfish poisoning.
Direct effects in vivo of angiotensins I and II on the canine sinus node
Authors: Lambert C. , Godin D. , Fortier P. , Nadeau R.
Published: April 2011

The chronotropic responses to angiotensins I and II (5 μg in 1 mL Tyrode's solution) injected into the sinus node artery were assessed before and after the intravenous administration of captopril (2 mg/kg) and saralasin (20 μg/kg) in anaesthetized dogs. The effects of angiotensin II given intravenously were also observed. The animals (n = 8) were vagotomized and pretreated with propranolol (1 mg/kg, i.v.) to prevent baroreceptor-mediated responses to increases in blood pressure. Injection of angiotensin I into the sinus node artery induced significant increases in heart rate (114 ± 6 vs. 133 ± 6 beats/min) and in systemic systolic (134 ± 13 vs. 157 ± 14 mmHg; 1 mmHg = 133.3 Pa) and diastolic (95 ± 10 vs. 126 ± 13 mmHg) blood pressures. Similar results were obtained when angiotensin II was injected into the sinus node artery, but intravenous injection induced changes in systolic (138 ± 8 vs. 180 ± 25 mmHg) and diastolic (103 ± 8 vs. 145 ± 20 mmHg) blood pressures only. Captopril induced a significant decrease in systolic (118 ± 11 vs. 88 ± 12 mmHg) and diastolic (84 ± 9 vs. 59 ± 9 mmHg) blood pressures without affecting the heart rate (109 ± 6 vs. 106 ± 6 beats/min). Saralasin produced a significant increase in systolic (109 ± 7 vs. 126 ± 12 mmHg) blood pressure only. Increments in heart rate and systolic and diastolic blood pressures in response to angiotensins I and II were, respectively, abolished by captopril and saralasin. It was concluded that angiotensin II has, in vivo, a direct positive chronotropic effect that can be blocked by saralasin. The antagonism by captopril of the response to angiotensin I suggests the presence of local tissue converting enzyme activity in the region of the sinus node.Key words: angiotensin, chronotropic effect, tissue converting enzyme.
Considerations concerning the neurobiological basis of muscle pain
Authors: Mense S.
Published: April 2011

Nociceptors in skeletal muscle can be sensitized by substances that are released from pathologically altered tissue. In the sensitized state, nociceptors can be activated by low-intensity stimulation; this is probably one of the mechanisms producing deep tenderness. Dorsal horn cells processing input from muscle nociceptors often have multiple receptive fields and additional input from other deep tissues or skin. This may be one of the reasons for the diffuse and ill-localized nature of muscle pain. The degree of convergence from deep tissues and skin in neurones with muscle input can be increased by noxious stimulation of deep tissues. This mechanism might explain phenomena such as spread and referral of muscle pain. In the development of chronic muscle pain, vicious circles may be involved which operate locally in the damaged tissue or via spinal reflexes that alter the biochemical environment of the nociceptors in skeletal muscle.Key words: nociceptor, dorsal horn neurone, sensitization, muscle pain, pain referral.
Central mechanisms of vascular headaches
Authors: Dostrovsky J. O. , Davis K. D. , Kawakita K.
Published: April 2011

The intracranial blood vessels supplying the dura and brain are innervated by sensory afferents from the trigeminal nerve. These fibers are believed to be responsible for conveying the pain associated with vascular head pain such as migraines. This paper reviews recently published data describing the existence of neurons within the cat trigeminal nucleus and thalamus that respond to electrical stimulation of the middle meningeal artery and superior sagittal sinus. Almost all of these neurons receive convergent input from the facial skin and most of the receptive fields include the periorbital region. On the basis of their cutaneous inputs, most of the neurons are classified as nociceptive. The characteristics of these cerebrovascular-activated neurons are consistent with their role in mediating vascular head pains and with the typical referral of such pains in man to the orbital region. This paper also presents preliminary results of recordings from rat trigeminal ganglion neurons activated by electrical stimulation of the middle meningeal artery and sagittal sinus. The latencies of activation of these neurons are indicative of conduction in slowly conducting myelinated axons and in unmyelinated axons. Some of the neurons could also be activated by mechanical stimuli applied to the vessels.Key words: headache, pain, trigeminal system, somatosensory, thalamus.
Effect of systemic inhibition of prostaglandin synthesis on muscle protein balance after trauma in the rat
Authors: Fisher Brian D. , Baracos Vickie E. , Reid David C.
Published: April 2011

Anaesthetized rats were subjected to a single impact trauma to the medial aspect of the right hindlimb (gastrocnemius muscle), and were compared with sham-treated controls. For 3 days after injury, muscles of the traumatized limb showed a marked catabolic response. Muscle protein repletion commenced after day 3, however, this process was not complete until 21 days after injury. Muscles of the uninjured limb of the traumatized rats also showed a distinct catabolic response, compared with rats that were never injured, although this response was less in magnitude than that of the injured limb. At 3 days after trauma, augmented synthesis of prostaglandin (PG)E2 by muscles of the injured and uninjured limb provided evidence of a local and systemic inflammatory response. Inhibition of PG synthesis by the systemic administration of naproxen (6-methoxy-α-methyl-2-napthaleneacetic acid) significantly reduced the catabolic loss of muscle protein seen locally and peripherally to the injury site.Key words: prostaglandin, trauma, skeletal muscle, naproxen, rat.
α2-Adrenergic receptors on the circular smooth muscle of canine small intestine
Authors: Ahmad Sultan , Allescher Hans D. , Jang Elliott , Rausa Jarmila , Daniel Edwin E.
Published: April 2011

