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At least 19 recordsLinked to original sources
PubMed1990

Pharmacological evaluation of the antagonism of nicotine's central effects by mecamylamine and pempidine.

The nature of mecamylamine's and pempidine's antagonism of nicotine in the central nervous system has not been defined clearly. Although these compounds are thought to be noncompetitive antagonists in the brain due to the fact that they do not compete effectively for agonist binding to brain tissue in vitro, pharmacological evidence is lacking. The alteration of nicotine's dose-response curves for depression of spontaneous activity and antinociception was determined in the presence of increasing concentrations of pempidine. Pempidine was found to increase the ED50 of nicotine (0.73 mg/kg) for depression of spontaneous activity in a dose-related manner. At a dose of 3 mg/kg, pempidine increased nicotine's ED50 4.7-fold. The maximum effect of nicotine was achieved in the presence of the highest dose of pempidine, suggesting competitive antagonism. However, pempidine did decrease the maximum effect of nicotine in producing antinociception at doses that increased the ED50 13.7-fold which suggests a noncompetitive action. The structural requirements for mecamylamine's antagonism of these nicotine effects was also determined in order to address the question of whether the antagonists are interacting at a receptor site. The structure-activity relationships of the mecamylamine analogs revealed that the N-, 2- and 3-methyl groups were important for optimal potency. Optical isomerism was found to have little effect on potency. Addition of pyridinyl groups to the nitrogen abolished the activity of these compounds. The structural requirements for the agonists and antagonists therefore appear to be quite different. The alterations produced similar results for antagonism of both effects of nicotine. Mecamylamine and pempidine therefore appear to exhibit both competitive and noncompetitive properties in antagonizing the central effects of nicotine.

Analgesia↗
PubMed1988

Antagonism of the nicotine-induced changes of the striatal dopamine metabolism in mice by mecamylamine and pempidine.

The ability of nicotinic receptor blockers, mecamylamine and pempidine, to antagonize the changes in striatal dopamine (DA) metabolism induced by repeated nicotine administration was studied. The contents of DA and its metabolites 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. Mice kept at 20-22 degrees C were given nicotine, 3 mg/kg, s.c., four times, at 30 min intervals, and sacrificed 20 min after the last dose. Hexamethonium, 10 mg/kg, i.p., was administered at 30 min before the first nicotine dose in order to prevent the peripheral effects of nicotine. Mecamylamine, 0.6 or 10 mg/kg, i.p., and pempidine, 0.6 or 20 mg/kg, i.p., were given at 60 min before sacrifice. Mecamylamine and pempidine decreased clearly the striatal 3-MT content, which suggests that the nigrostriatal dopaminergic neurons are physiologically controlled by a stimulatory nicotinic mechanism. The repeatedly administered nicotine caused deep hypothermia, and increased the striatal DOPAC content but decreased the 3-MT and HVA contents. The small dose of mecamylamine, which was the only dose found to effectively antagonize the nicotine-induced hypothermia, antagonized the decrease of HVA content. The large but not the small doses of mecamylamine and pempidine antagonized the nicotine-induced increase of DOPAC content but none of the doses studied antagonized the decrease of 3-MT content. Thus it seems that nicotine decreases the 3-MT content by a mechanism distinct from the mechanism mediating the increase of the DOPAC content. The decreased 3-MT content most probably results from desensitization of nicotinic cholinergic receptors (nAChR) and following decrease of cholinergic regulation of nigrostriatal dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

[Effects of mecamylamine and pempidine, secondary and tertiary amines, on the spinal reflex of cats (author's transl)].

The ganglionic blocking effects of the secondary and tertiary amines, mecamylamine and pempidine, on the spinal reflex of cats of both sexes were investigated. These blocking effects were then compared with findings in the quaternary ammonium compounds such as tetraethylammonium (TEA) and decamethonium (C10). Mecamylamine (5 mg/kg) and pempidine (1 mg/kg) inhibited spinal reflex potentials such as the monosynaptic reflex (MSR), the polysynaptic reflex (PSR) and the dorsal root reflex (DRR). Maximal inhibition occurred 40 min after intravenous administration these drugs. In the case of mecamylamine, the inhibited potentials recovered gradually after reaching the maximum inhibition. However, the inhibitory effect of pempidine was prolonged, and recovery of the potentials did not occur for 6 min or longer. Although 10 mg/kg of C10 and 0.025 mg/kg of nicotine transiently inhibited the MSR and PSR, these compounds had no effect on the DDR. TEA produced prolonged inhibition of the MSR and PSR, and slightly enhanced the DRR. These results demonstrated the differences in DRR responses to secondary and tertiary amines, and quaternary ammoniums.

