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PubMed1993

The action of diazepam in the isolated rat detrusor muscle.

Diazepam is one of the benzodiazepines, a group of drugs that depresses the central nervous system. It also inhibits the contractility of smooth muscles in the periphery, but the mechanism of this inhibitory action has not been clarified. Our study was undertaken to investigate the effect of diazepam on the contractility of the detrusor muscle. Detrusor muscle strips isolated from rat urinary bladder were examined by isometric myography. Diazepam, as well as baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, reduced the electric field stimulation-induced contractions; delta-aminovaleric acid, a GABAB receptor antagonist, completely antagonized the inhibitory effect of baclofen, but not the inhibitory action of diazepam. Diazepam reduced the basal tone of detrusor muscle concentration dependently, and this inhibitory action was not affected by tetrodotoxin. Diazepam suppressed the contractile responses to bethanechol, adenosine triphosphate and potassium chloride. Diazepam diminished the calcium-induced recovery of tension in calcium-free PSS. A23187, a calcium ionophore, partially recovered the basal tone which had been reduced by diazepam in normal physiologic salt solution (PSS). The loss of tension in calcium free PSS containing diazepam could not be recovered by addition of A23187. On the other hand, the loss of tension in calcium-free PSS containing 3,4,5-trimethoxybenzoic acid 8(diethylamino)octyl ester (TMB-8), an inhibitor of intracellular calcium release, was considerably recovered by addition of A23187. Based on these results, it is suggested that diazepam inhibits the contractility of detrusor muscle acting directly on the smooth muscle cell, which is unrelated to the activation of GABA receptors. Its inhibitory action appears to be mediated through interference with the influx of extracellular calcium.

Adenosine Triphosphate↗
PubMed2004

Acute exposure to methylmercury causes Ca2+ dysregulation and neuronal death in rat cerebellar granule cells through an M3 muscarinic receptor-linked pathway.

Acute exposure to low concentrations of methylmercury (MeHg) causes a severe loss of intracellular calcium (Ca2+(i)) homeostasis, which apparently contributes to neuronal death of cerebellar granule cells in culture. We examined the role of muscarinic receptors in MeHg-induced Ca2+ dysregulation and cell death in rat cerebellar granule cells in vitro using fura-2 single-cell microfluorimetry and viability assays, respectively. The nonspecific muscarinic receptor antagonist atropine significantly delayed the onset of MeHg-induced Ca2+ elevations and reduced the amount of Ca2+ released into the cytosol. Depletion of the smooth endoplasmic reticulum (SER) Ca2+ pool with thapsigargin or down-regulation of muscarinic receptors and inositol-1,3,4-triphosphate (IP3) receptors with bethanechol (BCh) caused similar reductions in the amplitude of the MeHg-induced Ca2+ increase, suggesting that MeHg interacts with muscarinic receptors to cause Ca2+ release from the SER through activation of the IP3 receptors. To determine whether this Ca2+ release plays a role in MeHg-induced cell death, cells were exposed to MeHg in the presence of specific muscarinic receptor inhibitors. Acute exposure to increasing concentrations of MeHg (0.2-1.0 microM) caused a corresponding increase in cell death at 24.5 h post-exposure. Prior down-regulation of muscarinic and IP3receptors with BCh protected against cell death. Protection was ablated by atropine and the M3 receptor antagonist 4-diphenylacetoxyl-N-methylpiperidine methiodide (DAMP), but not by the neuronal nicotinic receptor antagonist dihydro-beta-erythroidine hydrobromide (DHE). Thus activation of M3 muscarinic receptors with subsequent generation of IP3 evidently contributes to elevated [Ca2+]i and subsequent cytotoxicity of cerebellar granule cells by MeHg.

Animals↗
PubMed1990

A novel water-soluble dopamine-2 antagonist with anticholinesterase activity in gastrointestinal motor activity. Comparison with domperidone and neostigmine.