We have studied the distribution and properties of α2-adrenergic receptors in the circular muscle layer (containing deep muscular plexus) of canine small intestine. Using radioactively labelled rauwolscine, we located the binding sites to the neuronal membranes supporting the prejunctional action of α2-adrenergic agents in the gut. Moreover, although the functional data to suggest the existence of postjunctional α2-adrenergic receptors coupled to contraction are not available so far, we measured a substantial number of rauwolscine binding sites on the smooth muscle plasma membranes. Scatchard and Hill analyses of the saturation data were indicative of the presence of a single high affinity site (Hill coefficient 0.996) with a KD value of 8.8 nM and the maximum number of binding sites (Bmax) of 313 fmol/mg of protein. Competition studies suggested the presence of multiple subtypes of α2-adrenoceptors.Key words: [3H]rauwolscine, prejunctional, postjunctional, smooth muscle, enteric neurons.
Age-dependent alterations in the efficacy of phenylephrine-induced contractions in vascular smooth muscle isolated from the corpus cavernosum of impotent men
Authors: Christ George J. , Stone Brian , Melman Arnold
Published: April 2011

Steady-state contractile responses elicited by phenylephrine activation of the α1-adrenergic receptor subtype were studied in vascular smooth muscle strips isolated from the corpus cavernosum of impotent men. The dissociation constant of phenylephrine was determined by the method of partial irreversible receptor inactivation over a wide range of α1-adrenergic receptor alkylation levels. Statistical analysis of mean population values revealed a significantly greater mean efficacy for phenylephrine-induced contractions in older patients (60–73 years old) than in younger patients (40–59 years old), in the absence of similar alterations in the mean phenylephrine dissociation constant (affinity). In addition, there was no significant effect of the diabetic state on the mean phenylephrine affinity or efficacy estimates. However, despite the absence of age-or pathology-dependent variations in agonist affinity, as assessed by group mean calculations, a detailed examination of all isolated tissues on an individual basis revealed that the phenylephrine affinity estimates varied over a range of almost two orders of magnitude. Furthermore, a linear regression analysis revealed a highly significant positive correlation between agonist affinity and the location of the phenylephrine concentration–response curve, which was characterized by a slope significantly less than unity. In conclusion, an increased efficacy of phenylephrine-induced contractions in vitro is consistent with the hypothesis that augmented corporal vascular smooth muscle contractility in vivo may contribute to the pathophysiology of impotence in older patients.Key words: phenylephrine, α1-adrenergic receptor, human vascular smooth muscle, efficacy, impotence, corpus cavernosum.
Functional identification of central pressor pathways originating in the subfornical organ
Authors: Ciriello John , Gutman Michael B.
Published: April 2011

The functional projections from pressor sites in the subfornical organ (SFO) were identified using the 2-deoxyglucose (2-DG) autoradiographic method in urethane-anesthetized, sinoaortic-denervated rats. Autoradiographs of brain and spinal cord sections taken from rats whose SFO was continuously stimulated electrically for 45 min with stereotaxically placed monopolar electrodes (150 μA, 1.5-ms pulse duration, 15 Hz) following injection of tritiated 2-DG were compared with control rats that received intravenous infusions of pressor doses of phenylephrine to mimic the increase in arterial pressure observed during SFO stimulation. Comparisons were also made to autoradiographs from rats in which the ventral fornical commissure (CFV), just dorsal to the SFO, was electrically stimulated. The pressor responses during either electrical stimulation of the SFO or intravenous infusion of phenylephrine were similar in magnitude. On the other hand, stimulation of the CFV did not elicit a significant pressor response. Electrical stimulation of the SFO increased 2-DG uptake, in comparison to the phenylephrine-infused rats, in the nucleus triangularis, septofimbrial nucleus, lateral septal nucleus, nucleus accumbens, bed nucleus of the stria terminalis, dorsal and ventral nucleus medianus (median preoptic nucleus), paraventricular nucleus of the thalamus, hippocampus, supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus of the hypothalamus, and the intermediolateral nucleus of and central autonomic area of the thoracic spinal cord. In contrast, in rats whose CFV was stimulated, these nuclei did not demonstrate changes in 2-DG uptake compared with control animals that received pressor doses of phenylephrine. These data have demonstrated some of the components of the neural circuitry likely involved in mediating the pressor responses to stimulation of the SFO and the corrective responses to activation of the SFO by disturbances to circulatory and fluid balance homeostasis.Key words: cardiovascular reflex pathways, drinking, median preoptic nucleus, osmoreceptors, paraventricular nucleus of the hypothalamus, supraoptic nucleus.
Activation and inactivation of the GABAA receptor: insights from comparison of native and recombinant subunit assemblies
Authors: Mathers D. A.
Published: April 2011

