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Biomedical subjects

S R White

Publications and source records attributed to S R White.

At least 55 records · Page 3Linked to original sources
PubMed1996

Secondary diagnoses as predictive factors for survival or mortality in Medicare patients with acute pneumonia.

We wished to determine if a claims-based method for severity adjustment would predict mortality or survival in pneumonia based on age, gender, and secondary diagnoses. We used a discriminant analysis model of severity of illness developed from Medicare Part A claims data. Our data base was taken from a hospitalized population age 65 years or older coded as DRG 89 (pneumonia with complications/comorbidities). There were 35,677 cases with a mortality = 11.2% in the derivation cohort from 1989 to 1990, and 19,915 cases with a mortality = 9.8% in the validation cohort from 1991. In the derivation cohort, 98% of patients predicted to live, lived, whereas 18% of patients predicted to die, died. Of the three variables, secondary diagnoses had greatest explanatory power. Receiver operating characteristic curves showed that the model performed best at 40% survival. Results were confirmed with the 1991 validation cohort. The model could be applied to hospitals with as few as 172 discharges. This simple, claims-based method can predict survival in pneumonia. It may be useful in selecting medical records for intensified review of medical quality.

Aged↗
PubMed1995

Inhibitory effects of dopamine and methylenedioxymethamphetamine (MDMA) on glutamate-evoked firing of nucleus accumbens and caudate/putamen cells are enhanced following cocaine self-administration.

Rats were allowed to self-administer cocaine during a 3-h session for 15 days. One to 11 days after the last cocaine exposure, rats were anesthetized with urethane and effects of microiontophoretically-applied dopamine on glutamate-evoked firing of neurons in the nucleus accumbens and in the caudate/putamen were tested. Dopamine produced a dose-dependent inhibition of glutamate-evoked firing in both the nucleus accumbens and the caudate/putamen of rats that had been repeatedly exposed to self-administered cocaine and in control rats. However, the DA-induced inhibition was significantly greater in the group that had self-administered cocaine. The cocaine self-administration group was significantly sensitized to the inhibitory effects of dopamine in both early (1-3 day) and later (9-11 days) periods of cocaine abstinence. Following cessation of repeated cocaine self-administration sessions, nucleus accumbens cells were also sensitized to the inhibitory effects of methylenedioxymethamphetamine (MDMA), a drug that increases extracellular levels of DA and serotonin in the nucleus accumbens. This sensitization to DA- and MDMA-induced inhibition in the nucleus accumbens and in the striatum indicates that long-term neuroadaptations occur in these regions of the nervous system following repeated exposure to self-administered cocaine.

Animals↗
PubMed1995

Proliferation of guinea pig tracheal epithelial cells in coculture with rat dorsal root ganglion neural cells.

Neuropeptides secreted by sensory afferent nerves in airways may modulate growth of airway epithelial cells. To determine whether airway sensory C-fiber nerves secrete neuropeptides that stimulate airway epithelial cell proliferation, we measured S-phase traversal in guinea pig tracheal epithelial (GPTE) cells after coculture with rat dorsal root ganglion (DRG) cells. GPTE cells were grown in subconfluent culture on collagen-coated filters for 2 days. DRG cells were harvested from newborn rat pups and grown in primary culture for 7-10 days in separate wells. GPTE and DRG cells then were cocultured for 48 h, and 10 mM bromodeoxyuridine (BrdU), a thymidine analogue, was added in the final 24 h. Control GPTE cells were grown under similar conditions but without DRG cells. Coculture with DRG cells stimulated GPTE cell traversal of S phase. BrdU labeling in cocultured GPTE cells was 42.8 +/- 5.8 compared with 18.1 +/- 7.2% in control GPTE cells (P < 0.001, n = 6). Coculture in the presence of either the neurokinin (NK)1 receptor antagonists LY-297911 or CP-99,994, the NK2 receptor antagonist SR-48,968, or the calcitonin gene-related peptide (CGRP) receptor antagonist hCGRP-(8-37) (10(-7) M of each) during coculture attenuated proliferation of GPTE cells. Treatment with all three antagonists together during coculture decreased BrdU labeling to 2.4 +/- 0.9% of labeled cells vs. 8.5 +/- 0.5% of labeled cells during coculture without antagonists (n = 4, P < 0.02). DRG cells in coculture secreted substantial concentrations of CGRP [71.0 +/- 11.3 (+/- SE) pmol/ml], substance P (1.26 +/- 0.35 pmol/ml), and neurokinin A (0.45 +/- 0.10 pmol/ml) (n = 19 for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Migration and proliferation of guinea pig and human airway epithelial cells in response to tachykinins.

