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At least 667 records · Page 37Linked to original sources
PubMed1987

Pulmonary gas trapping in the guinea pig and its application in pharmacological testing.

Airway constriction produced by bronchoconstrictive aerosols in vivo can result in substantial postmortem pulmonary gas trapping in the guinea pig. In order to use gas trapping responses for the evaluation of potential antiasthma agents, we developed a multiple animal inhalation exposure apparatus and an accurate system for quantitating excised lung gas volumes in the guinea pig. Aerosols of histamine, methacholine, and leukotriene D4 were shown to produce gas trapping responses that were inhibited in a dose-dependent fashion by appropriate antagonists. The approach described provides an objective and sensitive measure of the severity of airway obstruction, does not require surgery or anesthesia, and allows excellent control of unwanted sources of experimental variation.

Administration, Inhalation↗
PubMed1988

Measurement of human small airway smooth muscle function in vitro. Comparison of bronchiolar strips and segments.

We have compared isotonic responses to methacholine of human bronchiolar segments and spiral strips. Both types of preparations contracted dose-dependently to methacholine and had a stable intrinsic contractile activity, which was significantly higher in segments (p less than 0.001). ANOVA indicated that the total variation in responses of both strips and segments was similar and was mainly due to a significant between-preparations/within-patients variation. There was a small but significant trend towards a decrease of sensitivity (EC50) in time for both segments and strips. Net contraction, i.e. the difference between resting length and the length at maximal contraction, did not change in time. Limited length-active shortening experiments indicated that 250 mg was a suitable load for both strips and segments. We concluded that, although human bronchiolar strips and segments are functionally comparable, bronchiolar segments are preferable because of their practical and theoretical advantages over bronchiolar strips.

Adult↗
PubMed1982

Effects of ketotifen, a benzocycloheptathiophene, on metacholine- and acetylcholine-induced contractions of canine respiratory smooth muscle.

The relaxant effects of ketotifen on isolated respiratory smooth muscle contracted by methacholine or acetylcholine were examined. Although potent dose-dependent relaxation was observed, it appears that more than 100 times the concentration is required to relax muscle contracted with cholinergic agonists than has been reported for muscle contracted by histamine. This observation offers a possible explanation for the findings of several investigators that dosages of ketotifen administered to patients protect against histamine-induced, but not methacholine- or acetylcholine-induced, bronchospasm.

Acetylcholine↗
PubMedDate not supplied

Airway cholinergic responsiveness in rabbits in relation to antigen sensitization and challenge.

The development of bronchial hyperresponsiveness to cholinergic agents in relation to antigen sensitization and repeated antigen challenge was investigated in a rabbit model. Rabbits immunized to produce preferentially specific IgE antibodies had a modest enhancement of their bronchoconstrictive response (measured as an increase in pulmonary resistance) to aerosolized methacholine compared to sham-immunized and unimmunized controls. A further enhancement was observed subsequent to a series of seven antigen challenges given transtracheally, such that the geometric mean dose of methacholine required to increase pulmonary resistance by 100% (PD100 RL) was 89 cumulative breath units (CBU) compared to 372 CBU for sham-immunized controls and 871 CBU for unimmunized controls (p less than 0.05 for ANOVA). Although methacholine also decreased dynamic compliance, the changes were not different among the three groups. Isolated intrapulmonary bronchi from the three groups did not differ in log concentration of methacholine yielding a half-maximal contraction (log EC50). The range of EC50 values was 15-fold compared to a 90-fold range of PD100 RL. In vivo cholinergic responsiveness of the pupillary muscle did not correlate with bronchial responsiveness. Thus, pulmonary antigen challenge of IgE-producing rabbits produced a marked increase in bronchial responsiveness which did not correlate with in-vitro bronchial responsiveness or with in vivo pupillary responsiveness.

Animals↗
PubMed1986

Effects of periods of conditioning stimulation and of neuropeptides on vagal action at the heart.

The strength of action of the parasympathetic innervation of the heart was tested, in anaesthetized dogs, by regular delivery of bursts of supramaximal electrical pulses at low frequency to the cut, cardiac end of the vagus nerve. Periods of 'conditioning' stimulation of the same nerve at relatively high frequencies (15-30 Hz, for 15-300 s) were found to cause a slowly developing potentiation (up to 280% increase in the vagally induced prolongation of pulse interval) of the cardiac action of the low-frequency stimulation. This potentiation lasted for periods of up to 30 min after the conditioning period. Similar potentiation could be elicited for the action of one vagus nerve by conditioning the vagus on the other side. Potentiation of vagal action was not associated with an enhancement of the response of the heart to injected methacholine. Several neuropeptides, reported to be present in cardiac autonomic nerves, were tested for ability to mimic this effect when administered by intravenous injection. Vasoactive intestinal polypeptide, neurotensin, somatostatin and substance P all failed to do so at the doses tested. Vasopressin did induce an enhancement of cardiac vagal efficacy, but effective pharmacological blockade of its action did not block the potentiation caused by conditioning stimulation. In the absence of any evidence of neuromodulation of vagal action by these neuropeptides, it was presumed that the effect could be attributed to a classical homosynaptic post-tetanic potentiation mechanism involving intracellular accumulation of calcium ions in prejunctional nerve terminals.

