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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the linkage of cholinergic receptors to the phosphoinositide signaling pathway to elucidate one facet of the autonomic response mechanism in fetal and adult sheep. Cholinergic stimulation with carbachol increases the production of 3H-inositol mono-, bis-, and trisphosphates in a time- and concentration-dependent manner in both fetal and adult myocardium. However, the maximal stimulation of inositol polyphosphates above basal activity was much greater in fetal (120 +/- 11%) than in adult (20 +/- 7%) myocardium (mean +/- SEM). Saturation binding analysis of myocardial muscarinic receptors using 3H-N-methylscopolamine revealed significantly higher receptor concentration in fetal (240 +/- 25 fmol/mg protein) than in adult (78 +/- 15 fmol/mg protein) myocardium (mean +/- SEM). Binding competition studies revealed a pattern of selectivity-atropine less than 4-diphenylacetoxy-N-methylpiperidine methiodide less than pirenzepine less than or equal to (4-hydroxy-2-butynyl)-1-trimethylammonium m-chlorocarbanilate chloride less than or equal to 11-2[[2-[(diethylamino)-methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one 116-compatible with the presence of muscarinic receptor (MR)2, MR3, and/or MR5 subtypes. Receptor subtype determination by Northern blot analysis revealed mRNA specific for the MR2 subtype in both fetal and adult myocardium, although expression was greater in fetal heart. We conclude that decreases in MR2 subtype protein and mRNA levels parallel the age-related decrease in carbachol-stimulated PLC activity. Our studies demonstrate differences between fetal and adult myocardium in the concentration of muscarinic cholinergic receptors and their linkage to a putative calcium mobilizing signaling pathway and suggest that this pathway may play a different role in the fetus than in the adult.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial cholinergic signaling changes with age. 132 73

To enhance our understanding of cholinergic mechanisms and muscarinic receptors in bronchoconstriction, we have characterized the muscarinic receptor subtypes in rabbit tracheal smooth muscle using radioligand binding and functional assays. The Kd for [3H]quinuclidinyl benzilate ([3H](-)QNB) binding determined from saturation isotherms was 12.6 x/divided by 1.1 pM (geometric mean x/divided by SEM), and the Bmax was 269 +/- 7 fmol/mg protein (arithmetic mean +/- SEM). Competitive inhibition studies with the muscarinic antagonists pirenzepine (PZ), 11[[2-[(diethylamino)-methyl]1-piperidinyl]acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX116), 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), and hexahydrosiladifenidol (HHSiD) demonstrated heterogeneity of muscarinic receptor subtypes in rabbit tracheal smooth muscle. PZ bound with low affinity to a single receptor site, indicative of an absence of M1 receptors. AF-DX116 (M2 selective) bound with high affinity to approximately 83% of muscarinic binding sites, and 4-DAMP and HHSiD (M3 antagonists) bound with high affinity to approximately 24 and 28% of muscarinic binding sites, respectively. Additionally, direct binding studies with [3H]4-DAMP demonstrated high-affinity binding with 23% of muscarinic binding sites. Thus, the majority of muscarinic receptors in rabbit tracheal smooth muscle bound with high affinity to an M2-selective antagonist, and the remaining receptor sites bound with high affinity to M3 antagonists. The inhibitory effects of atropine, PZ, AF-DX116, and 4-DAMP on methacholine-induced contraction of rabbit tracheal rings were compared. 4-DAMP was a potent inhibitor of methacholine-induced contraction, but PZ and AF-DX116 demonstrated low potency.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A minority of muscarinic receptors mediate rabbit tracheal smooth muscle contraction. 154 Mar 92

GTPase activity has been measured in synaptic membranes from bovine retina, with and without muscarinic receptor stimulation. Maximal stimulation above basal levels was achieved with 5 microM oxotremorine and 100 microM carbachol. (4-Hydroxy-2-butynyl)-1-trimethylammonium m-chlorocarbanilate chloride, which is selective for the M1 muscarinic receptor, failed to stimulate GTPase activity. 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) inhibition of oxotremorine stimulation demonstrated the presence of two populations of receptors, a low-affinity site (IC50 +/- SEM, 0.63 +/- 0.18 microM) which accounted for 63% of the inhibition and a high-affinity site (IC50 less than 1 nM) which accounted for the remaining 37%. When carbachol-stimulated GTPase activity was assayed, a single 4-DAMP inhibitory site was apparent (IC50 +/- SEM, 2.0 +/- 0.9 microM). Pirenzepine inhibited GTPase activity at a single site (IC50 values +/- SEM, 46.9 +/- 11 and 25.4 +/- 6.5 microM against oxotremorine and carbachol, respectively). Methoctramine was equipotent against carbachol and oxotremorine stimulation (IC50 values, 4.2 +/- 1.8 and 6.2 +/- 1.5 microM). Inhibition of maximal carbachol and oxotremorine stimulation by muscarinic antagonists at the major site had a rank order of potency of 4-DAMP = methoctramine greater than pirenzepine. Thus, the major site for muscarinic stimulation of GTPase activity in bovine retinal membranes is pharmacologically similar to M2 receptors.
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PMID:Muscarinic receptor stimulated GTPase activity in synaptic membranes from bovine retina. 161 99