γ-Aminobutyric acid (GABA) acts as an inhibitory transmitter in the vertebrate central nervous system, often by interacting with the GABAA type of receptor. Molecular cloning techniques have shown that GABAA receptors are assembled from at least five types of subunit, some of which are present in multiple forms. In this review, the functional properties of native GABAA receptors are compared with those of recombinant receptors, created by expression of appropriate cDNAs in frog oocytes or transfected mammalian cells. Native receptors typically display multiple conductance levels in the open state, complex kinetics, a Hill slope greater than unity, voltage dependence, and desensitization at high agonist doses. All of these features can also be exhibited by recombinant receptors, but marked qualitative and quantitative distinctions exist between receptors containing different combinations of subunits. It is argued that these functional differences are likely to be exploited in vivo by the expression of multiple, physiologically distinct GABAA receptors, distributed in an adaptive fashion throughout the nervous system.Key words: γ-aminobutyric acid, patch clamp, desensitization, cloned receptor, subunit.
Rigid analogues as probes of excitatory amino acid receptors
Authors: Curry Kenneth
Published: April 2011

The classes of coumpounds to be discussed are based on rigid analogues of glutamic and aspartic acids. The glutamate analogue 1-amino-1,3-cyclopentane dicarboxylic acid (1,3-ACPD) exists as two enantiomeric pairs of geometric isomers. The absolute configurations were assigned and the compounds were found to differentiate between the kainic acid (KA) and N-methyl-D-aspartic acid (NMDA) receptor subtypes when applied iontophoretically to hippocampal CA1 pyramidal neurones. The results indicate a high degree of specificity for the interaction of D-cis- 1,3-ACPD with the NMDA receptor, while the remaining three isomers of 1,3-ACPD were KA-like in their action. The results are augmented with binding studies and patch clamp analysis. The second class of compound is the closely related aspartate analogue 1-amino-1,2-cyclopentane dicarboxylic acid (1,2-ACPD). The geometric isomers have been examined and found to be somewhat less active than their 1,3-ACPD counterparts; however, the cis isomer does have antagonistic properties against quisqualate (QA) evoked excitation. The results indicate that while the three-dimensional arrangement of functional groups is important for the activation of receptor subtypes, other considerations must be made, including stereochemistry and receptor affinity for sterically hindered analogues of excitatory amino acids.Key words: excitatory amino acids, electropharmacology, receptor mapping, rigid analogues.
Involvement of excitatory amino acid receptors in long-term potentiation in the Schaffer collateral–commissural pathway of rat hippocampal slices
Authors: Collingridge G. L. , Blake J. F. , Brown M. W. , Bashir Z. I. , Ryan E.
Published: April 2011

The present article reviews studies from our laboratory, which have shown that excitatory amino acid receptors of the N-methyl-D-aspartate type are involved in the induction of long-term potentiation in the Schaffer collateral–commissural pathway of rat hippocampal slices. The nature of the excitatory amino acid receptors that mediate the response that is modified by the induction of long-term potentiation is also considered. The mechanism of induction of long-term potentiation is discussed, as are some possible stages that are required for the maintenance of this process. Some new data are presented concerning the ability of N-methyl-D-aspartate to potentiate synaptic transmission and to depress the amplitude of the presynaptic fibre volley. Concerning the potentiation, it is shown that brief (1–2 min) perfusion of slices with N-methyl-D-aspartate is sufficient to potentiate synaptic transmission for at least 3 h. The N-methyl-D-aspartate induced depression of the presynaptic fibre volley is shown to be transient and independent of synaptic transmission.Key words: long-term potentiation, N-methyl-D-aspartate, a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, synaptic plasticity, hippocampus.
Excitatory amino acids: new tools for old stories or Pharmacological subtypes of glutamate receptors: electrophysiological studies
Authors: Lodge David , Jones Martyn G. , Palmer Andrew J.
Published: April 2011

Although the N-methyl-D-aspartate (NMDA) subtype of L-glutamate receptor is well characterized, the significance of non-NMDA glutamate-sensitive binding sites is not well documented. In this study, a new tricyclic quinoxalinedione (NBQX) and an arthropod toxin (philanthotoxin) were shown to block responses of spinal neurones in vivo to kainate, quisqualate, and AMPA in parallel but had little effect on responses to NMDA. Philanthotoxin appeared to be a use-dependent antagonist consistent with a channel-blocking mode of action. On cortical wedges in vitro, however, NBQX proved to be a more potent antagonist of AMPA and quisqualate than of kainate (pA2 values of 7.1, 7.0, and 5.6, respectively) with no effect at 10 μM on responses to NMDA. These studies provide evidence that on cortical neurones, but not on spinal neurones, AMPA and kainate depolarize by pharmacologically different mechanisms.Key words: glutamate receptors, quinoxalinediones, philanthotoxin, AMPA, kainate.
Calcitonin gene-related peptide: am inhibitor of guinea pig gallbladder contraction
Authors: Kline Loren W. , Kaneko Toyoji , Benishin Christina G. , Pang Peter K. T.
Published: April 2011