Animals↗
PubMed1979

Hypothalamic receptors influencing the secretion of corticotrophin releasing hormone in the rat.

1. The production of corticotrophin releasing hormone (CRH) by the rat hypothalamus in vitro was studied in the presence and absence of various neurotransmitter substances and drugs which mimic or antagonize their actions.2. Acetylcholine, nicotine and bethanechol increased, in a dose-related manner, hypothalamic CRH release and content but the maximal responses to bethanechol or nicotine were less than those to acetylcholine.3. The actions of acetylcholine were antagonized by atropine, pempidine and hexamethonium but were completely inhibited only when atropine and pempidine were given together. The effects of nicotine were abolished by pempidine but not by atropine while those of bethanechol were abolished by atropine but not by pempidine.4. Acetylcholine-induced hypothalamic CRH activity was also antagonized by cyproheptadine but not by methysergide.5. 5-Hydroxytryptamine caused dose-related increases in hypothalamic CRH release and content. Its effects were antagonized by cyproheptadine and methysergide but not by atropine, pempidine or hexamethonium.6. Acetylcholine-induced increases in hypothalamic CRH production were reduced by GABA, noradrenaline, adrenaline, methoxamine and phenylephrine but not by isoprenaline. The actions of GABA were antagonized by bicuculline and those of noradrenaline by phentolamine but not by atenolol.7. The results suggest the presence of nicotinic and muscarinic cholinoceptors, 5-hydroxytryptamine receptors, alpha-adrenoceptors and GABA-receptors within the hypothalamus all of which may be important in the control of CRH secretion.

Animals↗
PubMed1972

Effects of muscarine given into the brain of fowls.

1. The effects of muscarine, given intraventricularly, in adult conscious fowls (Gallus domesticus) or microinfused into various brain regions of conscious young chicks, were tested on behaviour, electrocortical activity and respiratory rate. Its effects given intraventricularly or intravenously to anaesthetized fowls were also examined.2. After intraventricular injection, muscarine elicited immediate behavioural and electrocortical arousal; body temperature was unaffected. After a delay of 30-40 min, tachypnoea developed together with postural changes which included partial abduction of the wings away from the trunk, the back and tail becoming horizontal. These effects were prevented by intravenous or intraperitoneal atropine or hyoscine, but not by pempidine or methylatropine, and were potentiated by physostigmine. Hyoscine given intraventricularly or intravenously did not affect electrocortical activity.3. Intraventricular muscarine given to anaesthetized adult fowls produced brief apnoea. On return of respiration, amplitude of respiratory excursion was diminished for about 5 min; tachypnoea did not develop. Blood pressure also rose briefly. With larger doses of intraventricular muscarine, large amplitude electromyographic potentials developed in the dorsal neck muscles followed later by side-to-side neck movements.4. Muscarine given intravenously to anaesthetized adult fowls, raised blood pressure and perfusion pressure in a perfused hind limb, an effect most likely due to secretion of adrenal medullary catecholamines; these pressor effects were prevented by pempidine and phenoxybenzamine. Given directly to the perfused hind limb, muscarine lowered perfusion pressure.5. In young chicks, muscarine microinfused into the diencephalon or myelencephalon elicited intense bilateral electrocortical alerting associated with periods of alternating violent motor activity and quiescence. Microinfusion of muscarine into the telencephalon induced ipsilateral electrocortical desynchronization without affecting behaviour. These effects of muscarine were prevented by intravenous, intraperitoneal or intracerebral hyoscine, but once its effects were established could be antagonized only with difficulty; pempidine did not prevent these effects. Microinfusions of muscarine into the brain did not affect posture, respiration or temperature.

Alkaloids↗
PubMed1977

Involvement of cholinergic presynaptic receptors of nicotinic and muscarinic types in the control of the spontaneous release of dopamine from striatal dopaminergic terminals in the rat.

