Biomedical subjects

M A McAlexander

Publications and source records attributed to M A McAlexander.

5 recordsLinked to original sources

PubMed2001

A decrease in remodeling accounts for the accumulation of arachidonic acid in murine mast cells undergoing apoptosis.

The goal of this study was to examine arachidonic acid (AA) metabolism by murine bone marrow-derived mast cells (BMMC) during apoptosis induced by cytokine depletion. BMMC deprived of cytokines for 12-48 h displayed apoptotic characteristics. During apoptosis, levels of AA, but not other unsaturated fatty acids, correlated with the percentage of apoptotic cells. A decrease in both cytosolic phospholipase A(2) expression and activity indicated that cytosolic phospholipase A(2) did not account for AA mobilization during apoptosis. Free AA accumulation is also unlikely to be due to decreases in 5-lipoxygenase and/or cyclooxygenase activities, since BMMC undergoing apoptosis produced similar amounts of leukotriene B(4) and significantly greater amounts of PGD(2) than control cells. Arachidonoyl-CoA synthetase and CoA-dependent transferase activities responsible for incorporating AA into phospholipids were not altered during apoptosis. However, there was an increase in arachidonate in phosphatidylcholine (PC) and neutral lipids concomitant with a 40.7 +/- 8.1% decrease in arachidonate content in phosphatidylethanolamine (PE), suggesting a diminished capacity of mast cells to remodel arachidonate from PC to PE pools. Further evidence of a decrease in AA remodeling was shown by a significant decrease in microsomal CoA-independent transacylase activity. Levels of lyso-PC and lyso-PE were not altered in cells undergoing apoptosis, suggesting that the accumulation of lysophospholipids did not account for the decrease in CoA-independent transacylase activity or the induction of apoptosis. Together, these data suggest that the mole quantities of free AA closely correlated with apoptosis and that the accumulation of AA in BMMC during apoptosis was mediated by a decreased capacity of these cells to remodel AA from PC to PE.

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PubMed2000

Potassium channel blockade induces action potential generation in guinea-pig airway vagal afferent neurones.

Electrophysiological studies of vagal sensory nerves with cell bodies in the nodose ganglion and mechanically sensitive receptive fields in the guinea-pig trachea/bronchus, were performed. Exposure of the mechanically sensitive receptive fields to 4-aminopyridine (100 microM-1 mM) caused pronounced action potential discharge in all fibres studied. Action potential generation was also produced by alpha-dendrotoxin, and in a subset of fibres, by barium. By contrast, neither iberiotoxin, tetraethyl ammonium, glybenclamide, BDS-II, nor apamin caused action potential generation in the vagal afferent nerve fibres. Tetramethylrhodamine dextran was instilled into the trachea to retrogradely label cell bodies within the nodose ganglion. In these cells, 4-aminopyridine caused a large depolarization of the resting membrane potential, concomitant with an increase in input impedance. The data suggest 4-aminopyridine- and alpha-dendrotoxin-sensitive ion channels within the airway afferent nerve membrane hold the resting membrane potential below the threshold for action potential generation. Mechanisms that lead to an inhibition of these channels will likely lead to an increase in excitability of the airway afferent neurones.

4-Aminopyridine↗

PubMed1999

Adaptation of guinea-pig vagal airway afferent neurones to mechanical stimulation.