Calcitonin geae-related peptide (CGRP) relaxes vascular and intestinal smooth muscle. This study localized CGRP in the guinea pig gallbladder, examined the effects of CGRP on KCl- and ACh-induced contraction, and determined CGRPs site of action in the gallbladder. The gallbladder of male Hartley guinea pigs was used in in vitro tension studies, radioimmunoassay, or immunocytochemical studies. Radioimmunoassay showed that 8.0 ± 0.5 pmol/g of immunoreactive CGRP was present. Immunocytochemistry demonstrated that immunoreactive-CGRP nerve fibers occurred around blood vessels, in gallbladder smooth muscle layers, and were associated with ganglia. No immunoreactive cell bodies were observed, even after colchicine treatment. The in vitro tension studies showed that CGRP inhibits either KCl- or acetylcholine-stimulated contraction. CGRP may in part act directly on the gallbladder smooth muscle to inhibit contraction.Key words: calcitonin gene-related peptide, gallbladder, smooth muscle.
Downregulation of the Ah receptor in mouse hepatoma cells treated in culture with 2,3,7,8-tetrachlorodibenzo-p-dioxin
Authors: Prokipcak Rebecca D. , Okey Allan B.
Published: April 2011

The aromatic hydrocarbon (Ah) receptor behaves as a ligand-dependent transcription factor in the induction of cytochrome P450IA1. In cells exposed to the Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the Ah receptor undergoes a transformation from a form with low affinity for nucleic acids (cytosolic receptor) into a form that preferentially associates with the cell nucleus (nuclear receptor). We followed the fate of the Ah receptor in mouse hepatoma cells during short-term exposure to [3H]TCDD by analyzing both cytosolic and nuclear fractions for specific binding. Nuclear Ah receptor levels increased over the first 2 h of treatment and then decreased to about 50% of maximal concentrations by 5 h after start of treatment. The decrease in nuclear receptor was not accompanied by a reappearance of detectable Ah receptor in the cytosolic fraction; further incubation with [3H]TCDD in cytosols from lysed cells did not label any additional receptor sites in cytosolic extract. By the 6th h of incubation, the total receptor population in the cell was only about 15–20% of that detected at the start of the incubation. The levels of specific binding detected were unaffected by up to 20 h of incubation with the vehicle DMSO, confirming that the presence of TCDD is required for the observed downregulation to occur. These results indicate that there is a substantial ligand-dependent loss in total Ah receptor during short-term exposure of cells to TCDD in culture.Key words: Ah receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin, dioxin toxicity, Hepa-1 mouse hepatoma cells.
Arachidonic acid metabolites regulate the secretion of atrial natriuretic peptide in cultured rat atrial cardiocytes
Authors: Kovacic-Milivojevic Branka , Schultz Harold D. , Gardner David G.
Published: April 2011

Prostaglandins F2α and E2 increase release of immunoreactive (irANP) in primary cultures of rat atrial cardiocytes. This effect is independent of cell density in the cultures and does not appear to operate through a cAMP-dependent mechanism. Studies that probed the PGF2α effect with a number of different pharmacological antagonists suggest that it is tied to a calmodulin-dependent step. This latter effect does not appear to be related to increased calcium entry through voltage-gated channels in the plasma membrane nor to mobilization of ryanodine-sensitive intracellular calcium pools. Inhibitors of the lipoxygenase pathway, a second avenue of arachidonate metabolism, resulted in a decrease in irANP release from cultured atrial or ventricular cardiocytes. Leukotriene C4, a lipoxygenase product, had a modest effect to promote irANP release over a 24-h period. However, pretreatment of anesthetized rats with nordihydroguarietic acid, a lipoxygenase inhibitor, had no effect on stretch-dependent release of irANP from the heart in vivo. These findings suggest that the prostaglandins represent the more important group of arachidonate metabolites in regulating irANP release physiologically.Key words: ANP secretion, prostaglandins, leukotrienes, cardiovascular homeostasis.
Biosynthesis, secretion, and receptor selectivity of human brain natriuretic peptide
Authors: Nakao Kazuwa , Mukoyama Masashi , Hosoda Kiminori , Suga Shin-ichi , Ogawa Yoshihiro , Saito Yoshihiko , Shirakami Gotaro , Arai Hiroshi , Jougasaki Michihisa , Imura Hiroo
Published: April 2011