Rat striatal slices (two) were superfused continuously with L-3,5-3H tyrosine and 3H-dopamine (3H-DA) release was estimated in serial fractions of superfusates. The spontaneous release of 3H-DA was reduced by about 50% when slices were superfused with a calcium-free medium containing ethylene glycol bis (beta-aminoethyl ether)- N,N'-tetraacetic acid (EGTA) (10(-4) M) or with a medium containg tetrodotoxin (5 x 10(-7) M). These effects were not related to a change in 3H-DA synthesis since the rate of L-3,5-3H tyrosine hydroxylation, as measured by 3H-H2O formation was not significantly reduced. Acetylcholine (ACh) (10(-5) M) stimulated the release of 3H-DA (about 100%). This effect was abolished in the absence of calcium; it was partially blocked by pempidine (10(-5) M), atropine (10(-6) M) or scopolamine (10(-5), 10(-6) M). Oxotremorine (10(-5) M) enhanced 3H-DA release but to a lesser extent (60%) than ACh (10(-5) M); its action was completely blocked by atropine (10(-6) M) and unaffected by pempidine (10(-5) M). The ACh- (10(-5) M) and oxotremorine- (10(-5) M) stimulatine effects on 3H-DA spontaneous release were still detected in slices superfused in the presence of tetrodotoxin (5 x 10(-7) M). In the presence of the neurotoxin, the effect of ACh (10(-5) M) was significantly reduced by pempidine (10(-5) M) and the effect of oxotremorine (10(-5) M) was blocked by atropine (10(-6) M). These results suggest the presence of cholinergic presynaptic receptors of the nicotinic and muscarinic types on striatal dopaminergic terminals.

Acetylcholine↗
PubMed1970

Synaptic potentials recorded by the sucrose-gap method from the rabbit superior cervical ganglion.

1. Compound ganglionic potentials evoked by stimulation of the preganglionic nerves to the superior cervical ganglion of the rabbit were recorded by the sucrose-gap method.2. When the distal part of the ganglion was bathed in flowing isotonic sucrose solution or sodium-deficient solutions, ganglionic action potentials were no longer evoked, only large synaptic potentials.3. The compound synaptic potential, which remained unaltered for more than 1 h, originated in a population of cells at the interface between the Krebs and sucrose solutions. Hexamethonium reduced the size but did not alter the time course of the synaptic potential.4. It is suggested that a higher concentration of sodium ions is required for the generation of ganglionic action potentials than for either conduction in the postganglionic axons or production of synaptic potentials.5. When lithium replaced sodium in the solution bathing the distal part of the ganglion, the synaptic potential was greatly reduced in amplitude. Impulse propagation in the postganglionic axons was only slightly impaired when lithium replaced sodium in the solution bathing the axons.6. A quantitative assessment of the potency of the ganglion-blocking drugs nicotine, pentolinium, hexamethonium and pempidine was made by measuring the depression of the synaptic potentials produced by bathing the distal part of the ganglion in flowing isotonic sucrose solution. The concentrations which produced a 50% depression were 8.1 muM nicotine, 26.5 muM pentolinium, 111 muM hexamethonium and 22.2 muM pempidine.

Animals↗
PubMed1974

Effects of cholinomimetic agents given into the brain of fowls.

1 Effects of cholinomimetic agents, given into the IIIrd ventricle of adult fowls (Gallus domesticus) or infused into the hypothalamus of young chicks, were tested on behaviour, respiratory rate and body temperature.2 Carbachol evoked behavioural and electrocortical arousal but lacked postural and respiratory effects. Contrariwise, pilocarpine increased respiratory rate and induced postural changes, i.e. abduction of the wings, but lacked other behavioural effects and did not alter electrocortical activity. Benzoylcholine induced tachypnoea, postural changes and brief electrocortical arousal. Acetylcholine was ineffective unless given with physostigmine, when electrocortical arousal, postural changes and tachypnoea developed. Methacholine induced tachypnoea and postural changes.3 Effects of carbachol and pilocarpine were prevented by hyoscine and those of benzoylcholine by pempidine; hyoscine and pempidine were required together to prevent the effects of methacholine and to attenuate those of acetylcholine with physostigmine.

Acetylcholine↗
PubMed1975

An investigation of the tachycardia produced by intracerebro-ventricular injections of isoprenaline in mice.

