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PubMed1977

An analysis of the anatomical basis for the mechanical response to motor nerve stimulation of the rat vas deferens.

1. An anatomical basis was sought for the biphasic motor nerve response of the rat vas deferens. The motor nerve pathway to the tissue was stimulated at different points between the vertebral outflow and the intramural fibres, in the pithed rat and in isolated tissues, to examine the possibility of two anatomically separate groups of neurones. Different preparations of the isolated tissue were devised to detect whether different groups of smooth muscle fibres contributed to the two phases.2. The fibres mediating both phases of the response arose from the upper lumbar vertebral outflows. Both phases were elicited by pre- or post-ganglionic stimulation and could be depressed by hexamethonium. In the pithed rat or with hypogastric nerve stimulation in the isolated tissue, however, the initial ;twitch' phase was relatively resistant to such blockade.3. When the rat vas deferens was perfused through the lumen in situ or in vitro, the perfusion pressure response to motor nerve stimulation exhibited two phases similar to those of the longitudinal contractile response.4. Isolated rat vasa were bisected into portions, each of which was stimulated and longitudinal tension was recorded. The proportions of the two phases of the response varied along the length of the tissue. At the prostatic end the total response was relatively weak with a dominant ;twitch' and at the epididymal end the two phases were comparable in magnitude. The distribution of adrenergic nerve terminals within the muscle layers also varied along the length of the rat vas deferens.5. The effects of drugs were investigated on the motor responses of the above preparations. The ;twitch' phase was relatively susceptible to blockade by reserpine and lysergic acid diethylamide and the ;secondary' phase to phentolamine with both equally sensitive to guanethidine. Each phase had similar susceptibilities to blockade irrespective of which part of the tissue was involved.6. It was concluded that two types of nerve-muscle transmission may be involved in the rat vas deferens with the proportion of each varying along the length of the tissue but both displaying pharmacological characteristics of adrenergic fibres.

Adrenergic Fibers↗

PubMed1986

Salivation mediated by central M-2 muscarinic receptors in the cat.

In these experiments the effect on the cat's salivation of the choline ester, carbachol, the anticholinesterase, eserine, and the muscarinic ganglionic stimulants, McN-A-343 and AHR-602, injected into the cerebral ventricles was investigated and compared. Carbachol and eserine injected intracerebroventricularly (ICV) produced dose-related salivation. On the other hand, ICV McN-A-343 and AHR-602 evoked inconsistent salivation when injected in large doses. The antimuscarinic drug, atropine, injected into the cerebral ventricles abolished the salivation caused by carbachol and eserine similarly injected. However, salivation induced by ICV carbachol and eserine was not significantly altered by the ganglionic blocking agent, mecamylamine, injected into the cerebral ventricles. It is concluded that the ICV injection of carbachol and eserine evokes salivation in the cat by way of an action on central M-2 muscarinic receptors.

Animals↗

PubMed1990

The inhibitory action of halothane on reflex constriction in mesenteric capacitance veins.

Potent inhalational anesthetics depress autonomic reflex responses at multiple sites. Most studies emphasize cardiac chronotropic changes and changes in systemic blood pressure. Recently, active reflex venoconstriction of 500-1,000 microns O.D. mesenteric veins has been demonstrated. In the current study, the effects of halothane on the reflex responses of similar mesenteric veins were measured. Mesenteric vein diameter and intravenous pressure were measured in 500-1,000 microns O.D. veins from the mesentery of segments of terminal ileum externalized in situ from 27 New Zealand white rabbits anesthetized with alpha-chloralose. Mean arterial pressure was measured with femoral arterial cannulation, and heart rate was determined from the arterial pressure signal. In a separate group of six animals, sympathetic efferent nerve activity was measured from a postganglionic splanchnic nerve. Reflex venoconstriction and increases in mean arterial pressure and mesenteric vein pressure in response to bilateral carotid occlusion were attenuated by 0.5% and 1% inhaled halothane but not by superfusate equilibrated with 3% halothane. Decreases in mesenteric vein diameter and increases in mesenteric vein pressure in response to celiac ganglion stimulation were unaffected by both 0.5% inhaled halothane and superfusate equilibrated with 5% halothane. The bilateral carotid occlusion reflex-mediated increase in sympathetic efferent nerve activity was depressed by both 0.5% and 1% inhaled halothane. The effect of inhaled halothane on prestimulation baseline vein diameter was inconsistent. Superfusate equilibrated with 5% but not 3% halothane caused baseline venodilation. These results suggest a mechanism whereby control of venous tone is inhibited by halothane proximal to the postganglionic neuron. This could involve central or ganglionic inhibition.

Animals↗

PubMed1977

Dissimilarity between the responses to adenosine triphosphate or its related compounds and non-adrenergic inhibitory nerve stimulation in the longitudinal smooth muscle of pig stomach.