Adult Flinders-Sensitive Line (FSL) rats are significantly more sensitive to the behavioral and physiologic effects of muscarinic agonists than are control, Flinders-Resistant Line (FRL) rats; therefore, they resemble humans with depressive disorders. The present study examined the sensitivity of prepubertal and pubertal FSL and FRL rats to the hypothermic and locomotor inhibitory effects of the muscarinic agonist, oxotremorine, and compared these findings to the regional development of muscarinic receptor binding in similarly aged rats. The FSL rats were significantly more sensitive (-1.85 degrees +/- 0.2 degrees C) than the FRL rats (-0.65 degrees +/- 0.15 degrees C) to the hypothermic effect of 0.25 mumol/kg of oxotremorine at the earliest age tested (18 days postpartum) and became progressively more sensitive throughout the period of testing (FSL -2.8 degrees +/- 0.24 degrees C versus FRL -0.5 degrees +/- 0.16 degrees C at 61 days postpartum, data represent the mean +/- SEM of pooled male and female). Significant increases in muscarinic receptor number in FSL rat brain were observed only in older (61 days postpartum) rats. These results are consistent with the suggestion that the FSL rat is a genetic animal model of depression, but also indicate that the differences in muscarinic sensitivity cannot be accounted for exclusively by differences in the number, per se, of muscarinic receptors.
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PMID:Early development of muscarinic supersensitivity in a genetic animal model of depression. 206 20

Muscarinic agonists are potent constrictors of airway smooth muscle. In many tissues, muscarinic agonists also reduce intracellular cyclic AMP by inhibiting its synthesis. In airway smooth muscle, the role muscarinic agonists have in the regulation of cyclic AMP content is not established. The hypothesis of our study was that muscarinic agonists reduce cyclic AMP accumulation in dog tracheal smooth muscle, and that this reduction involves a pertussis toxin-sensitive regulatory protein (Gi) that couples occupancy of the muscarinic receptor by the agonist to inhibition of adenylate cyclase. We measured cyclic AMP accumulation in tracheal smooth muscle from 4 dogs, and found that acetylcholine (10(-4) M) diminished basal and isoproterenol-stimulated cyclic AMP accumulation by 37.6 +/- 12.1% and 39.4 +/- 1.9%, respectively (mean +/- SEM, p less than 0.05). This reduction of cyclic AMP was dose-dependent and inhibited by atropine (10(-5) M). Incubation of dog tracheal smooth muscle with pertussis toxin (12.5 micrograms/ml) for 21 h catalyzed covalent modification of a membrane protein with an approximate Mr of 40,000. In control strips, acetylcholine decreased isoproterenol-stimulated cyclic AMP content by 33.7 +/- 5.6% (p less than 0.05). However, in strips treated with pertussis toxin (10 micrograms/ml), acetylcholine decreased cyclic AMP by only 7.9 +/- 4.8%; this change was not significant. Thus, pertussis toxin (10 micrograms/ml) attenuated muscarinic cholinergic regulation of cyclic AMP. These findings are consistent with muscarinic cholinergic regulation of adenylate cyclase via Gi in dog tracheal smooth muscle. In addition, the techniques we employed should permit the evaluation of other functions of pertussis toxin-sensitive G proteins in airway smooth muscle.
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PMID:Muscarinic cholinergic inhibition of cyclic AMP accumulation in airway smooth muscle. Role of a pertussis toxin-sensitive protein. 284 36