Animals↗
PubMed1992

Immunohistochemical, morphological and functional changes in the peripheral sudomotor neuro-effector system in elderly people.

Age-related changes in the human peripheral sudomotor neuro-effector system have been investigated in six 80-year-olds and six young adults. Histochemical and immunohistochemical studies on forearm skin biopsies showed diminished vasoactive intestinal polypeptide (VIP) and calcitonin gene related peptide (CGRP)-like immunoreactivity and a virtual absence of acetylcholinesterase in the elderly sudomotor nerve endings compared to the young. Reduced size of nerve bundles and decreased density of sympathetic nerve endings adjacent to the sweat glands of old people were shown by the neuronal marker, protein gene product (PGP 9.5), and by electron microscopy. Image analysis techniques were also used to demonstrate a marked regression in secretory coil size with age. Functional decrements accompanying the neurochemical and morphological changes in the neuro-effector system were measured in ten 80-year-olds by local quantitative nicotine axon reflex responses and compared with 12 young adults. These studies demonstrate marked regressive changes in both the nerve endings and target cells in old age and appear to express a significant loss of vigour in trophic interactions.

Acetylcholinesterase↗
PubMed1992

Sites at which neuropeptide Y modulates parasympathetic control of heart rate in guinea pigs and rats.

Immunohistological evidence indicates that neuropeptide Y (NPY) is present in the cardiac innervation of numerous species. The present experiments determined if NPY influences in vivo parasympathetic control of heart rate in guinea pigs and rats by either pre- or postganglionic mechanisms or by an interaction at muscarinic receptors at the sino-atrial node. Urethane-anesthetized animals were prepared with arterial and venous catheters, and ECG leads. The cervical vagi were sectioned and propranolol was administered to minimize reflex changes in heart rate. Methacholine injection, carbachol injection, or electrical stimulation of the peripheral end of the vagus nerve was performed to activate the neuroeffector site, intracardiac ganglion cells, or preganglionic neurons, respectively. All three trials were performed before, during, and after NPY infusion. No differences in methacholine- or carbachol-induced bradycardia were observed between control and NPY groups in either species. NPY infusion inhibited vagal-mediated bradycardia in guinea pigs and in rats. However, NPY inhibited vagal-mediated bradycardia at a lower dose in guinea pigs (1 microgram/kg/min) than in rats (4 micrograms/kg/min). These data indicate that NPY modulates cardiac vagal preganglionic, but not postganglionic nerve function or neuroeffector sites at the sino-atrial node, in guinea pigs and rats. Furthermore, due to the different effective dosages, NPY may play a greater modulatory role in guinea pigs than in rats.

Animals↗
PubMed1983

Distribution of three hexose derivatives across the pancreatic epithelium: paracellular shunts or cellular passage?

It has been proposed that the pancreatic epithelium is permeable to three presumably passively distributed non-electrolytes, namely sucrose, inulin and mannitol, via paracellular shunts, and that the increased flux of sucrose and inulin seen during augmented digestive enzyme secretion is due to an increase in the permeability of these shunts. The present study considers this hypothesis by comparing the permeability of the epithelium to three different hexose derivatives, mannitol, inositol and 3-O-methyl-glucose, in both the unstimulated state and after the augmentation of protein secretion with a cholinergic drug. The epithelium was found to be more permeable to mannitol than to either inositol or 3-O-methyl-glucose. In the unstimulated state, the concentration of mannitol in ductal fluid at the steady state was approx. 54% of its concentration in the interstitium, as compared to 12% for inositol and 8% for 3-O-methyl-glucose. Cholinergic stimulation substantially increased the concentration of inositol and 3-O-methyl-glucose in secretion, but did not increase that of mannitol. The increase in the concentration of inositol occurred in the absence of an increase in its rate of transepithelial movement. Taken together, the results suggest that: (1) there is a substantial passage of mannitol through the cells of the epithelial layer, and (2) the increased concentration of inositol and 3-O-methyl-glucose in ductal fluid that occurs with stimulation is due to an increase in their efflux from secretory cells.

3-O-Methylglucose↗
PubMed1984

Cyclic GMP-dependent protein kinase activation in canine tracheal smooth muscle by methacholine and sodium nitroprusside.