Restoration of the epithelial lining of a damaged airway is a necessary component of airway repair. Tachykinins, including substance P (SP) and neurokinin A (NKA), are localized to sensory nerves within the airway mucosa. These tachykinins regulate several airway functions, but their role in the repair of the epithelium has not been explored. To determine whether tachykinins stimulate migration and proliferation of airway epithelial cells, guinea pig tracheal epithelial (GPTE) and human bronchial epithelial (HBE) cells were grown in primary culture for 4-5 days. Epithelial cell migration was assessed in a blindwell chemotaxis chamber, and proliferation was determined by immunohistochemistry after incorporation of the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU). Both GPTE and HBE cells migrated after stimulation with 10(-11) M NKA [23.0 +/- 3.6 vs. 5.4 +/- 1.2 cells per 10 high-power fields (hpf), P < 0.001, n = 8 for GPTE cells; 18.4 +/- 2.3 vs. 3.8 +/- 0.5 cells per 10 hpf for control, P < 0.001, n = 4 for HBE cells]. Migration was stimulated within 2 h, was maximal after 6 h, and was attenuated substantially by the neurokinin 2 (NKA)-receptor antagonist SR-48968. NKA-stimulated migration was both chemokinetic and chemotactic, and it could be blocked by inhibition of protein synthesis with cyclohexamide, inhibition of microtubular function with colchicine, or inhibition of actin microfilament elongation with cytochalasin D.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture.

Isocapnic dry gas hyperventilation provokes hyperpnea-induced bronchoconstriction in guinea pigs by releasing tachykinins from airway sensory C-fiber neurons. It is unknown whether dry gas hyperpnea directly stimulates C-fibers to release tachykinins, or whether this physical stimulus initiates a mediator cascade that indirectly stimulates C-fiber tachykinin release. We tested the hypotheses that mucosal hypothermia and/or hyperosmolarity--physical consequences of airway heat and water loss imposed by dry gas hyperpnea--can directly stimulate C-fiber tachykinin release. Neurons isolated from neonatal rat dorsal root ganglia were maintained in primary culture for 1 wk. Cells were then exposed for 30 min at 37 degrees C to graded concentrations of NaCl, mannitol, sucrose, or glycerol (0-600 mOsm) added to isotonic medium, or to isotonic medium at 25 degrees C without or with 462 mOsm mannitol added. Fractional release of substance P (SP) was calculated from supernatant and intracellular SP contents following exposure. Hyperosmolar solutions containing excess NaCl, mannitol, or sucrose all increased fractional SP release equivalently, in an osmolarity-dependent fashion. In marked contrast, hypothermia had no effect on fractional SP release under isotonic or hypertonic conditions. Thus, hyperosmolarity, but not hypothermia, can directly stimulate tachykinin release from cultured rat sensory C-fibers. The lack of effect of glycerol, a solute which quickly crosses cell membranes, suggests that neuronal volume change represents the physical stimulus transduced by C-fibers during hyperosmolar exposure.

Animals↗
PubMed1995

Role of muscarinic receptors in the cerebellar control of the vestibulospinal reflex gain: cellular mechanisms.

Most of the inhibitory Purkinje (P-) cells of the cerebellar anterior vermis fire out-of-phase with respect to the excitatory vestibulospinal neurons during roll tilt of the animal, thus exerting a positive influence on the gain of the vestibulospinal reflex (VSR). The responses of these P-cells depend on activation of glutamatergic excitatory mossy fibers-granule cells, but they are likely to be shaped by GABAergic inhibitory interneurons. The cerebellar cortex contains cholinergic fibers and both muscarinic and nicotinic receptors. In decerebrate cats intravermal injection of the muscarinic agonist bethanechol increased the VSR gain. The cellular mechanisms underlying these gain changes were studied in anesthetized Sprague-Dawley rats by microiontophoresis. Application of bethanechol (10-60 nA, 300 s) increased the response of vermal P-cells to pulses of glutamate (22/33 cells) or GABA (23/25 cells). These effects, which were blocked by the muscarinic antagonist scopolamine, lasted up to 15-40 min and occurred regardless of whether bethanecol altered the basal firing rate of the cells. We propose that the increase of P-cell responses to both excitatory and inhibitory neurotransmitters following activation of muscarinic receptors enhances the amplitude of modulation of these neurons to animal tilt, thus increasing the gain of the VSR.

