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PubMed2004

Involvement of ryanodine receptors in muscarinic receptor-mediated membrane current oscillation in urinary bladder smooth muscle.

The urinary bladder pressure during micturition consists of two components: an initial, phasic component and a subsequent, sustained component. To investigate the excitation mechanisms underlying the sustained pressure, we recorded from membranes of isolated detrusor cells from the pig, which can be used as a model for human micturition. Parasympathomimetic agents promptly evoke a large transient inward current, and subsequently during its continuous presence, oscillating inward currents of relatively small amplitudes are observed. The two types of inward current are considered to cause the phasic and sustained pressure rises, respectively. Ionic substitution and applications of channel blockers revealed that Ca(2+)-activated Cl(-) channels were responsible for the large transient and oscillating inward currents. Furthermore, the inclusion of guanosine 5'-O-(2-thiodiphosphate) in the patch pipette indicates that both inward currents involve G proteins. However, applications of heparin in the patch pipette and of xestospongin C in the bathing solution suggest a signaling pathway other than inositol 1,4,5-trisphosphate (IP(3)) operating in the inward current oscillations, unlike the initial transient inward current. This IP(3)-independent inward current oscillation system required both sustained Ca(2+) influx from the extracellular space and Ca(2+) release from the intracellular stores. These two requirements are presumably SKF-96365-sensitive cation channels and ryanodine receptors, respectively. Experiments with various Ca(2+) concentrations suggested that Ca(2+) influx from the extracellular space plays a major role in pacing the oscillatory rhythm. The fact that distinct mechanisms underlie the two types of inward current may help in development of clinical treatments of, for example, urinary incontinence and residual urine volume control.

Animals↗

PubMed1980

Secretory response of dispersed rat submandibular cells. I. Potassium release.

The secretory response of dispersed rat submandibular cells as it relates to the net efflux of K+ following sympathomimetic and parasympathomimetic stimulation was evaluated. The cholinergic agonists acetylcholine and carbamylcholine were found to have equal efficacy but dissimilar receptor affinity. Median effective concentrations (EC50's) were 1.7 x 10(-7) M and 7.1 x 10(-7) M, respectively. Pilocarpine was found to be acting as a "partial" agonist and had an EC50 at 5.6 x 10(-7) M. (-)-Norepinephrine and (-)-epinephrine were found to have similar efficacy and potency with EC50's at 5.6 x 10(-7) M and 3.8 x 10(-7) M, respectively. (-)-Phenylephrine was found to act as a partial agonist with an EC50 at 3.8 x 10(-6) M, whereas (-)-isoproterenol stimulation resulted in no net K+ efflux within the concentrations tested (10(-8) M--10(-3) M). Extracellular Ca2+, but not Mg2+, was shown to be required to elicit a net K efflux following either cholinergic or alpha-adrenergic stimulation.

Acetylcholine↗

PubMed1980

Secretory response of dispersed rat submandibular cells. II. Mucin secretion.

The secretory response of dispersed rat submandibular cells as it relates to the secretion of D-[1-14C]glucosamine hydrochloride-labeled mucin following sympathomimetic and parasympathomimetic stimulation was evaluated. The adrenergic agonists (-)-norepinephrine and (-)-epinephrine were found to have equal efficacy and potency with a median effective concentration (EC50) of 7.1 x 10(-7) M. (-)-Isoproterenol was found to be acting as a "partial" agonist and had an EC50 of 3.9 x 10(-7) M. (-)-Phenylephrine addition resulted in a small, but significant, secretion of mucin at higher doses tested (10(-4) M--10(-3) M). Neither cholinergic nor alpha-adrenergic receptor stimulation was able to elicit a net increase in the secretion of mucin. However alpha-adrenergic receptor activation in conjunction with beta-adrenergic receptor activation facilitated the rate of secretion. Extracellular Ca2+ and Mg2+ were not required for the secretion of mucin, but extracellular Ca2+ enhanced the rate of secretion following alpha- and beta-adrenergic receptor activation. However extracellular Ca2+ did not enhance mucin secretion following beta-adrenergic receptor activation. Both cellular Ca2+ and beta-adrenergic receptor activation were required to elicit a secretory response following sympathomimetic stimulation.

Adrenergic beta-Agonists↗

PubMed1982

Regulation of intestinal goblet cell secretion. I. Role of parasympathetic stimulation.