Methacholine (3 microM) and sodium nitroprusside (300 microM) increased cGMP-dependent protein kinase activity ratios (activity without cGMP divided by activity with 2 microM cGMP) in canine tracheal smooth muscle from a control value of 0.47 to 0.55 and 0.71, respectively. This correlates with 3-fold and 6-fold increases in cGMP concentrations in response to methacholine and sodium nitroprusside, respectively. Addition of charcoal to the homogenizing buffer prior to homogenization had no significant effect on the cGMP-dependent protein kinase response to either agent, suggesting that activation of the enzyme was not occurring as a result of cGMP release during homogenization. In order to limit cGMP dissociation from cGMP-dependent protein kinase during the assay procedure, it was necessary to perform assays at a reduced temperature (0 degree C) and with an abbreviated incubation time (2.5 min). When assayed at 30 degrees C, activated cGMP-dependent protein kinase rapidly lost activity. This inactivation occurred whether the enzyme had been activated exogenously, by exposing a supernatant fraction of canine trachealis to 0.1 microM cGMP, or endogenously, by treating intact canine trachealis with methacholine or sodium nitroprusside. By assaying instead at 0 degree C, the inactivation of cGMP-dependent protein kinase was minimized. Therefore, the activity ratio obtained by this new modified assay provided an estimate of the endogenous activation state of cGMP-dependent protein kinase. The data indicate that cGMP responses in canine trachealis to both methacholine and sodium nitroprusside are functionally linked to activation of cGMP-dependent protein kinase and are consistent with the hypothesis that cGMP, via cGMP-dependent protein kinase activation, regulates smooth muscle contractility.

Animals↗
PubMed1985

Effect of activation of muscarinic receptors on intracellular free calcium and secretion in bovine adrenal chromaffin cells.

Stimulation of the nicotinic receptor of bovine chromaffin cells results in a rise in intracellular free calcium [( Ca2+]i) and subsequent release of catecholamine. This response is totally dependent on the presence of external Ca2+. Monitoring [Ca2+]i using quin-2 demonstrated a rise in [Ca2+]i in response to muscarinic agonists which was approximately 4-times less than that obtained in response to nicotinic stimulation. This atropine-sensitive [Ca2+]i rise occurred after a 10-s lag and was found to be independent of the external Ca2+, implying the existence of an intracellular Ca2+ source. Despite producing this [Ca2+]i rise low concentrations of the muscarinic agonist, methacholine (under 1 X 10(-3) M), failed to trigger secretion itself and did not effect the secretory response elicited by nicotine. Challenging the cells with higher methacholine concentrations (over 1 X 10(-3) M) resulted in the same [Ca2+]i rise, no secretion, but an inhibition of secretion due to nicotine. This latter response, however, was found to be atropine-insensitive and therefore non-muscarinic. The [Ca2+]i rise and secretion due to depolarization by 55 mM K+ were largely unaffected by prior addition 1 X 10(-2) M methacholine, inferring that high concentrations of methacholine inhibit nicotine-induced secretion by interacting with the nicotinic receptor. These results provide evidence consistent with the existence of an intracellular Ca2+ store mobilized by muscarinic receptor activation in bovine chromaffin cells and show that, despite causing a rise in [Ca2+]i, bovine chromaffin cell muscarinic stimulation does not effect secretion itself or secretion induced by either nicotine or high K+.

Aminoquinolines↗
PubMed1986

Prostacyclin synthesis by the corpora cavernosa of the human penis: evidence for muscarinic control and pathological implications.

The present study demonstrates that human corpus cavernosum tissue has the capacity to produce prostacyclin (PGI2), a vasodilator and potent inhibitor of platelet aggregation. The release of PGI2 was stimulated by cholinergic (muscarinic) but not adrenergic agents. Since penile erection in man is dependent upon parasympathetic stimulation, the vasodilatory action of PGI2 may contribute to the initiation and maintenance of erection.

Atropine↗
PubMed1987

The effect of lead on cholinergic contractile function in the rat forestomach.

Previous studies have demonstrated that subchronic exposure to lead in rats slows gastric emptying. Therefore, the isometric contractile response of the forestomach from lead-treated rats was examined in vitro. Male Wistar rats were fed 4% lead acetate in their diet (NIH-07); controls were pair-fed. After 7 weeks, blood lead levels reached 180-389 micrograms/dl. The forestomach was dissected and suspended in buffer which for lead-treated rats contained 1.2 X 10(-5) M lead acetate. Subchronic lead exposure had no effect on the maximum tonic contraction induced by KCl, methacholine or serotonin. However, lead-treated tissue showed enhanced sensitivity to methacholine with a reduction in EC50 to 59.7% of control. This effect was not observed in control tissue exposed to lead (1.2 X 10(-5) M) only in vitro. Higher in vitro concentrations of lead (16 X 10(-5) M) produced an increase in methacholine EC50. Physostigmine-induced increase in tension was also significantly greater in tissue from lead-treated rats. Electric field stimulation, which produced a contraction attributable to postganglionic acetylcholine release, was unaltered in lead-treated tissue. These results indicate that lead intoxication did not impair the contractile apparatus of the forestomach smooth muscle. The lack of net effect on activation of intramural cholinergic neurons, despite the enhanced sensitivity to a cholinergic agonist, may indicate reduction in acetylcholine release in lead-treated tissue.

Administration, Oral↗
PubMed1979

Influence of cholinergic agents on dopamine release from medial basal hypothalamus.

The ability of acetylcholine to influence the stimulation-induced release of [3H]dopamine in medial basal hypothalamus was evaluated. A muscarinic facilitation of electrical field-stimulated but not potassium-stimulated release was observed. These data suggest a muscarinic enhancement of dopamine release perhaps via an action at the level of the cell body. These data suggest that observed effects of cholinergic agents on prolactin release may be mediated in part through such a cholinergic-dopaminergic interaction.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