Animals↗
PubMed1994

The muscarinic agonist, bethanechol, enhances GABA-induced inhibition of Purkinje cells in the cerebellar cortex.

An important function of cholinergic projections to the cerebellar cortex may be to modulate the effects of classical afferent inputs to the cerebellar cortex. This hypothesis is supported by the recent observation that cholinergic agonists act at muscarinic receptors in the cerebellar cortex to facilitate Purkinje cell responses to glutamate, the excitatory neurotransmitter of parallel fibers [Brain Res., 617 (1993) 28-36]. Since Purkinje cell excitability is influenced by inhibitory input from basket and stellate cells as well as by excitatory input from granule cells and climbing fibers, the present study investigated whether muscarinic agonists could also modify the Purkinje cell responses to GABA, the putative inhibitory transmitter of basket and stellate neurons. In anesthetized rats, microiontophoretic application of bethanechol produced a long-lasting enhancement of GABA-evoked inhibition of firing of Purkinje cells in the cerebellar vermis (22/25 cells) regardless of whether bethanechol increased, decreased or failed to alter the basal firing rate of the cell. The muscarinic antagonist scopolamine prevented the bethanechol-induced increase in the GABA response. It appears, therefore, that cholinergic activation of muscarinic receptors enhances not only the excitatory but also the inhibitory component of cerebellar cortex circuitry. Further experiments are required to investigate whether this combination of effects may potentiate the signal processing capabilities of the cerebellar cortex.

Action Potentials↗
PubMed1994

Methylenedioxymethamphetamine depresses glutamate-evoked neuronal firing and increases extracellular levels of dopamine and serotonin in the nucleus accumbens in vivo.

The nucleus accumbens has been implicated as an important site for the actions of many drugs that are used recreationally. This study examined the effects of methylenedioxymethamphetamine (MDMA), a euphoric and hallucinogenic drug, on glutamate-evoked neuronal firing and on extracellular levels of dopamine and serotonin in the nucleus accumbens of the rat. Microiontophoretic application of MDMA inhibited glutamate-evoked firing of most of the nucleus accumbens cells that were tested (83 of 86), as did microiontophoretic application of dopamine and serotonin. MDMA-induced inhibition of glutamate-evoked firing was partially blocked by the dopamine antagonist SCH39166 and was attenuated by combined pretreatment with inhibitors of both serotonin and catecholamine synthesis, p-chlorophenylalanine and alpha-methyl-p-tyrosine. MDMA applied directly into the nucleus accumbens and adjacent regions of the ventral striatum through a dialysis probe increased extracellular levels of both dopamine and serotonin. These results indicate that MDMA has inhibitory effects on glutamate-evoked neuronal firing in the nucleus accumbens and suggest that the inhibition is mediated by increased extracellular dopamine and serotonin. Furthermore, these results permit MDMA to be added to the extensive list of abused drugs that have been demonstrated to elevate extracellular levels of dopamine and serotonin in the nucleus accumbens.

Animals↗
PubMed1994

Cotransmitter-mediated locus coeruleus action on motoneurons.

This article reviews evidence for a direct noradrenergic projection from the dorsolateral pontine tegmentum (DLPT) to spinal motoneurons. The existence of this direct pathway was first inferred by the observation that antidromically evoked responses occur in single cells in the locus coeruleus (LC), a region within the DLPT, following electrical stimulation of the ventral horn of the lumbar spinal cord of the cat. We subsequently confirmed that there is a direct noradrenergic pathway from the LC and adjacent regions of the DLPT to the lumbar ventral horn using anatomical studies that combined retrograde tracing with immunohistochemical identification of neurotransmitters. These anatomical studies further revealed that many of the noradrenergic neurons in the LC and adjacent regions of the DLPT of the cat that send projections to the spinal cord ventral horn also contain colocalized glutamate (Glu) or enkephalin (ENK). Recent studies from our laboratory suggest that Glu and ENK may function as cotransmitters with norepinephrine (NE) in the descending pathway from the DLPT. Electrical stimulation of the LC evokes a depolarizing response in spinal motoneurons that is only partially blocked by alpha 1 adrenergic antagonists. In addition, NE mimicks only the slowly developing and not the fast component of LC-evoked depolarization. Furthermore, the depolarization evoked by LC stimulation is accompanied by a decrease in membrane resistance, whereas that evoked by NE is accompanied by an increased resistance. That Glu may be a second neurotransmitter involved in LC excitation of motoneurons is supported by our observation that the excitatory response evoked in spinal cord ventral roots by electrical stimulation of the LC is attenuated by a non-N-methyl-D-aspartate glutamatergic antagonist. ENK may participate as a cotransmitter with NE to mediate LC effects on lumbar monosynaptic reflex (MSR) amplitude. Electrical stimulation of the LC has a biphasic effect on MSR amplitude, facilitation followed by inhibition. Adrenergic antagonists block only the facilitator effect of LC stimulation on MSR amplitude, whereas the ENK antagonist naloxone reverses the inhibition. The chemical heterogeneity of the cat DLPT system and the differential responses of motoneurons to the individual cotransmitters help to explain the diversity of postsynaptic potentials that occur following LC stimuli.