A novel water-soluble dopamine-2 antagonist, N-[4-[2-(dimethylamino) ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) was synthesized and assayed for its gastrointestinal smooth muscle stimulating activity in vivo and in vitro. In the in vivo study, gastrointestinal contractile activity was measured by means of chronically implanted force transducers in conscious dogs; it was found that HSR-803 at 3.0 mg/kg IV probably stimulated gastric contractile force twice during the digestive state and significantly antagonized dopamine-(1.0 mg/kg per hour) inhibited gastric contractions in doses of 0.3, 1, and 3 mg/kg IV. With a background IV infusion of HSR-803 at 3 mg/kg per hour, the contraction-stimulating activity of acetylcholine (0.05 mg/kg per minute) was greatly enhanced while the response to bethanechol was not changed. As a result, HSR-803 was found to have a strong anticholinesterase activity besides the antidopamine-2 activity; i.e., the anticholinesterase activity of HSR-803 at 3 mg/kg per hour was equivalent to that of neostigmine at 10 micrograms/kg per hour, and dopamine-2 antagonistic activity of HSR-803 was similar to that of domperidone on a weight basis. No symptom suggesting actions on the central nervous system was noticed in HSR-803 up to 10 mg/kg IV in conscious dogs. In the in vitro study, HSR-803 inhibited cholinesterase dose-dependently, and IC50 was 2.9 x 10(-6) mol/L, while those of neostigmine and domperidone were 2.3 x 10(-8) mol/L and 1.7 x 10(-5) mol/L, respectively. In conclusion, HSR-803 stimulates endogenous acetylcholine release by antagonizing the dopamine-2 receptor on the postsynaptic cholinergic neurons, and the anticholinesterase activity of HSR-803 may cause the released acetylcholine to accumulate at cholinergic receptor sites. Thus, HSR-803 is potentially capable of enhancing cholinergic activity in the gastrointestinal region.

Animals↗
PubMed1980

Palate morphogenesis. V. Effects of cholinergic agonists and antagonists on rotation in embryo culture.

Morphological studies have shown that the pterygopalatine ganglion in the day-14.5 mouse palatal shelf lies adjacent to the putative contractile system of region-2 cells in the posterior palate. It is of interest to learn whether the ganglion could influence rotation of the palate. Results of embryo culture experiments showed that acetylcholine appeared to play a role in posterior shelf rotation since cholinergic agents (pyridostigmine, bethanechol and carbachol) stimulated elevation of that end of the palate. To characterize the putative receptors mediating the effects of the cholinergic agonists on palate shelf elevation, muscarinic or nicotinic antagonists were introduced into the emrbyo culture system. Atropine, a muscarinic blocking agent, did not produce any significant effect on palate shelf rotation when tested in overnight and 2 h embryo cultures at 3 X 10(-5) M and 10(-4) M, respectively. Neither did atropine inhibit significantly the stimulation produced by 10(-8) M bethanechol, Thus, the cholinergic effect was probably not on muscarinic receptors of the contractile system. However, hexamethonium, a nicotinic antagonist, at 10(-6) M and 10(-4) M profoundly inhibited posterior shelf rotation to about 35% of the control value in a 2 h incubation. In addition, 10(-4) M hexamethonium inhibited posterior palate rotation to 11% of the control value after overnight culture. Furthermore, hexamethonium was able to reverse the stimulation of posterior rotation produced by carbachol. Partial inhibition of palate rotation by hexamethonium was also demonstrated when pregnant dams were injected with drug at doses approximately corresponding to 10(-6) and 10(-4) M. Hexamethonium treatment resulted in approximately 30% of the palates not completely rotated at day 15.5 compared to only 9.3% in the control. Hexamethoniuim also produced a significant increase in the palate gap and a comparable decrease in palate fusion. These effects were slightly greater at the posterior end of the palate. Thus, the cholinergic ganglion in the posterior palate may play a role in regulating shelf rotation at that end through a nicotinic pathway.

Acetylcholinesterase↗
PubMed1982

Muscarinic agonists inactivate potassium conductance of guinea-pig myenteric neurones.

1. The effects of muscarinic agonists applied both by perfusion and ionophoresis to myenteric neurones of the guinea-pig ileum were investigated by intracellular recording methods. 2. Perfusion with muscarinic agonists (acetylcholine, oxotremorine, methacholine, bethanechol) in concentrations of 100 nM to 10 microM caused membrane depolarizations. Brief ionophoretic applications of oxotremorine, or acetylcholine in the presence of hexamethonium, evoked depolarizations with a latency of 100 ms to 1 s and a duration of 5-60 s. 3. The depolarizations were completely antagonized by low concentrations (1-10 nM) of the muscarinic antagonists hyoscine or atropine. 4. The latency and time course of the muscarinic depolarizations were about one thousand times longer than those of nicotinic responses evoked in the same cell by acetylcholine applied from the same ionophoresis electrode. 5. The muscarinic depolarization was associated with a conductance decrease and reversed polarity at a membrane potential close to the potassium equilibrium potential. 6. The muscarinic depolarization became smaller but did not disappear completely during prolonged (up to 60 min) perfusion or repeated (more than 0.02 Hz) ionophoretic applications of muscarinic agonists. 7. Lower concentrations (3-30 nM) of oxotremorine, which did not change membrane potential, reduced the amplitude and duration of the calcium-dependent increase in potassium conductance which follows a burst of action potentials. 8. It is concluded that the muscarinic depolarization of myenteric neurones is due to potassium inactivation.

