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At least 19 recordsLinked to original sources

PubMed1976

An analysis of the mode of action of carbachol on the chick biventer cervicis nerve--muscle preparation.

The mechanism of contracture evoked by carbachol in the isolated chick biventer cervicis nerve--muscle preparation was studied. At concentrations lower than 11 muM, carbachol progressively induced contracture at a rate much slower than did acetylcholine. A spontaneous increase of the response to carbachol, but not to acetylcholine, was observed 2-4 hr after isolation of the muscle. By contrast, no change of the response occurred in the denervated muscle. Anticholinesterase treatment shifted the dose-response curve for carbachol markedly to the left as far as the contracture attained after 4-6 min incubation was concerned. The shift was much less marked for the dose-response curve plotted against the initial rate of response defined as the contracture obtained after 1 min incubation. No enhancement of response was detected by inhibition of acetylcholinesterase in the denervated muscle. beta-Bungarotoxin which blocked neuromuscular transmission within 30 min, caused a transient enhancement of the response to carbachol. After 2-3 hr treatment, however, the spontaneous increase of response to carbachol was counteracted by the toxin. No potentiation of the response by anticholinesterase agents was observed after toxin treatment. When added in the presence of physostigmine or echothiophate, beta-bungarotoxin reduced the response to carbachol to the control level in 2 hr. The response to carbachol in the muscle treated with alpha-bungarotoxin and washed subsequently was also not potentiated by anticholinesterase treatment. Repetitive nerve stimulation in the presence of hemicholinium-3 caused a neuromuscular blockade but did not appreciably antagonize the response to carbachol more than that to acetylcholine either in the absence or presence of physotigmine. When calcium ion in the medium was decreased from 2.7 to 0.54 mM, ther response to nerve stimulation was nearly completely inhibited, but the response to carbachol was not affected and could still be potentiated by anticholinesterase. It is concluded that carbachol has both direct and indirect effects on the chick biventer cervicis muscle. At a low concentration, particularly in the presence of an anticholinesterase and if sufficient time of incubation is allowed, the indirect effect caused by release of acetylcholine may become more prominent than the direct action on the post-synaptic receptor. Both the mechanism and the store of acetylcholine for this indirect action appear to be different from those for the nerve impulse.

Acetylcholine↗

PubMed1975

Pre- and postjunctional neuromuscular blockade by carbachol.

Carbachol, when applied to the bathing Ringer solution of frog sartorius muscles, caused depolarization of the endplate and a blockade of endplate potentials (EPP's), miniature EPP's (mepp's) and the iontophoretic acetylcholine potential. In muscles treated with an analog of hemicholinium-3, alpha, alpha'bis(dimethylammonium acetaldehyde diethylacetal)-p-p'-diacetylbiphenyl dibromide (DMAE), depolarization of the endplate by carbachol was blocked and the blockade by carbachol of the iontophoretic acetylcholine potential was prevented. These responses to carbachol were attributed to a postjunctional action that was antagonized by DMAE. In contrast, the blockade by carbachol of EPP's and mepp's was enhanced in DMAE-treated muscles at a time when carbachol-induced depolarization was blocked. This response to carbachol was attributed to a pre-junctional action. Carbachol either blocked transmitter release by a mechanism that was insensitive to DMAE or enhanced the prejunctional blocking actions of DMAE. Succinylcholine had actions similar to carbachol. DMAE prevented depolarization by succinylcholine but enhanced neuromuscular blockade by succinylcholine. SKF 525-A (beta-diethylaminoethyl diphenylpropylacetate hydrochloride), like DMAE, prevented depolarization but not transmission blockade caused by carbachol.

Acetylcholine↗

PubMed1975

Drug-biomolecule interactions: bioelectrometric study of the mechanism of carbachol interactions with the cornea and its relation to miotic activity.

The augmentation of carbachol miotic activity attributable to enhanced transcorneal absorption, which results from the action of cationic adjuvants included in ophthalmic vehicles, suggested a study of carbachol-corneal tissue interaction as a further step toward understanding the phenomenon. The present study was performed in vivo using an innocuous electrometric technique. A fixed charge density of the corneal epithelial surface versus carbachol concentration profile was obtained from the electrometric results; it revealed three distinct concentration regions defined by precipitous decreases of fixed charge over extremely small concentration ranges. This anomalous behavior is attributed to cooperative alterations in the binding affinities of fixed anionic sites on the tissue surface, which result in an all-or-none release of protons and/or other nicrocations. The unmasked anionic sites become reoccupied with carbachol except in the last region where the reoccupation by carbachol is competitive with other cations in the solution in contact with the surface. This behavior, postulated on the basis of the construction of a carbachol-tissue binding isotherm from which thermodynamic interaction affinities were computed, was corroborated by the observed dependency of the duration of miotic activity on carbachol concentration. Allosteric interactions between anionic binding sites, which are mediated through electron inductive and electrostatic field effects and likely involve a cooperative alteration in tissue water structure, are implicated as underlying the observed phenomena.