Animals↗
PubMed1994

Migration of human and guinea pig airway epithelial cells in response to calcitonin gene-related peptide.

Calcitonin gene-related peptide (CGRP) is contained within and secreted by nerves and neuroepithelial bodies in the airway epithelium. To determine whether CGRP is a chemoattractant, tracheal epithelial cells isolated from 23 guinea pigs, and bronchial epithelial cells isolated from seven human donors were grown in primary culture for 4 to 5 days. Cell migration was assessed in a blindwell chemotaxis chamber. A gelatin-coated polycarbonate filter (8-microns pore size) separated the upper wells containing 5 x 10(4) cells from the lower wells containing chemoattractant (either CGRP or insulin). Cells were stimulated for 6 h, after which migrated cells on the filter were stained and counted. Both insulin and CGRP elicited migration of guinea pig tracheal epithelial (GPTE) cells. Exposure to 30 micrograms/ml insulin caused migration of 26.5 +/- 4.0 cells versus 4.3 +/- 0.6 cells per 10 hpf for control (P < 0.001). Treatment with 10(-9) M CGRP elicited migration of 39.6 +/- 2.5 cells versus 2.6 +/- 0.9 cells per 10 hpf for control (P < 0.001). Human bronchial epithelial (HBE) cells also migrated after stimulation with either insulin or CGRP: after 10(-9) M CGRP, HBE cell migration was 41.0 +/- 6.1 cells versus 3.4 +/- 0.3 cells per 10 hpf (P < 0.002; n = 3). Checkerboard analysis showed that the migration to CGRP was both chemotactic and chemokinetic. Incubation with 10(-8) M hCGRP-(8-37), a receptor antagonist for CGRP, plus 10(-9) M CGRP decreased GPTE cell migration to 9.8 +/- 2.4 cells versus 38.6 +/- 1.2 cells per 10 hpf for 10(-9) M CGRP alone (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Augmentation of stimulated eosinophil degranulation by VLA-4 (CD49d)-mediated adhesion to fibronectin.

We examined the effect of VLA-4-mediated adhesion to purified fibronectin (FN) on the stimulated release of the granular protein, eosinophil peroxidase (EPO), in human peripheral blood eosinophils. In initial studies, optimal time-course and concentration-effect relationships were determined; eosinophil adhesion to FN-coated styrene plates was maximal in wells coated with 10 micrograms/ml FN after incubation in the wells for 60 min (17,097 +/- 3,670 adherent eosinophils/well versus 6,789 +/- 925 adherent eosinophils/well in control wells; P < 0.005). Treatment of eosinophils with 10(-8) to 10(-6) M formylmethionylleucyl-phenylalanine (FMLP) + 5 micrograms/ml cytochalasin B (CYTB) caused a concentration-dependent increase in EPO release, which was augmented by preincubation of eosinophils for 120 min in FN-coated (10 micrograms/ml) styrene wells versus eosinophils preincubated in control wells. At 10(-6) M FMLP+CYTB, initial adhesion to FN for 120 min caused an increase in the secretion of EPO from 367 +/- 26 to 485 +/- 25 ng/10(6) eosinophils (P = 0.0001). Treatment of eosinophils during incubation in FN-coated wells with the anti-VLA-4 monoclonal antibody HP2/1 attenuated stimulated EPO secretion caused by 10(-6) M FMLP+CYTB from 497 +/- 40 to 285 +/- 26 ng/10(6) eosinophils (P < 0.02). Similarly, treatment with HP2/1 caused a decrease in eosinophil adhesion to FN-coated styrene from 12,693 +/- 1,866 to 6,206 +/- 852 adherent cells/FN-coated well (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1994

Anticonvulsant withdrawal-emergent psychopathology.