Murine neuroblastoma cells (clone N1E-115) possess both high- and low-affinity muscarinic receptors. The low-affinity muscarinic receptor, when stimulated, initiates the formation of cyclic GMP by activating the enzyme guanylate cyclase; whereas stimulation of the high-affinity receptor inhibits prostaglanding E1-mediated cyclic AMP formation by inhibiting the enzyme adenylate cyclase. We have reported that lithium ion (Li+) inhibits cyclic GMP formation mediated by the muscarinic receptor agonist, carbachol, in a concentration-dependent manner and that neither ammonium nor sodium ions have such an effect. We extended this study to show that Li+ was an apparently noncompetitive inhibitor of the low-affinity muscarinic receptor with an IC50(+/- SEM) = 13.6 +/- 0.8 mM. In addition, Li+ with a similar IC50 inhibited the cyclic GMP response in intact cells to sodium azide, which is thought to stimulate guanylate cyclase directly. Moreover, though Li+ was found to have a slight inhibitory effect on prostaglandin E1-stimulated cyclic AMP formation (15% inhibition at 10 mM), it had no effect on the function of the high-affinity muscarinic receptor in intact murine neuroblastoma cells.
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PMID:Lithium ions inhibit function of low- but not high-affinity muscarinic receptors of murine neuroblastoma cells (clone N1E-115). 299 50

The influence of sympathetic innervation on the growth and intrinsic rate of beating established by fetal rat heart was studied by culturing fetal atrial tissue in sympathetically innervated and denervated anterior eye chambers of adult Sprague-Dawley rats. One anterior eye chamber in each host rat was sympathetically denervated by removing the ipsilateral superior cervical ganglion. In oculo, atrial grafts were vascularized by blood vessels sprouting from the iris and innervated by sympathetic and parasympathetic fibers from the ground plexus of the iris. Innervation was assessed by light-activated efferent nerve stimulation to the grafts that changed their rates of beating. The norepinephrine contents of 16 atria cultured for 2.5 months in sympathetically innervated and denervated eye chambers were 5.7 +/- 1.1 ng/implant vs. 0.2 +/- 0.07 ng/implant (mean +/- SEM), indicating permanent sympathetic denervation of the anterior eye chamber and the implanted atria. By 8 weeks in oculo, atria maturing in sympathetically innervated anterior eye chambers were 86% larger than those in denervated eye chambers (2.22 +/- 0.29 vs. 1.19 +/- 0.13 mm2); the weight of innervated transplants was over 3 times that of noninnervated grafts (2.35 +/- 0.75 vs. 0.76 +/- 0.21 mg). After implanted atria had ceased growing rapidly (2.5 months in oculo), bipolar electrodes were implanted adjacent to the cornea to record impulses from atrial grafts while host rats were unanesthetized. The dark-adapted baseline heart rates of sympathetically innervated and noninnervated atria were virtually identical (289 vs. 290 bpm). Graft intrinsic heart rate was estimated by combined beta-adrenergic and muscarinic receptor blockade with atenolol (1.0 mg/kg) and methylatropine (10 micrograms/kg). Sympathetically innervated transplants had lower intrinsic heart rates than noninnervated atria (134 +/- 25 vs. 213 +/- 12 bpm). These data suggest that sympathetic innervation of the developing heart influences both growth and intrinsic rate of beating.
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PMID:Sympathetic innervation alters growth and intrinsic heart rate of fetal rat atria maturing in oculo. 302 82

Serotonin (5-HT), found in abundance in intestinal enterochromaffin cells, has been shown to be released in response to neural, humoral, and intraluminal stimuli but the mechanisms controlling release are poorly understood. The purpose of this study was to determine whether 5-HT release induced by the muscarinic agonist, methacholine, is mediated by enteric nerves or is a direct action at the mucosal cell level. We mounted rabbit mucosal sheets containing intact submucosal neural elements, but stripped of muscularis propria and myenteric plexus, in modified Ussing chambers and measured the release of 5-HT in response to 5 X 10(-5) M methacholine added to both mucosal and serosal surface bathing solutions, in the presence and absence of selective neural blockade with 1 X 10(-6) M tetrodotoxin. 5-HT release in control tissues (no drugs) as measured by radioimmunoassay was 25.7 +/- 6 ng/cm2/30 min (mean +/- SEM). In the presence of mucosal and serosal methacholine, total 5-HT release increased significantly (P less than 0.05) to 66.7 +/- 9 ng/cm2/30 min. When tetrodotoxin alone was applied, 5-HT release significantly increased to 55.2 +/- 9 ng/cm2/30 min compared to matched control. In the presence of tetrodotoxin, methacholine increased 5-HT release to 79.3 +/- 9 ng/cm2/30 min, which was significantly greater than with tetrodotoxin alone. These results provide evidence of an inhibitory neural regulation of basal 5-HT release since release increased in the presence of neural blockade. They also suggest that a muscarinic receptor at or near the enterochromaffin cells mediates mucosal 5-HT release since 5-HT is further increased by methacholine even in the presence of neural blockade.
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PMID:Serotonin release is mediated by muscarinic receptors on duodenal mucosal cells. 330 52