The in vivo effects of the parasympathomimetic drug pilocarpine on rat intestinal goblet cells were analyzed by autoradiography, light microscopy (LM), and electron microscopy (EM). Pilocarpine accelerated the release of mucus by compound exocytosis from crypt (but not surface) goblet cells throughout the small and large intestine. Pilocarpine-induced mucus secretion was blocked by atropine alone in ileum and colon, but total inhibition in proximal small intestine required a combination of atropine and tubocurarine. The sensitivity of morphological-autoradiographic methods for detection of goblet cell secretion was compared with that of a biochemical detection method, separation of labeled high-molecular-weight glycoproteins by Sepharose 4B gel filtration of luminal washings. Even when secretion of labeled mucus by compound exocytosis was clearly demonstrated by LM, EM, and autoradiography, gel filtration assay of luminal washings from pilocarpine-injected rats failed to reveal an increase in labeled high-molecular-weight glycoproteins. Autoradiographs of mucosal tissue after luminal washing showed that newly secreted, labeled mucus was retained in the crypts and was thus unavailable to the biochemical assay. Thus, direct observation of exocytosis in individual goblet cells provides a qualitative, but sensitive, assay for short-term acceleration of intestinal mucus secretion.

Animals↗

PubMed1992

Cation channels in basolateral membranes of sheep parotid secretory cells.

We observed 240-pS K+ channels in 63% of cell-attached patches, and 30-pS K+ channels were observed in 95% of cell-attached patches. The 240-pS K+ channel had the relative permeability sequence of K+ (1) = Rb+ (1) > Cs+ (0.3) >> Na+ (0.03) and the relative conductance sequence of K+ (1) > Rb+ (0.22) > Cs+ (0.05) > Na+ (0). It was activated by intracellular free Ca2+ and by depolarization. It was blocked by 10 mmol/l tetraethylammonium (TEA) applied extracellularly. The 30-pS K+ channel had the relative permeability sequence of K+ (1) = Rb+ (1) > Cs+ (> Na+ (< 0.09) and the relative conductance sequence of K+ (1) > Rb+ (0.45) > Cs+ (0) = Na+ (0). Its activity was not sensitive to cytosolic free Ca2+ or membrane potential, and it was not blocked by 10 mmol/l TEA extracellularly. Acetylcholine (10 mumol/l) activated the 240-pS voltage-activated and Ca(2+)-activated K+ channels but did not activate the 30-pS K+ channels. We conclude that the 30-pS K+ channel probably determines the properties of the basolateral membrane in unstimulated sheep parotid secretory cells, whereas the 240-pS voltage-activated and Ca(2+)-activated K+ channel may be important during parasympathomimetic stimulation.

Animals↗

PubMed1979

Effects of methacholine and hypocapnia on airways and collateral ventilation in dogs.

We studied the effects of hypocapnia and methacholine on small airways resistance (Rsaw) and collateral ventilation in anesthetized paralyzed dogs. The animals were ventilated with air while either 10% CO2 or air (hypocapnia) was infused through a segment obstructed with a fiber-optic bronchoscope. Measurements were made before and after instillation of methacholine into the obstructed segment. Collateral resistance (Rcoll) and Rsaw increased with hypocapnia and methacholine. The time constant for collateral ventilation increased with hypocapnia, but did not change with methacholine because of decreases in the compliance of the obstructed segment. We conclude that collateral channels respond to methacholine and hypocapnia in a manner similar to small airways and that local parasympathomimetic stimulation, unlike lung deflation does not increase the time constant for collateral ventilation.

Airway Resistance↗

PubMed1988

Stimulation of ciliary beat frequency by autonomic agonists: in vivo.

beta 2-Adrenergic bronchodilator and muscarinic cholinergic bronchoconstrictor agonists both stimulate ciliary activity in vitro. To test the hypothesis that increases in autonomic activity would result in increases in ciliary beat frequency (CBF) in vivo, a correlation analysis heterodyne laser light-scattering system was developed and validated to measure the stimulating effects of sympathomimetic and parasympathomimetic agonists on tracheal CBF in intact, anesthetized beagles. The mean baseline CBF from 42 studies of 274 measurements in 9 (5 male and 4 female) adult beagles was 6.6 +/- 1.1 Hz. The stimulating effects of a beta 2-adrenergic agonist, fenoterol, and a muscarinic cholinergic agonist, methacholine, on CBF were studied on four and eight beagles, respectively. The studies were randomized and blinded. Aerosolized 10(-5) M fenoterol stimulated the CBF from the base line of 6.8 +/- 2.5 to 32.0 +/- 17.9 Hz in four dogs. Aerosolized methacholine stimulated the CBF from the base line of 5.8 +/- 0.7 to 9.4 +/- 3.0 Hz for 10(-8) M, and to 12.6 +/- 3.1 Hz for 10(-6) M in eight dogs. These are the first data obtained in intact animals that demonstrate CBF in the lower respiratory tract is regulated by autonomic agonists.