We prospectively investigated psychopathology in 32 epilepsy inpatients openly withdrawn from all antiepileptic drugs (AEDs) prior to entering a controlled trial of an investigational AED. Psychiatric ratings and seizures increased significantly with AED discontinuation. Anxiety and depression were the most prominent symptoms. Thirty-eight percent of patients developed moderate-to-severe psychopathology, and 28% dropped out of the study at various stages due to psychiatric symptoms. In 22 patients openly restarted on AEDs, psychiatric ratings returned to baseline within 2 weeks. Increases in partial seizures were weakly related to emergent anxiety and depression. Increases in generalized seizures were related to increases in global impairment but not to increases in specific psychopathology. AED withdrawal-emergent psychopathology was not fully explained by increases in seizures, demographic factors, or psychiatric history and may be partially due to pharmacodynamic effects following drug discontinuation.

Anticonvulsants↗
PubMed1994

An endogenous signal triggering erythroid differentiation: identification as thyroid hormone.

The identification of thyroid hormone as an endogenous signal for erythroid differentiation began with our studies on the spontaneously differentiating murine erythroleukemia clone 3-1. We observed that the spontaneous differentiation frequency was dependent on a heat stable factor present in fetal calf serum or calf bone marrow. We also noted that the bone marrow extract stimulated erythroid colony-forming units in mouse bone marrow cells, suggesting the relevance of this factor in normal erythroid differentiation. The bone marrow extract did not supplant the requirement of erythropoietin but was synergistic. Purification of the bone marrow extract indicated that the differentiation-inducing activity for clone 3-1 cells cochromatographed with a low-molecular-weight, UV (280 nm)-absorbing component(s). These observations and previous reports identifying the avian erythroblastosis virus oncogene v-erbA as a mutated thyroid hormone receptor which blocked erythroid differentiation led us to test thyroid hormone in our assay. Both triiodothyronine and thyroxine were highly active, and the active constituents in the chromatographically purified fraction were identified as triiodothyronine and thyroxine. Although thyroid hormone action has been associated with both in vivo and in vitro erythroid differentiation, its role has been often relegated to a secondary status. We suggest that thyroid hormone is required for the commitment of erythroid cells to terminal differentiation.

Animals↗
PubMed1994

Beta adrenergic modulation of formyl-methionine-leucine-phenylalanine-stimulated secretion of eosinophil peroxidase and leukotriene C4.

The inhibitory effect of beta-2 adrenergic receptor stimulation on leukotriene C4 (LTC4) secretion and eosinophil peroxidase (EPO) release caused by exogenous activation with 10(-8) to 10(-6) M formyl-met-leu-phe (fMLP) + 5 micrograms/ml of cytochalasin B (Cyto B) in purified human peripheral blood eosinophils was studied. Cells from normal subjects were isolated by negative immunoselection and remained > or = 98% viable as determined by trypan blue exclusion. Duplicate aliquots of eosinophils (10(5) cells/intervention) were activated with 1) fMLP + Cyto B alone, 2) fMLP + Cyto B after pretreatment with 10(-8) M albuterol, 3) 10(-8) M albuterol + fMLP + Cyto B after pretreatment with 10(-8) M propranolol or 4) vehicle control. After incubation, the supernatants were tested for concentration of LTC4 and EPO. Concentration-related release of EPO was demonstrated for 10(-8) M fMLP + 5 micrograms/ml of Cyto B to 10(-6) M fMLP + 5 micrograms/ml of Cyto B, and the greatest concentration of fMLP was used in all subsequent studies. FMLP + Cyto B caused substantial LTC4 secretion in eosinophils (300 +/- 83.0 pg/ml) as compared to sham-activated eosinophils (3.3 +/- 1.9 pg/ml; P < .02). Similarly, maximum EPO release increased from 277 +/- 17.8 to 3956 +/- 1230 ng/10(6) cells (P < .02) after activation with fMLP + Cyto B. Treatment with albuterol decreased markedly both LTC4 secretion to 144 +/- 54.0 pg/ml (P < .05 vs. fMLP + Cyto B-activated eosinophils) and EPO release to 1993 +/- 368 ng/10(6) cells (P < .05 vs. fMLP + Cyto B-activated eosinophils).(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗
PubMed1993

Activation of muscarinic receptors induces a long-lasting enhancement of Purkinje cell responses to glutamate.