Animals↗

PubMed1978

Pharmacological studies on N-demethylated carbachol.

In attempts to find a drug more active than pilocarpine, the tertiary nitrogen derivative of carbachol, N-demethylated carbachol, was synthetized and tested on several autonomic nervous system preparations. N-Demethylated carbachol was active at muscarinic and nicotinic sites in vivo and in vitro. In superfusion studies, N-demethylated carbachol contracted the smooth muscle of the guinea pig ileum as well as skeletal muscles of frog recus abdominis and chick biventer cervicis. N-Demethylated carbachol decreased blood pressure in the rat, with an ED50 ("/- SEM) of 4.82 +/- 0.78 mg/kg. After close arterial injection to the cat superior cervical ganglion, N-demethylated carbachol elicited contractions of the nictitating membrane (ED50 of 1.68 +/- 0.24 mg/kg) that were not significantly affected by atropine. N-D-methylated carbachol stimulated salivation in dog Wharton duct preparations with an ED50 of 2.55 +/- 0.81 mg/kg. In contrast, pilocarpine had no effects on skeletal muscles in vitro, produced ganglionic effects blocked by atropine, had a prominent effect on salivation, and tended to elevate blood pressure.

Animals↗

PubMed1978

Carbachol-induced sensitivity changes in skeletal muscle and their mechanism of action.

Pretreatment of carbachol (in vitro), in various doses (5.5 pM to 550 nM), produced a significant decrease in the sensitivity of the frog rectus abdominis muscle to acetylcholine (ACh), in a dose-dependent manner. This action was observed with a 60 min incubation period. Contractions induced by potassium chloride (KCl) were unaffected by carbachol. Physostigmine (10 micrometer) potentiated the decrease in sensitivity induced by carbachol, whereas human plasma antagonised it. Low calcium (0.27 mM) in the medium and hexamethonium (300 micrometer) antagonised the sensitivity decrease induced by carbachol. These results suggest that carbachol decreases the sensitivity to ACh by releasing ACh from the presynaptic nerve terminals. The results further suggest that carbachol may release ACh by depolarising the presynaptic nicotinic receptors.

Acetylcholine↗

PubMed1977

Potentiation by carbachol and aminophylline of histamine- and db-cAMP-induced parietal cell activity in isolated gastric glands.

The response to combinations of gastric acid secretagogues was studied in isolated glands from the rabbit gastric mucosa in terms of changes in oxygen consumption and accumulation of the weak base aminopyrine (AP). The latter reflects the acid secreting status of the glands. The following secretagogues were investigated: histamine, carbachol, aminophylline and db-cAMP. The histamine respiratory dose-response curve was shifted to the left in the presence of the phosphodiesterase inhibitor aminophylline. Both ED-50 and maximum response were significantly increased. Histamine-induced AP accumulation was also strongly enhanced by aminophylline (5 X 10(-4) M). These results are consistent with the hypothesis that histamine stimulation of acid secretion is mediated by cyclic AMP. Carbachol-stimulated oxygen consumption could not be potentiated by aminophylline and the combined effect was only additive. The response to a combination of histamine and carbachol was a significant increase in oxygen consumption above what could be expected from an additive effect alone. Carbachol addition to glands prestimulated with histamine gave a rapid increase in the respiratory rate resulting in a new steady state level within 10-15 min, as compared with a time constant of about 40 min when both drugs were added simultaneously. Likewise AP accumulation increased more rapidly and reached a higher value after addition of histamine + carbachol as compared with histamine alone. The db-cAMP-stimulated oxygen consumption was in all respects equally affected by carbachol as was histamine stimulation. This indicates that the well known cholinergic potentiation of histamine stimulation is not due to an increased sensitivity of the histamine receptor but is of a more general nature. A mechanism involving intracellular availability of Ca2+ is proposed as one possible explanation of this potentiation.

Aminophylline↗

PubMed1976

Gastric secretory response to different doses of carbachol and pentagastrin in man.