Animals↗

PubMed1995

Vagal neuroeffector mechanisms affecting transpulmonary pressure in the intact rat.

Experiments were conducted with chloralose-urethan anesthetized rats to assess the effects of 1) bilateral stimulation of the cervical vagus nerves and 2) parasympathomimetic and sympathomimetic agents. Transpulmonary pressure (Ptp) was used as an index of airway smooth muscle tone, and peak inspiratory Ptp (Ptppeak) values were used for a comparison of responses. In untreated animals, vagal stimulation elicited an increase in Ptppeak of 155%. Cooling of the vagus nerves to 15 degrees C abolished the response of Ptppeak to vagal stimulation. Although isoproterenol (1-10 micrograms/kg i.v.) did not alter resting Ptppeak, it did prevent vagal stimulation from evoking an increase in Ptppeak. Nadolol (1.5 mg/kg i.v.) augmented the increase in Ptppeak elicited by vagal stimulation. Vagal stimulation did not evoke any change in Ptppeak after the administration of both nadolol and atropine or after combined administration of nadolol, atropine, and either serotonin aerosol or prostaglandin F2 alpha. In rats pretreated with capsaicin 1 wk before the experiment, vagal stimulation evoked an increase in Ptppeak that was not statistically different from that of untreated control animals. Therefore, nonadrenergic noncholinergic systems did not appear to play an independent role in the response of the airways to the activation of the vagus nerves.

Administration, Inhalation↗

PubMed1999

Pharmacological management of incontinence.

Many patients with incontinence do not need surgery - for these patients symptoms can often be considerably improved by conservative measures, including drugs. Several different pharmacological actions are potentially useful depending on the underlying cause of the incontinence: a) Detrusor instability (DI) responds to drugs reducing bladder contractility: Anticholinergic agents, e.g. oxybutynin and tolterodine, act at postganglionic parasympathetic cholinergic receptor sites on the detrusor muscle, reducing the strength of the detrusor contraction. Tricyclic antidepressants, e.g. imipramine, have anticholinergic effects, block presynaptic uptake of amine neurotransmitters and directly inhibit detrusor muscle. Alpha-adrenergic antagonists may have a role to play by dual actions on bladder overactivity (due to altered receptor function) and by reducing outlet resistance. b) Genuine stress incontinence (GSI) may be treated using alpha-adrenergic agonists, e.g. phenylpropanolamine, to increase outlet resistance by stimulating smooth muscle of the urethra and bladder neck. c) In nocturnal enuresis reduction of nocturnal urine output with the anti-diuretic hormone (ADH) analogue DDAVP (1-deamino, 8-arginine vasopressin) is beneficial. d) Bladder emptying may be facilitated in patients with retention and 'overflow' incontinence by alpha-adrenergic antagonists, which reduce outlet resistance, and perhaps by parasympathomimetics, e.g. bethanecol. e) In postmenopausal women, systemic oestrogen replacement reduces filling symptoms including urge incontinence. Evidence for oestrogen replacement alone in GSI is lacking, but combination with alpha-agonists is beneficial in milder GSI. For the future, tolterodine and other new anticholinergics offer the hope of treatment for DI with fewer of the side effects that limit the use of established drugs. Better understanding of the pathophysiology of DI may provide new targets for drug therapy, such as hyperpolarisation of detrusor muscle membrane. Alpha-agonists may find a greater role in the future, as may ADH analogues for noctural symptoms.

Adrenergic alpha-Agonists↗

PubMed1987

[Acute effect of prostigmin on lung function and breathing of patients with myasthenia gravis at rest and following ergometric exercise].

The acute effects of a single intravenous Prostigmin injection (0.5 mg) on lung function and gas exchange during rest and bicycle ergometry were measured in 26 patients with myasthenia gravis. The mean age of the patients was 44.6 +/- 17.6 years and the mean duration of myasthenia gravis 5.4 +/- 6.3 years. Lung function parameters obtained from 15 patients showed a normal total lung capacity with an increase in functional residual capacity and residual volume, while vital capacity was diminished. While the application of Prostigmin showed no acute effects on these lung volumes, there was a significant increase in airway resistance, even into the pathologic range. Data obtained during spiro-ergometry concerning gas exchange, circulation and muscle metabolism correspond to those expected from healthy individuals; application of Prostigmin did only influence the heart rate, which can be explained by parasympathomimetic activity. We conclude that dyspnoea in patients with myasthenia gravis need not necessarily be a symptom of the illness itself but can also be caused by therapy; in the latter case bronchodilatators are required.