The cerebellar cortex contains diffusely distributed cholinergic fibers and both muscarinic and nicotinic receptors. Behavioral studies suggest that an important function of this cholinergic innervation may be to modulate the effects of afferent input to the cerebellar cortex. The present study compared the effects of the muscarinic agonist bethanechol on basal firing rates and on glutamate-evoked firing of Purkinje cells in the vermis of the cerebellum of anesthetized rats. Microiontophoretic application of bethanechol produced a slowly developing, long-lasting enhancement of glutamate-evoked firing which was often disassociated from the bethanechol effect on the basal firing rate. Bethanechol increased the glutamate response of 22/33 Purkinje cells regardless of whether bethanechol increased, decreased or failed to alter the basal firing rate of the cell. The muscarinic antagonist scopolamine prevented the bethanechol-induced increase in the glutamate response. For 7/33 Purkinje cells, bethanechol decreased the glutamate-evoked response. However, this decrease did not appear to be mediated by muscarinic receptors because it was not blocked by scopolamine and it was mimicked by application of the vehicle alone. Acetylcholine application produced a long-lasting increase in the glutamate response of 4/5 Purkinje cells that was similar to the bethanechol effect. These data indicate that the cerebellar cholinergic system exerts a prominent modulatory influence on Purkinje cell excitability by acting through muscarinic receptors.

Acetylcholine↗
PubMed1993

Spectrum of EEG findings in Menkes disease.

We evaluated electroencephalograms (EEGs) in 10 boys with Menkes disease, ranging in age from 9 days to 27 months. Three of 10 tracings were normal (the newborn, his 27-month-old half-brother with the classic phenotype, and a 27-month-old mildly affected patient). Plasma copper levels were low in all patients except the newborn and tended to be lowest in patients whose EEGs were moderately or severely abnormal. EEG differences in Menkes patients could reflect biochemical and molecular heterogeneity with respect to copper availability and utilization in the brain.

Child, Preschool↗
PubMed1993

Effect of mode of activation of human eosinophils on tracheal smooth muscle contraction in guinea pigs.

We studied the relationship between mode of activation of isolated human eosinophils and in situ responsiveness in isolated tracheal smooth muscle (TSM) of guinea pigs. Human peripheral blood eosinophils were activated with either 10(-7) M phorbol myristate acetate (PMA) or 10(-6) M formyl-methionyl-leucyl-phenylalanine (fMLP) + 5 micrograms/ml cytochalasin B (CYB), and activation was confirmed by measurement of eosinophil peroxidase (EPO) secretion by kinetic assay. EPO secretion was similar after activation with fMLP+CYB (10.2 +/- 3.2% of total eosinophil content) and PMA (10.0 +/- 2.8% of total content; P = NS). Topical application of 6 x 10(6) eosinophils/cm2 activated with fMLP+CYB to the TSM segment caused 0.51 +/- 0.14 g/cm active tension (AT) in five preparations (P < 0.03 vs. baseline); cells activated with PMA caused no contractile response (0.04 +/- 0.03 g/cm AT, P = NS vs. baseline). Both PMA- and fMLP+CYB-activated cells caused augmentation of muscarinic responsiveness of guinea pig trachealis. The dose of intravenous acetylcholine required to cause a threshold response (ED0.3) was -7.3 +/- 0.1 log mol/kg at baseline vs. -8.7 +/- 0.5 log mol/kg after treatment with fMLP+CYB-activated eosinophils (P = 0.05) and -6.9 +/- 0.1 log mol/kg at baseline vs. -7.5 +/- 0.1 log mol/kg after PMA-activated cells (P < 0.01). Both AT and augmented muscarinic responsiveness were blocked by pretreating the eosinophils with 200 microM A-63162, an inhibitor of 5-lipoxygenase, before activation with fMLP+CYB. We demonstrate that eosinophils activated comparably (as assessed by EPO secretion) cause augmented muscarinic responsiveness and/or direct contraction of guinea pig TSM through secretion of a product of the 5-lipoxygenase pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetamides↗