Biosynthesis, secretion and receptor selectivity of human brain natriuretic peptide (hBNP) were studied. The BNP mRNA level in the ventricle was approximately 40% of that in the atrium and, taking tissue weight into account, the total amount of BNP mRNA in the ventricle was about twofold greater than the total amount in the atrium. The plasma BNP-like immunoreactivity (-LI) level in normal subjects was 0.90 ± 0.07 fmol/mL, which was 16% of the ANP-LI level. In contrast, the plasma BNP-LI level markedly increased in patients with congestive heart failure, with a progressive rise in proportion to its severity. There was a significant step-up of the plasma BNP-LI level in the coronary sinus (CS) compared with that in the aortic root, and the difference in the plasma BNP-LI level between the CS and the aorta (Ao), Δ(CS–Ao)BNP, increased with the severity of congestive heart failure. In addition, the difference in the BNP-LI level between the anterior inverventricular vein (AIV) draining the ventricle and the aorta (Δ(AIV–Ao)BNP) was comparable to Δ(CS–Ao)BNP, indicating that BNP is secreted predominantly from the ventricle. Binding ability to human clearance receptors (C receptors) and cyclic GMP (cGMP) production of hBNP were investigated and compared with those of ANP. hBNP bound to human C receptors very weakly (about 7%), but exerted cGMP production similar to ANP in cultured human mesangial cells and bovine endothelial cells. In conclusion, hBNP is a novel cardiac hormone mainly synthesized in and secreted from the ventricle and plays physiological and pathophysiological roles in the dual cardiac natriuretic peptide system.Key words: brain natriuretic peptide, atrial natriuretic peptide, natriuretic peptide receptor.
Modulation of Ca2+ channels by atrial natriuretic peptide in the bovine adrenal glomerulosa cell
Authors: Barrett P. Q. , Isales C. M. , Bollag W. B. , McCarthy R. T.
Published: April 2011

In the bovine adrenal glomerulosa cell, calcium influx through voltage-dependent calcium channels is critical to maintaining an aldosterone secretory response. In patch clamp, atrial natriuretic peptide (ANP) inhibits T-type calcium channel current yet stimulates L-type calcium channel current. In the present study the channel effects of ANP observed in the patch-clamp configuration were extended and related to populations of cells. We observed the following. (i) The effect of ANP on T-channel current resulted in the reduction in the open state probability. ANP decreased the mean open state duration from 14.2 to 1.8 ms/sweep. (ii) In the weakly depolarized cell stimulated by 8 mM K+, ANP reduced the level of aequorin luminescence (a measure of cytosolic calcium) and completely inhibited the stimulated rate of aldosterone secretion, returning it to prestimulation values. These effects are consistent with a decrease in net calcium channel influx and the reported inhibition of T-channel current. In contrast, the calcium channel blocker, nitrendipine, which at low dose selectively blocks L-type calcium channel flux, only slightly reduced luminescence, and partially inhibited the sustained secretory response. (iii) In the strongly depolarized cell, stimulated by 60 mM K+, ANP increased the level of aequorin luminescence consistent with an increase in net calcium channel influx and the reported stimulation of L-channel current. These results indicate that under physiological conditions the inhibition of T-type calcium channels may be involved in the inhibition of the aldosterone secretion induced by ANP.Key words: ANP, aldosterone secretion, calcium channels, intracellular calcium, adrenal glomerulosa.
Hypochlorous acid mobilizes cellular zinc
Authors: Fliss Henry , Ménard Michel , Desai Manish
Published: April 2011

Neutrophil oxidants, in particular hypochlorous acid (HOCl), can cause injury to healthy tissues at sites of inflammation. Some of this injury may be caused by oxidant-induced mobilization of metals. We examined the ability of HOCl to mobilize Zn2+ in target tissues. Arterial endothelial cell cultures and heart tissue sections were incubated for 90 s in buffered saline, pH 7.3, containing a suspension of N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide (100 nmol/mL), a Zn2+-specific fluorescent chelator, and were subsequently exposed to 200 μM HOCl for 5 min. The cellular fluorescence was analyzed histologically and showed a marked increase in intensity after HOCl treatment, which was indicative of an increase in cellular free Zn2+ concentration. Incubation of HOCl-treated tissues with dithiothreitol, a membrane-permeable metal chelator, caused a sharp decline in cellular fluorescence. This study shows for the first time that HOCl can mobilize cellular Zn2+. In view of the multiple cellular roles played by Zn2+, its mobilization by oxidants at sites of inflammation may contribute to the observed injury. The ability of dithiothreitol to chelate the mobilized Zn2+ suggests that it may be able to reverse Zn2+-mediated injury.Key words: hypochlorous acid, zinc mobilization, dithiothreitol, neutrophil oxidants, N-(6-methoxy-8-quinolyl)-p-toluene-sulfonamide.
Comparison of force and EMG measures in normal and reinnervated tibialis anterior muscles of the rat
Authors: Zepetnek Joanne E. Tötösy de , Gordon Tessa , Stein Richard B. , Zung Hor Ven
Published: April 2011