In 6 healthy students, the gastric secretion of acid, pepsin, and IF was measured during one hour at basal conditions, and during one hour of stimulation with 0.01 mug/kg/h and thereafter during one hour of stimulation with 0.1 mug/kg/h of pentagastrin. On separate days the same dose of pentagastrin was given in combination with 0.15 mug/kg/h or 1.5 mug/kg/h of carbachol, or stimulation was performed with each of the two doses of carbachol alone. A dose-dependent relationship was found between carbachol and the output of acid, pepsin, and IF. The responses to carbachol were independent of changes in plasma gastrin concentration. The acid- and IF-secretions stimulated by the largest dose of pentagastrin were significantly increased by the largest dose of carbachol, whereas the secretion of pepsin was not. Pentagastrin and carbachol seem to interact by competitive augmentation on the gastric secretion of acid and IF.

Adult↗

PubMed1976

Stimulation of 45Ca influx in rat parotid gland by carbachol.

Secretion of alpha-amylase by rat parotid glands was stimulated by 10(-5) M carbachol when Ca was present in the bathing medium. The optimal Ca concentration was 1.0 mM in the absence of Mg ion. Lowering the extracellular Na to near one-half and one-quarter of normal levels produced a significant increase in carbachol-induced secretion. The metabolism of 45Ca by the slices could be described by three components of exchange. The faster two, with time constants of 4 and 16 minutes, each appeared to represent a mixture of free extracellular Ca and rapidly exchanging superficially bound Ca. Influx into the slower (tau = 78 minutes) component (apparently intracellular) was enhanced by 10(-5) M carbachol. This was apparent by standard flux techniques only in low (65 mM) Na solutions, but was readily discernible in normal Na (125 mM) with the "lanthanum-residual" technique. The increase in 45Ca influx due to carbachol resembles the secretory response to carbachol in being potentiated by low Na, blocked by 1.0 mM La, and blocked by 10(-4) M atropine. It was concluded on the basis of this and other evidence that the primary step in the induction of exocytosis by carbachol in the parotid gland is an increased influx of Ca.

Amylases↗

PubMed1976

Role of calcium in exocrine pancreatic secretion. II. Comparison of the effects of carbachol and the inophore A-23187 on enzyme secretion and calcium movements in rabbit pancreas.

1. The secretory effects of carbachol and the ionophore A-23187 on the isolated rabbit pancreas and rabbit pancreas fragments are compared in order to obtain more insight in the involvement of calcium in the stimulus-secretion coupling of pancreatic enzyme secretion. 2. The divalent cation ionophore A-23187 mimicks the effect of carbachol on pancreatic enzyme secretion in both preparations. 3. The action of the ionophore is dependent on the presence of extracellular calcium. The carbachol effect is much less dependent on calcium, as it occurs even in a Ca2+ -free medium containing 10(-4) M ethyleneglycol-bis(beta-aminoethylether)-N,N-tetraacetic acid. 4. Carbachol causes a marked increase in the 45Ca2+ efflux from pre-loaded pancreas fragments in both a normal Krebs-Ringer bicarbonate medium and this Ca2+ -free medium. 5. Although the tissue still contains about 50% of its original 45Ca2+ content, at the time of stimulation, the ionophore has little or no effect on the 45Ca2+ efflux. This indicates that the cytoplasmic 45Ca2+ concentration is very low, and hence that most of the 45Ca2+ must be sequestered in one or more intracellular stores. 6. It is concluded that both substances stimulate pancreatic enzyme secretion by increasing the cytoplasmic calcium concentration, through an increase in the calcium permeability of the plasma membrane in the case of the ionophore, and through a release of Ca2+ from intracellular stores in the case of carbachol.

Animals↗

PubMed1976

Carbachol, angiotensin-II, ventircular spread and water balance in rats.

Injections into the preoptic areas and anterior hypothalamus of a little as 1.0 ng/mu1 carbachol (5.5 X 10(-6) M, 11 pmols total dose) and 0.1 ng/mul angiotensin-II (10(-7) M, 0.2-0.4 pmols) were dipsogenic or antidiuretic-natriuretic. Lateral ventricular (VL) thresholds for drinking also were 11 pmols for carbachol and 0.2 pmols for angiotensin. The low VL threshold for carbachol supports, without proving, arguments that a limbic cholinergically-coded thirst circuit could reflect leakage form placements near VL to the third ventricle. In contrast, VL thresholds for antidiuresis-natriuresis were 110 pmols for carbachol and 2 pmols for angiotensin. Carbachol was more effective rostral to the paraventricular nucleus and angiotensin dorsal to the supraoptic nucleus. However, lower thresholds in these areas were insufficient to localize receptors, since all cannulas positive for antidiuresis-natriuresis traversed ventricles, and cannulas not traversing ventricles were negative.