Adult↗

PubMed1983

Long-term alpha-adrenergic-blocking therapy in detrusor-urethra dyssynergia.

Neurogenic dyssynergia was treated with alpha-adrenergic blockers. Only 21 of 43 highly selected patients with residual urines and low flow rates continued therapy with phenoxybenzamine for more than 6 months, despite initial benefits. The causes of therapy discontinuation are discussed. A combination of 5 mg dibenzylin, 3 times daily, with parasympathomimetic drugs is often necessary. The mechanisms of action of alpha-adrenergic-blocking agents are discussed.

Adolescent↗

PubMed1976

Airway responses to methacholine in allergic and nonallergic subjects.

After inhalation challenge with methacholine, bronchoconstrictor responses were produced in allergic subjects with asthma and hay fever as well as nonallergic subjects. Our results indicate that allergic persons possess a greater pulmonary responsiveness to inhalation of this parasympathomimetic agent than nonallergic subjects; however, patterns of response were different in the 2 types of allergic subjects, those with asthma and those with hay fever. Whereas both types of allergic subjects responded with changes in specific airway conductance when nonallergic subjects did not, only asthmatic subjects differed from nonallergic subjects when comparisons of spirometry were made. These data suggest that there is hypersensitivity of both central and peripheral airways in asthmatics and in the larger central airways of nonasthmatic allergic subjects.

Adult↗

PubMed1990

Autonomic pathophysiology in heart failure patients. Sympathetic-cholinergic interrelations.

We conducted this study in an effort to characterize and understand vagal abnormalities in heart failure patients whose sympathetic activity is known. We measured sympathetic (peroneal nerve muscle sympathetic recordings and antecubital vein plasma norepinephrine levels) and vagal (R-R intervals and their standard deviations) activities in eight heart failure patients and eight age-matched healthy volunteers, before and after parasympathomimetic and parasympatholytic intravenous doses of atropine sulfate. At rest, sympathetic and parasympathetic outflows were related reciprocally: heart failure patients had high sympathetic and low parasympathetic outflows, and healthy subjects had low sympathetic and high parasympathetic outflows. Low dose atropine, which is known to increase the activity of central vagal-cardiac motoneurons, significantly increased R-R intervals in healthy subjects, but did not alter R-R intervals in heart failure patients. Thus, our data document reciprocal supranormal sympathetic and subnormal parasympathetic outflows in heart failure patients and suggest that these abnormalities result in part from abnormalities within the central nervous system.

Adult↗

PubMed2005

Passive body heating ameliorates sleep disturbances in patients with vascular dementia without circadian phase-shifting.

OBJECTIVE: This study investigated the sleep-promoting, thermoregulatory, and circadian phase-shifting actions of passive body heating (PBH) in elderly insomniac patients (IPs) with mild-to-moderate vascular dementia. METHODS: Thirteen elderly IPs with vascular dementia (mean age 76.9 years; male/female ratio 2/11) were subjected to a PBH trial session. This session comprised a 3-day baseline period, 2-day PBH period, and 1-day post-PBH period. In the PBH period, the subjects received PBH (immersion in hot water about 40.0 degrees C to mid-thorax level) for 30 minutes beginning 2 hours before bedtime. Sleep-waking, estimated by actigraph, core body temperature (cBT), and heart rate variability were continuously monitored. Dim-light melatonin-onset time (DLMO) was determined in the baseline and post-PBH periods. RESULTS: PBH significantly improved subjects' sleep quality; sleep latency decreased; sleep efficiency increased; and wake time after sleep onset decreased. These trends were more prominent in the latter half of the sleep time. PBH induced a rapid cBT elevation of approximately 0.80 degrees C, on average, followed by enhanced heat loss (DeltacBT: difference in cBT between just after the PBH and bedtime), lasting 1.5 hours before sleep. There was a significantly positive correlation between DeltacBT and sleep latency. PBH induced no significant phase shift in DLMO. Heart-rate variability data showed that PBH induced parasympathomimetic action during sleep time in the subjects. CONCLUSION: PBH may have a sleep-promoting effect by intervening in the thermoregulatory and autonomic systems in elderly IPs with vascular dementia.

Aged↗

PubMed1978

Regulation of the secretory process of granular components from the convoluted tubular cells of the mouse submandibular gland.