The relationship between motor unit force and the recorded voltage produced by activated muscle unit fibres (electromyogram, EMG) was examined in normal and reinnervated rat tibialis anterior muscles. The number, cross-sectional area, and radial distance from the recording electrode of muscle fibres in a given unit, obtained directly from a sample of glycogen-depleted motor units, were analysed in relation to the magnitude of the EMG signal produced by that unit. EMG peak to peak amplitude and area varied as approximately the square root of twitch force in both normal and reinnervated units. Furthermore, the EMG amplitude increased approximately as the total cross-sectional area of the motor unit (number of muscle fibres × the average cross-sectional area of the fibres) and inversely with approximately the square root of the distance of fibres from the recording electrodes on the surface of the muscle.Key words: motor unit size, electromyogram, reinnervation, glycogen depletion.
Mast cell ionic channels: significance for stimulus–secretion coupling
Authors: Janiszewski Janusz , Huizinga Jan D. , Blennerhassett Michael G.
Published: April 2011

The activation of mast cells (MC) due to immunological stimulation causes an immediate and dramatic inflammatory response. We review current evidence indicating that the membrane permeabilities for calcium, chloride, sodium, and potassium have a significant role in the activation of these cells, and in some cases, specific ionic channels have been identified. Moreover, a number of intracellular mechanisms controlling these channels are pointed out, including different classes of G proteins, intracellular calcium, cAMP, and products of phosphoinositol breakdown. However, the interplay between factors controlling membrane conductances for different ions is not currently understood. The diversity of ionic effects on MC activation is depicted, illustrating that the ionic mechanisms of MC activation are specific for different MC types. Since nerve/mast cell interaction is a key element in the burgeoning field of neuroimmunology, we discuss the role of ionic channels as targets of neurotransmitter action in MC activation.Key words: ionic channels, mast cells, neuroimmunology.
Protective effect of adenosine against a calcium paradox in the isolated frog heart
Authors: Touraki Maria , Lazou Antigone
Published: April 2011

The effect of adenosine on the calcium paradox in the isolated frog heart was studied. Addition of adenosine during calcium depletion protected the frog heart against a calcium paradox. This protective effect was indicated by reduced protein and creatine kinase release, maintenance of electrical activity, and recovery of mechanical activity during reperfusion. Tissue calcium determination results showed that adenosine protected frog myocardial cells by reducing the massive calcium influx during reperfusion possibly through an action on calcium channels. Adenosine exerted its action in a dose-dependent manner; a concentration of 10 μM adenosine provided maximum protection of myocardial cells against the calcium paradox damage. Higher concentrations of adenosine produced side effects on both electrical and mechanical activity. These results are discussed in terms of the possible mechanism involved in the protective effect of adenosine.Key words: calcium paradox, adenosine, frog heart.
Differing significance of Na+–Ca2+ exchange in the regulation of cytosolic Ca2+ in rat exocrine gland acini and cardiac myocytes
Authors: Hurley Thomas W. , Dale William E. , Rovetto Michael J.
Published: April 2011

In order to compare the importance of Na+–Ca2+ exchange in the regulation of cytosolic Ca2+ concentration [Formula: see text], acini obtained from rat pancreas and submandibular glands as well as cardiac myocytes were loaded with Na+ by inhibition of Na+–K+ ATPase activity then loaded with rara-2. In the exocrine tissues, incubation in K+-free buffer or with ouabain had no substantial effect on resting [Formula: see text] or on the changes in [Formula: see text] following exposure to carbachol as compared with acini incubated under control conditions. In contrast, rat cardiac myocytes, treated identically, showed marked changes in [Formula: see text] under resting and stimulated conditions as compared with controls. We conclude that the Na+–Ca2+ exchange systems of rat pancreatic and submandibular gland acini contribute little to the overall regulation of [Formula: see text] at rest during cholinergic stimulation.Key words: submandibular glands, pancreatic acini, salivary glands, fura-2, cytosolic Ca2+, Na+–Ca2+ exchange.
Are gap junctions necessary for cell-to-cell coupling of smooth muscle?: an update
Authors: Garfield R. E. , Thilander G. , Blennerhassett M. G. , Sakai N.
Published: April 2011

Earlier, it was questioned whether gap junctions (GJs) were necessary for cell–cell communication in smooth muscle, and GJs were not seen in some smooth muscles. We reexamined this question in the myometrium and in intestinal smooth muscle, in light of current knowledge of the presence and function of GJs. In the uterus, numerous studies show that an increase in GJ number is associated with the onset of delivery and is required for effective parturition. In all cases, this increase in GJ number and the changes in uterine contractility were correlated with increased electrical and metabolic coupling. Evidence for the much smaller, but detectable, degree of electrical coupling in the preterm uterus is explained by the small (but again detectable) number of GJs present. In the intestine, GJs are readily detected in the circular muscle layer but have not been described in the adjacent longitudinal layer. While our immunohistochemical studies failed to detect GJs in the longitudinal layer, this may not be adequate to prove their absence. Therefore, current knowledge of GJ number and function is adequate to explain cell–cell coupling in the uterus. Although it remains uncertain whether GJs are absent from the longitudinal muscle of the intestine, there is no definitive evidence that cell–cell coupling can occur by means other than GJs.Key words: gap junctions, myometrium, connexins, smooth muscle, cell communication.
Dietary sodium induced cardiac hypertrophy
Authors: Harmsen Eef , Leenen Frans H. H.
Published: April 2011