Action Potentials↗
PubMed1996

Acute gastrointestinal toxic effects of suspensions of unencapsulated and encapsulated ibuprofen in rats.

PURPOSE: The study examined the gastrointestinal (GIT) toxicity effects of suspensions of encapsulated and unencapsulated ibuprofen in male Wistar rats. METHODS: Rats were randomly divided into four experimental groups and four control groups, and dosed with suspensions of encapsulated and unencapsulated ibuprofen (17 mg/kg and 44 mg/kg). Bethanechol chloride, a cholinomimetic agent (5 mg/kg), was administered 30 minutes after the dosing, to induce gastric irritation. Blood plasma concentrations were monitored in another set of rats for 12 hours using the encapsulated and unencapsulated systems, to establish drug release and exposure to the mucosa. RESULTS: Evaluation of the upper GI segments after 7 hours revealed that the 44 mg/kg dose of the encapsulated drug significantly reduced the number of lesions present compared to the unencapsulated drug (p < 0.05). At 17 mg/kg, the encapsulated drug reduced toxicity, but not significantly compared to the unencapsulated ibuprofen. Necrosis of the mucosa was observed histopathologically in the unencapsulated drug at both doses, whereas the encapsulated drug treatment revealed preserved mucosa. The encapsulated system had a maximum plasma concentration, Cmax, and time taken to reach Cmax, (Tmax) of 26.7 mu g/ml +/- 1.5 and 3.6 +/- 0.2 hr, respectively. The area under the plasma concentration-time curve, (AUC(0-12)), was 158.8 +/- 23.5 mu g.h/ml, confirming drug release and absorption. CONCLUSIONS: Encapsulation of ibuprofen significantly reduced gastrointestinal toxicity especially at the higher dose level and drug was released enough to subject the GI mucosa to irritation, but without the usual toxic effects.

Animals↗
PubMed1993

Different muscarinic receptor subtypes mediating the phasic activity and basal tone of pig isolated intravesical ureter.

1. We have studied the effects of muscarinic cholinoceptor agonists and specific antagonists on both phasic activity and basal tone of the isolated intravesical ureter of the pig by means of isometric techniques in vitro. 2. Acetylcholine in the presence and absence of physostigmine increased both phasic activity and basal tone of ureteral strips in a concentration-dependent manner. Moreover carbachol, methacholine and oxotremorine-M increased both contractile parameters while bethanechol and McN-A-343 evoked only increases in tone without affecting the frequency of the phasic contractions. 3. The nicotinic receptor blocker, hexamethonium (10(-6)-10(-4) M), failed to modify the contractions evoked by a single dose of carbachol (10(-5) M), whilst the muscarinic antagonist, atropine inhibited both phasic and tonic responses. 4. The muscarinic M1 (pirenzepine), M2 (AF-DX 116 and methoctramine), M3 (4-DAMP, HHSiD and p-F-HHSiD), and putative M4 receptor (tropicamide) antagonists significantly reversed increases in both frequency of phasic activity and baseline tone induced by a submaximal dose of carbachol (10(-5) M). The pIC50 values for inhibition of the induced phasic activity were: atropine (10.16) > 4-DAMP (9.12) > HHSiD (8.22) = methoctramine (7.98) = p-F-HHSiD (7.88 > tropicamide (7.62) = pirenzepine (7.53) = AF-DX 116 (7.45) and for inhibition of basal tone were: atropine (10.73) > 4-DAMP (9.32) > HHSiD (8.65) = pirenzepine (8.43) = p-F-HHSiD (8.38) > methoctramine (7.79) > tropicamide (7.53) > AF-DX 116 (7.04). 5. The antagonist profile indicates that an M1 receptor mediates the tonic response while the phasic activity could involve either both M2 and M3 or an M4 muscarinic receptor. These results suggest that different muscarinic receptor subtypes mediate the phasic and tonic contractile activity induced by a submaximal concentration of carbachol in the porcine intravesical ureter.

Animals↗