1. Intracellular and extracellular electrophysiological recording techniques were employed to examine the mechanisms involved in adaptation of guinea-pig airway sensory neurones to suprathreshold mechanical stimulation in vitro. Extracellular recordings performed using an in vitro airway preparation revealed two unambiguously distinct subsets of mechanically sensitive nerve endings in the trachea/bronchus. In one group of fibres, the mechanical stimulus caused a brief burst of action potentials, after which the nerve rapidly adapted. In the other group of fibres, repetitive action potentials were evoked as long as the stimulus was maintained above threshold. 2. The adaptation response strictly correlated with ganglionic origin of the soma. Those fibres derived from the nodose ganglion adapted rapidly, whereas those derived from the jugular ganglion were slowly or non-adapting. 3. Intracellular recordings from airway-identified neurones in isolated intact ganglia revealed that the majority of neurones within either the nodose or jugular ganglion adapted rapidly to prolonged suprathreshold depolarizing current injections. 4. The electrophysiological adaptation of nodose ganglion-derived neurones following prolonged suprathreshold current steps was greatly reduced by 4-aminopyridine. However, 4-aminopyridine did not affect the adaptation of rapidly adapting nodose ganglion-derived nerve endings in response to mechanical stimuli. 5. The data suggest that ganglionic origin dictates adaptive characteristics of guinea-pig tracheal and mainstem bronchial afferent neurones in response to mechanical stimulation. Also, the rapid adaptation of nodose nerve endings in the trachea observed during a mechanical stimulus does not appear to be related to the adaptation observed at the soma during prolonged suprathreshold depolarizing current injections.

4-Aminopyridine↗

PubMed1998

Inhibition of 5-lipoxygenase diminishes neurally evoked tachykinergic contraction of guinea pig isolated airway.

The role of endogenous 5-lipoxygenase products in modulating tachykinergic neurotransmission in guinea pig isolated trachea was investigated. Tachykinin-containing afferent nerve fibers were stimulated with either electrical field stimulation or antidromic stimulation of the right vagus nerve. This resulted in contractions of the isolated caudal trachea and bronchus that could be blocked with either tetrodotoxin or a combination of neurokinin-1 and neurokinin-2 receptor antagonists. The 5-lipoxygenase inhibitor ZD 2138 (1 microM) significantly inhibited these neurally mediated tachykinergic contractions, by approximately 50%, yet had no effect on the contractions evoked by stimulating tachykinergic fibers in an action potential-independent fashion with capsaicin or by exogenously applied neurokinin A. The effect of ZD 2138 on action potential-driven tachykinergic contractions was mimicked by pobilukast, pranlukast, montelukast and zafirlukast, four structurally unrelated antagonists of the cysteinyl leukotriene 1 receptor subtype. Pobilukast had no effect on the tachykinergic contraction in tissues pretreated with ZD 2138. Likewise, ZD 2138 had no effect on the tachykinergic contractions in tissues pretreated with pobilukast. Intracellular electrophysiological recording of the membrane properties of jugular ganglion neurons, the source of tachykinins in the guinea pig trachea/bronchus, demonstrated that leukotriene D4 caused a membrane depolarization of vagal afferent C-fiber neurons and an increase in input impedance, both of which were abolished by zafirlukast. Taken together, these data indicate that in the resting guinea pig isolated trachea/bronchus, endogenous 5-lipoxygenase activity leads to the production of cysteinyl leukotrienes that amplify action potential-dependent release of tachykinins from airway afferent nerve fibers.

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PubMed1997

Enhancement of tachykinin-induced contractions of guinea pig isolated bronchus by corticotropin-releasing factor.

The effect of corticotropin-releasing factor (CRF) on contractions of guinea pig isolated airways in response to electrical or chemical stimulation of tachykinergic nerve fibers was studied. CRF (1 microgram/ml) caused a 70% enhancement of the peak magnitude of the response to electrical field stimulation (EFS). CRF had a similar effect on contractions of the isolated bronchus evoked by capsaicin. CRF also potentiated contractions evoked by exogenously applied substance P. This effect was selective, as CRF has no effect on contractions evoked by neurokinin A or the substance P analog ASMSP. The potentiation of the substance P-induced contractions of airway smooth muscle was blocked by the CRF receptor antagonist alpha helical (9-41) CRF. These data support the hypothesis that CRF enhances the airway smooth muscle response to stimulation of tachykinin-containing nerve fibers and that this effect is due to a post-junctional mechanism of action.

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