In humans, high sodium intake not only increases the blood pressure, and thus can cause left ventricular hypertrophy (LVH), but also appears to increase LVH independent of this increase in blood pressure. In both normo- and hyper-tensive rats the hypertrophic effect of increased dietary sodium intake on the heart has been clearly established. In normotensive rats, this effect is strain and age dependent, and seems independent of hemodynamic effects of high sodium intake. In both rats and humans, dietary sodium appears to increase wall thickness, resembling pressure overload rather than an increased left ventricular diameter as expected of volume overload. The mechanisms through which high dietary sodium induces hypertrophy are still unknown. It is possible that dietary sodium increases either adrenergic stimulation and (or) enhances sensitivity for adrenergic stimulation and that this hypertrophic response mainly acts via stimulation of α1-adrenergic receptors. Stimulation of the α1-adrenergic receptors will increase the inositol phosphate – diacyl glycerol pathway and enhance the Na+/H+ exchange. The activity of this exchanger might play an important role in the development of dietary sodium induced cardiac hypertrophy.Key words: heart, dietary sodium, left ventricular hypertrophy, hemodynamics, sympathetic activity.
In vivo loads on airway smooth muscle: the role of noncontractile airway structures
Authors: Robinson Philip , Okazawa Mitsushi , Bai Tony , Paré Peter
Published: April 2011

The degree of airway smooth muscle contraction and shortening that occurs in vivo is modified by many factors, including those that influence the degree of muscle activation, the resting muscle length, and the loads against which the muscle contracts. Canine trachealis muscle will shorten up to 70% of starting length from optimal length in vitro but will only shorten by around 30% in vivo. This limitation of shortening may be a result of the muscle shortening against an elastic load such as could be applied by tracheal cartilage. Limitation of airway smooth muscle shortening in smaller airways may be the result of contraction against an elastic load, such as could be applied by lung parenchymal recoil. Measurement of the elastic loads applied by the tracheal cartilage to the trachealis muscle and by lung parenchymal recoil to smooth muscle of smaller airways were performed in canine preparations. In both experiments the calculated elastic loads applied by the cartilage and the parenchymal recoil explained in part the limitation of maximal active shortening and airway narrowing observed. We conclude that the elastic loads provided by surrounding structures are important in determining the degree of airway smooth muscle shortening and the resultant airway narrowing.Key words: elastic loads, tracheal cartilage, airway smooth muscle shortening.
Normalization of contractile parameters in canine airway smooth muscle: morphological and biochemical
Authors: Stephens N. L. , Halayko A. , Jiang H.
Published: April 2011

Asthma research has recently highlighted the importance of correctly normalizing force development for purposes of comparing stiffness properties of smooth muscles between different airways, between airways at different stages of maturity, and between airways from different animal species. This problem does not exist in striated muscle where the entire tissue consists almost entirely of muscle and where cross bridges cycle at the same rate throughout a contraction when load correlation is made. In the bronchus, cross-sectional area of true muscle may constitute only 20–30% of the total tissue cross section, and load-independent cycling rate varies fourfold during the course of a contraction because of the occurrence of normally cycling and latch bridges. These features are responsible for the difficulty in force normalization in smooth muscle. Our studies indicate that normalization with respect to true muscle cell cross-sectional area (derived by quantitative morphometry of appropriate tissue transverse sections) is the most valid. This is only so, however, when it has been proved that the actomyosin content per unit weight of the different muscle tissues is the same.Key words: isometric force, force normalization, muscle cell stress, actomyosin stress.
Renorenal reflexes: Interaction between efferent and afferent renal nerve activity
Authors: Kopp Ulla C.
Published: April 2011

In rats, stimulation of renal mechanoreceptors by increasing ureteral pressure results in a contralateral inhibitory renorenal reflex response consisting of increases in ipsilateral afferent renal nerve activity, decreases in contralateral efferent renal nerve activity, and increases in contralateral urine flow rate and urinary sodium excretion. Mean arterial pressure is unchanged. To study possible functional central interaction among the afferent renal nerves and the aortic and carotid sinus nerves, the responses to renal mechanoreceptor stimulation were compared in sinoaortic denervated rats and sham-denervated rats before and after vagotomy. In contrast to sham-denervated rats, there was an increase in mean arterial pressure in response to renal mechanoreceptor stimulation in sinoaortic-denervated rats. However, there were no differences in the renorenal reflex responses among the groups. Thus, our data failed to support a functional central interaction among the renal, carotid sinus, and aortic afferent nerves in the renorenal reflex response to renal mechanoreceptor stimulation. Studies to examine peripheral interaction between efferent and afferent renal nerves showed that marked reduction in efferent renal nerve activity produced by spinal cord section at T6, ganglionic blockade, volume expansion, or stretch of the junction of superior vena cava and right atrium abolished the responses in afferent renal nerve activity and contralateral renal function to renal mechanoreceptor stimulation. Conversely, increases in efferent renal nerve activity caused by thermal cutaneous stimulation increased basal afferent renal nerve activity and its responses to renal mechanoreceptor stimulation. These data suggest a facilitatory role of efferent renal nerves on renal sensory receptors.Key words: vagotomy, sinoaortic denervation, substance P, prostaglandins, mechanoreceptor stimulation.
Effects of torbafylline on muscle atrophy: prevention and recovery
Authors: Aboudrar Souad , Desplanches Dominique , Bergen Fränzi Graber-von , Favier Roland , Okyayuz-Baklouti Ismahan , Hoppeler Hans
Published: April 2011