Stimulatory cholinergic pathways participate in the regulation of GH release, and cholinergic receptor antagonists inhibit GH secretion in normal man. Whether similar mechanisms are active in subjects with insulin-dependent diabetes is not known, yet this is of potential importance since GH hypersecretion has been implicated in both the acute and chronic complications of diabetes mellitus. To address this question we studied the effects of cholinergic receptor blockade on stimulated GH release in 18 type I diabetic men. Paired tests were performed using 1 of 2 different stimuli (30 g arginine, iv, or physical exercise for 30 min) with or without prior administration of the selective cholinergic muscarinic receptor antagonist pirenzepine (30 mg, iv). Arginine elicited a mean peak serum GH level of 9.0 +/- 1.9 (+/- SEM) micrograms/L, which was completely suppressed by pirenzepine (1.5 +/- 0.4 micrograms/L; n = 8; P less than 0.01). Blood glucose rose after arginine infusion and was not affected by pirenzepine. Serum GH levels rose during physical exercise to a mean peak of 7.3 +/- 1.6 micrograms/L, which was abolished by pirenzepine (1.2 +/- 0.3 micrograms/L; n = 10; P less than 0.01). Blood glucose was not influenced by pirenzepine. Two subjects had no serum GH response to exercise. We conclude that GH secretion in subjects with insulin-dependent diabetes, as in normal subjects, is modulated by cholinergic pathways and is responsive to pharmacological suppression by muscarinic receptor blockade. This may have implications for therapeutic trials designed to lower elevated GH levels in subjects with diabetes mellitus.
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PMID:Cholinergic muscarinic receptor blockade suppresses arginine- and exercise-induced growth hormone secretion in type I diabetic subjects. 333 12

A method for measurement of human basal and stimulated gastric bicarbonate secretion was developed in the present investigation. The mechanisms involved in the regulation of basal, vagus nerve stimulated as well as fundic distension induced bicarbonate secretion were studied. The investigations were performed in healthy subjects and duodenal ulcer patients, the latter group before and/or after a proximal gastric vagotomy operation. Healthy subjects as well as ulcer patients were premedicated with a histamine H2-receptor antagonist and gastric bicarbonate secretion was determined by use of a gastric perfusion system in combination with computerized continuous recordings of pH and PCO2. The contribution of alkaline saliva to the measured gastric bicarbonate secretion was minimized by continuous salivary suction and correction was made for swallowed saliva by measurement of amylase in the gastric aspirate. A high rate of gastric perfusion facilitated the identification of alkaline duodenogastric reflux and also eliminated its influence on the measurement of gastric bicarbonate secretion. Validation of the measuring system by instillation of small amounts of bicarbonate showed a satisfactory correlation between added and recovered bicarbonate in the range of bicarbonate determinations usually recorded. Decreasing intragastric pH to between 3 and 4 converted all secreted bicarbonate into CO2, but did not affect the measured value of bicarbonate secretion. Vagal stimulation accomplished by sham feeding increased gastric bicarbonate secretion in sixteen healthy subjects from 410 +/- 39 mumol/h to 692 +/- 67 mumol/h (mean +/- SEM, p less than 0.001). This response was independent of intragastric pH in the range of 2 to 7. The muscarinic receptor antagonist, benzilonium bromide, almost abolished the sham feeding response while indomethacin left it nearly unchanged. Nine duodenal ulcer patients had identical basal and vagally stimulated bicarbonate output as healthy subjects. Two months after proximal gastric vagotomy, the basal bicarbonate secretion was significantly increased, whereas the output in response to sham feeding was unaltered. In the early postoperative period, anticholinergics reduced the enhanced basal bicarbonate secretion to a preoperative level. In six healthy subjects, graded fundic distension with a balloon to volumes of 150 ml, 300 ml and 600 ml, each distension period lasting 60 minutes, increased the bicarbonate secretion by 46% (p less than 0.05), 28% (NS) and 84% (p less than 0.05), respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Studies on gastric bicarbonate secretion in man. 347 32


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