Autonomic regulation of the secretion of granule components in the convoluted tubular cells of male mouse submandibular glands was investigated with the use of an agar gel diffusion test using an antisera for male specific components. Whereas the injection of neither a parasympathomimetic agent (pilocarpine) nor a beta-adrenergic agent (isoproterenol) decreased the amount of the components in the glands, the injection of alpha-adrenergic agents (norepinephrine or phenylephrine) significantly decreased the amount of male specific components. Phenoxybenzamine, an alpha-blocker, completely inhibited these actions of norepinephrine and phenylephrine. These facts suggest that the alpha-adrenergic receptor participates in the secretion of male specific components present in the granules in the convoluted tubular cells of mouse submandibular glands.

Animals↗

PubMed1981

Stimulatory and inhibitory effects of substance P on rat submandibular secretion.

Intravenous infusions of the undecapeptide substance P caused a moderate but transient secretory response from the rat submandibular gland. The electrolyte composition of the saliva elicited by this peptide was qualitatively similar to that of the secretion induced by parasympathomimetic agents. Substance P inhibited the secretory response to acetylcholine and isoproterenol, but did not modify the binding of specific ligands to glandular autonomic receptors. It is concluded that this naturally occurring peptide plays a role in the physiologic regulation of salivary secretions, which involves both direct stimulatory effects and a modulating action on the effect of autonomic neurotransmitters on the salivary gland cells. The latter may involve similar effects of substance P and the neurotransmitters on a metabolic pathway localized beyond receptor activation.

Acetylcholine↗

PubMed1999

The effects of the novel anxiolytic drug lesopitron, a full and selective 5-HT1A receptor agonist, on pupil diameter and oral temperature in man: comparison with buspirone.

We investigated the effects of two 5-HT1A receptor agonists, buspirone and lesopitron, upon pupil size in human volunteers at an ambient luminance level of 32 Cd m(-2) and in darkness. Pupil diameter was monitored with a binocular infrared television pupillometer, before and after the administration of treatments for 4 h at 20-min intervals. Two experiments were conducted. In Experiment 1, 14 healthy male volunteers participated in seven weekly sessions, each associated with the ingestion of one capsule (buspirone 5, 10 and 20 mg, lesopitron 10, 20 and 40 mg and placebo), according to a double-blind balanced, cross-over design. Both buspirone and lesopitron tended to decrease pupil diameter. In darkness, only the highest dose of buspirone (20 mg) caused a miosis that was statistically significant. However, at the luminance level of 32 Cd m(-2) buspirone 10 and 20 mg evoked statistically significant miotic effects, as did the highest dose of lesopitron (40 mg). The miotic effect was significantly greater at 32 Cd m(-2) than in darkness after each dose of buspirone and the highest dose (40 mg) of lesopitron. In Experiment 2, pupil diameter and oral temperature were monitored with an electronic thermometer at 40-min intervals. Twenty healthy male volunteers participated in two weekly sessions, each associated with the sublingual application of 100 microl hydroalcoholic solution (lesopitron 20 mg, placebo), according to a double-blind balanced cross-over design. Lesopitron caused a significant miosis both in darkness and at the luminance level of 32 Cd m(-2); the miosis was greater at 32 Cd m(-2) than in darkness. Lesopitron tended to decrease oral temperature; this effect however, was not statistically significant. The greater effectiveness on the pupil of lesopitron administered sublingually in a solution indicates the importance of first-pass metabolism in reducing the effectiveness of the drug when administered by the mouth. The miosis observed in both experiments may be due to either a sympatholytic or a parasympathomimetic effect of the drugs, or both. The light-dependence of the miosis indicates that the 5-HT1A receptor agonists can modulate the light reflex, possibly via the noradrenergic control of central cholinergic neurones in the Edinger-Westphal nucleus.

Adult↗

PubMed1990

Pupillary responses to dilute pilocarpine in preganglionic 3rd nerve disorders.

Supersensitivity of the iris sphincter to dilute parasympathomimetic agents is considered a diagnostic hallmark of a postganglionic oculomotor nerve disorder. Nine of 13 patients with preganglionic 3rd nerve palsies showed supersensitive pupillary responses using pilocarpine 0.1%. The presence of supersensitivity was not related to the cause of 3rd nerve dysfunction or interval time from onset to testing, but was related to the extent of associated iris sphincter paresis. Some patients with long-standing preganglionic 3rd nerve palsies had features of postganglionic damage, including light-near dissociation and segmental paresis of the iris sphincter. These observations suggest that 1 mechanism of cholinergic supersensitivity in some chronic cases of preganglionic 3rd nerve disorders may be transsynaptic degeneration of postganglionic fibers. In another set of experiments, pharmacologically dilated pupils in normal subjects constricted more to dilute pilocarpine than their normal-sized fellow pupils. Cholinergic supersensitivity in pupil-involving 3rd nerve palsies might also occur simply because the affected pupil is larger than the unaffected pupil.

Adolescent↗