The effects of torbafylline on the prevention of and the recovery from 5 weeks of hindlimb suspension induced atrophy were analyzed in rat soleus and extensor digitorum longus muscles. Muscle alterations were investigated by determining a suite of electrophysiological, histochemical, and muscle ultrastructural characteristics. Administration of torbafylline during the suspension period was ineffective in preventing any of the observed muscle atrophic changes. Application of torbafylline during the recovery period resulted in a faster recovery of some soleus muscle structural and functional properties. Mitochondrial volume densities and capillary to fiber ratios returned towards baseline values earlier in the recovery process with torbafylline. Furthermore, the drug significantly improved soleus muscle fatigue resistance 4 weeks after cessation of hindlimb suspension.Key words: xanthine, rat muscle contraction, histocytochemistry, mitochondria, capillaries.
The role of migrating myoelectric complexes in the regulation of digesta transport in the preruminant calf
Authors: Girard C. L. , Sissons J. W.
Published: April 2011

Four calves were equipped with an electromagnetic flow probe inside the tranverse duodenum and with electrodes at intervals of 2 cm on either side of the probe. Amounts of 0.5, 2.0, 3.5, and 5.0 kg of whole milk were given according to a latin square design. Recordings of digesta flow and myoelectric activity were made during a 5.6-h period after feeding to quantify the influence of migrating myoelectric complexes on digesta flow through the transverse duodenum of preruminant calf under different levels of milk intake. Immediately after feeding, a phase of irregular spiking activity appeared; its length increasing linearly (p = 0.002) with the amount of milk fed. Increasing milk intake led to linear increases in duration (p = 0.001) and total electrical activity (p = 0.002) of the irregular activity phases, quadratic shortening of the quiescent phases (p = 0.021), and linear decrease (p = 0.006) in the numbers of migrating myoelectric complexes. Intermittent flows of digesta, each of them corresponding to a strong spike burst, appeared during irregular spiking activity phases. Augmentation of the milk ingested did not affect the volume of each gush of digesta but caused a cubic increase in the number of gushes (p = 0.023) and in the total volume of digesta (p = 0.009). These cubic effects implied that with increased intake of milk, the duodenum endeavoured to accelerate the flow of digesta in an attempt to return to an "empty state" in about the same time for all levels of milk consumed. This was achieved mainly through adjustments in the duration and activity of the irregular spiking activity phase.Key words: calf, myoelectric complex, digesta transport, milk intake.
The effects of ATP, inorganic phosphate, protons, and lactate on isolated myofibrillar ATPase activity
Authors: Parkhouse W. S.
Published: April 2011

The purpose of this study was to examine the effects of lactate, protons, inorganic phosphate, and ATP on myofibrillar ATPase activity. Myofibrils were isolated from carp (Cyprinius carpio L.) fast-twitch white muscle, and myofibrillar ATPase activities were assessed under maximal activating calcium levels (pCa 4.0) at 10 °C in reaction media containing metabolic profiles similar to those seen in fatiguing muscles. The Ca2+-activated ATPase activity was assessed by an ATP regenerating assay that coupled the myofibrillar ATPase to pyruvate kinase and lactate dehydrogenase. This assay allowed the effects of ATP, inorganic phosphate, protons, and lactate on myofibrillar ATPase activity to be assessed. The coupled assay was found to give similar myofibrillar ATPase kinetics, with the exception of higher maximal activities, to those seen with a standard end-point assay. Myofibrillar ATPase activity was depressed by 35% when ATP concentrations were lowered to 2.5 mM. Lowering ATP levels to 0.5 mM reduced the myofibrillar ATPase activities by 85%. Lactate had no effect on myofibrillar ATPase activities. Inorganic phosphate levels up to about 20 mM significantly decreased the myofibrillar ATPase activities, after which further increases in inorganic phosphate content had minimal effects. The changes in ATPase activities were related to total inorganic phosphate, not to the content of diprotonated inorganic phosphate. Myofibrillar ATPase activity was highest at pH 7.5 and lowest at pH 6.0. The interactive effects of low ATP, decreased pH, and high inorganic phosphate levels were not additive, giving similar decreases in activity to those produced by increased inorganic phosphate levels alone. These results suggest that alterations in metabolites accompanying exercise may regulate myofibrillar ATPase activity and contribute to fatigue by inhibiting myofibrillar ATP hydrolysis rates.Key words: fatigue, muscle, ATPase, fish, inorganic phosphate.