1. Isoprenaline, 3.5-20 ng, injected intracerebroventricularly in atropinized mice under pentobarbitone anaesthesia produced a dose-dependent tachycardia. 2. Pretreatment with either reserpine or pempidine blocked nervously-mediated tachycardia as shown by marked reduction of that due to stimulation of the spinal outflow in pithed mice. After pretreatment with these drugs, intracerebroventricular isoprenaline caused tachycardia of a similar degree and time course to that in mice not so pretreated. 3. Pretreatment with either reserpine or pempidine caused supersensitivity to the tachycardia due to intravenous isoprenaline. 4. When allowance was made for this supersensitivity in the effect of intracerebroventricular isoprenaline in pretreated mice, a small dose-dependent residual effect remained that could be attributed to leakage of isoprenaline into the peripheral circulation. 5. This was confirmed by the appearance of a late-developing tachycardia on intracerebroventricular injection of isoprenaline in spinal mice. 6. It is therefore concluded that the tachycardia caused by intracerebroventricular isoprenaline in mice is, at least initially, of central origin.

Adrenal Glands↗
PubMed1974

A microinjection study of the control of antidiuretic hormone release by the supraoptic nucleus of the hypothalamus in the cat.

1. The release of antidiuretic hormone (ADH) has been studied in the chloralose anaesthetized cat after microinjection of various agents directly into the brain, in particular the supraoptic nucleus of the hypothalamus (SON). The concentration of ADH in jugular venous blood was determined using the waterloaded, alcohol anaesthetized rat assay. The position of the microinjection cannula was located post mortem in stained brain sections.2. Nicotine, noradrenaline (NA) and hypertonic saline caused release of ADH, whereas microinjections of isotonic saline did not affect the blood level of the hormone.3. Nicotine administered to other sites in the central nervous system (C.N.S.) could also cause ADH release. Hypertonic saline proved to be an ineffective stimulus at all the tested sites outside the supraoptic region.4. The ganglion-blocking agents hexamethonium and pempidine inhibited the releasing action of nicotine at the SON in most of the experiments. These blocking drugs had no effect on osmotic release. When administered alone, both hexamethonium and pempidine had variable, but analogous effects on the hormone output.5. The alpha-adrenoreceptor blocking drug, phentolamine, stimulated ADH release, but the beta-receptor blocking drug, propranolol, had no such effect. Both drugs appeared to have inhibitory action on noradrenergic release of ADH, but neither had a consistent effect on the osmotic release of the hormone.

Animals↗
PubMed1975

Drinking behaviour in the cat induced by renin, angiotensin I, II and isoprenaline.

1. Angiotensin I, II and hog renin, infused into the lateral cerebral ventricles (I.C.V.) of water replete cats, each induced water drinking behaviour. 2. Intravenous infusion of high doses of angiotensin I or II also elicited a drinking response. The dipsogenic effect of I.V. renin was not marked. 3. Drinking in response to I.C.V. angiotensin II was abolished after autonomic ganglion blockade with I.V. hexamethonium or pempidine and was significantly reduced after I.V. atropine methonitrate. 4. The dipsogenic response to I.C.V. angiotensin II was unaffected by either peripheral adrenergic neurone blockade with I.V. bethanidine, alpha-adrenoceptor blockade with phentolamine or beta-adrenoceptor blockade with sotalol. 5. Atropine, atropine methonitrate, hexamethonium and pempidine given I.C.V did not inhibit the diposgenic response to I.C.V. angiotensin II. 6. Bethanidine I.C.V. produced a dose related reduction in the dipsogenic response to I.C.V. angiotensin II. 7. The alpha-adrenoceptor blocking agents tolazoline and phenoxybenzamine given I.C.V did not affect angiotensin induced drinking but the response was regularly inhibited by phentolamine I.C.V. 8. The beta-adrenoceptor blocking agents propranolol and practolol given I.C.V. each inhibited angiotensin induced drinking. The L-isomer of propranolol was a more effective blocker than the D-isomer. 9. Isoprenaline given I.C.V induced drinking in ten of sixteen cats. Subcutaneous administration of isoprenaline also elicited drinking but the onset of the response was delayed and the amount consumed slightly less than after I.C.V infusion.

Angiotensin II↗