Angiotensin II↗

PubMedDate not supplied

Cardiovascular effects of carbachol and other cholinomimetics administered into the cerebral ventricles of conscious cats.

1. The cholinomimetic substances acetylcholine, nicotine, tetramethylammonium chloride and carbachol were infused intracerebroventricularly (i.c.v.) into conscious, normotensive cats and their effects on behaviour, blood pressure and heart rate recorded. 2. Intracerebroventricular acetylcholine, nicotine and tetramethylammonium chloride each produced small, mainly stimulant, effects on the cardiovascular system which were not accompanied by any marked behavioural effects. 3. Intracerebroventricular carbachol at a dose of 30 microgram produced marked and persistent cardiovascular stimulant effects accompanied by a striking rage/fear reaction. When the dose of carbachol was reduced to 7.5 microgram the behavioural effects were no longer seen but marked cardiovascular stimulant effects remained. 4. The cardiovascular stimulant effects of i.c.v. carbachol were apparently mediated via the peripheral sympathetic system since they were abolished by peripheral adrenergic neurone blockade. 5. The blood pressure and heart rate increases produced by i.c.v. carbachol were blocked by prior i.c.v. treatment with atropine, hexamethonium, guanethidine, bethanidine or propranolol. 6. The data are consistent with an interaction between central cholinergic and catecholaminergic neural pathways involved in central regulation of blood pressure and further suggest the involvement of beta-adrenoreceptors in the responses to centrally-administered cholinomimetics.

Acetylcholine↗

PubMed1979

Effects of noradrenaline and carbachol on temperature regulation of rats.

1 Noradrenaline (0.2 to 20 micrograms) and carbachol (0.1 to 1 microgram) injected into the preoptic/anterior hypothalamic area, evoked dose-dependent falls in core temperature at all sites tested, followed in most experiments by delayed increases that were not dose-related. Muscarine (0.1 to 10 microgram) produced effects similar to those evoked by carbachol. 2 These falls in core temperature were associated with increases in tail temperature, locomotor activity and CO2 elimination (a measure of metabolic rate). 3 The temperature responses to noradrenaline (10 microgram) and to carbachol (1 microgram) were antagonized by intrahypothalamic injections of phentolamine (10 microgram) and atropine (1 microgram), respectively. 4 Analysis of the temperature responses and their respective latencies indicates that carbachol-induced hypothermia was mediated by cholinoceptors in the anterior hypothalamus, whereas hypothermia after noradrenaline was mediated by adrenoceptors throughout the preoptic/anterior hypothalamic area. 5 Vasodilatation of the tail blood vessels contributed significantly to the hypothermia evoked by carbachol, and to that evoked by injections of noradrenaline into the anterior hypothalamus. 6 Hypothermia induced by noradrenaline injection into the preoptic area, was mediated by effector mechanisms additional to non-evaporative heat loss.

Animals↗

PubMed1978

A study of carbachol-atropine interaction on intestinal smooth muscle vesicles, using a fluorescent probe.

Plasma membrane vesicles were prepared from guinea pig ileum longitudinal muscle. The vesicles were characterized by electron microscopy and analysis of lipid and protein content. They were shown to be free of gross contamination from actomyosin, sarcoplasmic reticulum, and mitochondria. 8-Anilino-1-naphthalene sulphonic acid (ANS) binding characteristics were similar to those found in other membranes. Both carbachol and atropine increased the fluorescence of ANS bound to this membrane, the maximum increase for atropine being greater than that for carbachol. Since neither drug effected the apparent affinity constant for the ANS-membrane interaction. It may be assumed that the increased fluorescence was due to an increase in the number of ANS binding sites. The carbachol-dependent increase in ANS fluorescence was blocked noncompetitively by atropine but not by tubocurarine or diphenhydramine. These latter two antagonists also increased ANS fluorescence but at much higher concentrations than either carbachol or atropine. Neither atropine nor carbachol increased ANS fluorescence on either erythrocyte ghosts or liposomes (prepared from a lipid extract of the muscle membrane).

Anilino Naphthalenesulfonates↗

PubMed1979

Vagal effects on histamine, carbachol, and prostaglandin F2 alpha responsiveness in the dog.

To investigate whether an individual dog's responsiveness to histamine correlates with its responsiveness to other bronchoconstrictor agents and to investigate whether varying vagal effects account for the previously described range of histamine responsiveness, we compared dose-effect relationships of histamine to those of two pharmacological dissimilar agents, carbachol and prostaglandin F2 alpha before and after vagal blockade. There was a highly significant correlation between histamine and both carbachol (P less than 0.001) and prostaglandin F2 alpha (P less than 0.001) responsiveness. The range of responsiveness to prostaglandin F2 alpha was greater than that for histamine or carbachol. When histamine and carbachol were given simultaneously, a purely additive effect was found. Vagal blockade had no significant effect on histamine or carbachol responsiveness, but significantly diminished the responsiveness to prostaglandin F2 alpha; however, it neither narrowed the range nor changed the rank order of responsiveness. We conclude that the range of responsiveness is not specific for any one agent and that vagal mechanisms do not play a role in producing this range.

Airway Resistance↗

PubMed1978

Comparative responses of tracheal spirals and parenchymal strips to histamine and carbachol in vitro.

The responses of isolated guinea pig tracheal spirals and parenchymal strips to histamine and carbachol were compared. The parenchymal strip, a 1.5 x 1.5 x 20-mm strip cut from the periphery of the lung, constricted at a lower dose and had a larger maximal response to histamine than to carbachol. In contrast, the response of the tracheal spiral to equimolar doses of histamine or carbachol was the same. The responsiveness of both muscle strips to histamine was decreased by treatment with the H1 receptor antagonist mepyramine (0.1 micrometer), and the response to carbachol was blocked by treatment with atropine (0.1 micrometer). Indomethacin (3 micrometer), cimetidine (1 micrometer), propranolol (10 micrometer), and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (4 micrometer) did not alter the differential response of the two strips to histamine and carbachol. The differential response of parenchymal strips with many, few, or no conducting airways and blood vessels was identical, suggesting that the contractile element is alveolar duct smooth muscle or alveolar contractile elements. This differential pharmacologic response in vitro is consistent with the in vivo observation that histamine causes more peripheral airway constriction than does acetylcholine.

Acetylcholine↗

PubMed1976

Centrally mediated cardiovascular effects of intracisternal application of carbachol in anesthetized rats.

The pressor response to the intracisternal (i.c.) injection of carbachol (1 mug) in anesthetized rats was analyzed. This response was significantly reduced by the intravenous (i.v.) injection of guanethidine (5 mg), hexamethonium (10 mg) or phentolamine (5 mg), and conversely, potentiated by i.v. desmethylimipramine (0.3 mg), while propranolol (0.5 mg) i.v. selectively inhibited the enlargement of pulse pressure and the tachycardia following i.c. carbachol (1 mug). On the other hand, the pressor response to i.c. carbachol (1 mug) was almost completely blocked by i.c. atropine (3 mug) or hexamethonium (500 mug), and significantly reduced by i.c. chlorpromazine (50 mug) but significantly potentiated by i.c. desmethylimipramine (30 mug). The pressor response to i.c. carbachol (1 mug) remained unchanged after sectioning of the bilateral cervical vagal nerves but disappeared after sectioning of the spinal cord (C7-C8). From the above result it is suggested that the pressor response to i.c. carbachol ortral and peripheral adrenergic mechanisms, and that the sympathetic trunk is the main pathway.

Animals↗

PubMed1975

The effect of carbachol and pentagastrin on the gastric secretion of acid pepsin, and intrinsic factor (IF) in man.

Intravenous infusions of carbachol and pentagastrin were given separately or simultaneously in 6 healthy students. The volume of gastric secretion and the concentration and output of acid, pepsin, and IF increased significantly during infusion of carbachol alone, whereas the plasma gastrin concentration remained unchanged. Carbachol had no effect on the acid, pepsin, and IF secretion by pentagastrin. The results indicate an effect of carbachol on acid, pepsin, and IF secretion, independent of changes in plasma gastrin concentration. No synergistic or potentiating effect was demonstrated between carbachol and pentagastrin.

Carbachol↗

PubMed1979

The effect of neuroleptic drugs on drinking induced by central administration of angiotensin or carbachol.

The effect of a series of neuroleptic drugs on the drinking response elicited by intracerebroventricular injection of either angiotensin or carbachol into conscious rats was studied. The i.p. injection of haloperidol, cis-flupenthixol, or fluphenazine antagonized both angiotensin-induced and carbachol-induced drinking. When injected into the lateral ventricles, the neuroleptics haloperidol, fluphenazine, cis-fluphenthixol and sulpiride were potent inhibitors of angiotensin-induced drinking, but had little effect on the dipsogenic action of carbachol. Clozapine, administered centrally, antagonized drinking caused by both angiotensin and carbachol. Pimozide and chlorpromazine were also potent inhibitors of angiotensin-induced drinking, while trans-flupenthixol was inactive. Our results support the concept of an involvement of dopamine in angiotensin-induced drinking.

Angiotensin II↗