1 Transmural electrical stimulation (TMS) of longitudinal smooth muscle strips taken from the cardiac portion of the pig stomach produced biphasic responses consisting of initial contractions followed by relaxations. The excitatory component was enhanced by neostigmine and abolished by atropine. After atropine treatment, TMS and nicotine or 1,1-dimethyl-4-phenyl-piperazinium, caused a relaxation or a relaxation followed by an after-contraction. All of these responses were abolished or reduced reversibly with tetrodotoxin and cocaine, while hexamethonium only abolished the response to ganglion-stimulating agents.2 The relaxation caused by TMS reached a maximum amplitude at 5-10 Hz, and was entirely resistant to the effects of alpha- and beta-adrenoceptor blocking agents, or a combination of them, and also to guanethidine. These results strongly suggested that the relaxation was elicited by stimulation of intramural non-adrenergic inhibitory neurones.3 In the presence of atropine and guanethidine, adenosine triphosphate (ATP, 5-20 muM) caused only a tonic contraction, and ATP (25-200 muM) or adenosine diphosphate (25-200 muM) produced a contractile response or a biphasic one (tonic contraction preceded by a slight relaxation). Adenosine monophosphate and adenosine caused only the tonic contraction over the range of concentrations (25-200 muM).4 Stimulation of the intramural inhibitory neurones of the tissue consistently evoked an inhibitory junction potential, which showed a summation during repetitive stimulation. One the other hand, ATP elicited mainly a small depolarization of a few mV.5 When the desensitization to ATP of the muscle was achieved in the presence of atropine and guanethidine, the relaxation induced by stimulation of the non-adrenergic inhibitory neurones could be evoked without any modification.6 Dipyridamole neither potentiated the inhibitory responses due to stimulation of the intramural inhibitory neurones nor showed any consistent effect on the ATP-induced response.7 From these results, it is unlikely that ATP, or any related compound, is the transmitter substance of the intramural inhibitory neurones in the longitudinal smooth muscle of the pig stomach.

Adenosine Triphosphate↗

PubMed1961

Actions of triethylcholine on neuromuscular transmission.

The effects of the triethyl analogue of choline (triethyl 2-hydroxyethyl ammonium) on muscular activity have been studied in conscious rabbits, chicks, dogs and a cat. The contractions of the tibialis anticus and soleus muscles of cats under chloralose anaesthesia, and of the tibialis anticus muscle of rabbits under urethane anaesthesia and the isolated diaphragm preparation of the rat were also used. In conscious animals, triethylcholine caused a slowly developing muscular weakness which was more severe after exercise and which resembled the symptoms of myasthenia gravis. In nerve-muscle preparations triethylcholine had a selective action in reducing the contractions of muscles elicited by a high rate of nerve stimulation while leaving unaffected the contractions caused by slower rates of stimulation. During the paralysis of the tibialis muscle of the cat produced by triethylcholine, action potentials recorded from the motor nerve were unaffected and the muscle responded normally to injected acetylcholine and to direct electrical stimulation. The failure of neuromuscular transmission produced by triethylcholine was reversed by injection of choline, but anticholinesterases were ineffective. Choline reduced the toxicity of triethylcholine in mice. It is concluded that triethylcholine produces transmission failure at the neuromuscular junction by interfering with the ability of the nerve endings to synthesize acetylcholine. The possibility that triethylcholine is itself acetylated by the nerve endings and released as an inactive neurohormone is discussed. It was shown that triethylcholine was devoid of depolarizing action and curare-like blocking action. It possesses a transient ganglion blocking action of the tetraethylammonium-type as shown in experiments in which it caused a fall in blood pressure and blocked the response of the nictitating membrane to pre- but not to post-ganglionic stimulation of the cervical sympathetic nerve.

Acetylcholine↗

PubMed1994

Cholinergic influence on duodenal mucosal bicarbonate secretion in the anesthetized rat.

Bicarbonate secretion by duodenum distal to the Brunner's glands area was titrated in situ in rats anesthetized with thiobarbiturate. The unselective muscarinic antagonist atropine (0.4 mg/kg) inhibited secretion stimulated by bethanechol (15 micrograms.kg-1.h-1) but not that stimulated by carbachol (15 micrograms.kg-1.h-1). The nicotinic antagonist hexamethonium (10 mg.kg-1.h-1), however, abolished the latter response. The muscarinic M1-selective antagonists pirenzepine and telenzepine (0.025, 0.25 and 2.5 mg/kg) did not decrease but caused a dose-dependent rise in duodenal mucosal HCO3- secretion, an effect abolished by cervical vagotomy or infusion of the alpha-adrenoceptor antagonist phentolamine (0.1 mg.kg-1.h-1). Phentolamine alone caused a sustained increase in secretion. McN-A-343 (0.025, 0.25, and 2.5 mg/kg), an M1-selective agonist and ganglionic stimulator, increased the HCO3- secretion; this effect was not prevented by vagotomy but was attenuated by pirenzepine. Intracerebroventricular infusion of pirenzepine and telenzepine did not cause any changes in secretion. These findings suggest that peripheral muscarinic M1 and nicotinic receptors mediate cholinergic stimulation of duodenal mucosal HCO3- secretion. Pirenzepine and telenzepine may act stimulatory by antagonizing muscarinic M1-transmission in peripheral sympathetic ganglia, thus decreasing postsynaptic adrenergic inhibition.

Anesthesia↗

PubMed1993

Sympathetic stimulation alters left ventricular relaxation and chamber size.

Alterations in left ventricular (LV) contractility, relaxation, and chamber dimensions induced by efferent sympathetic nerve stimulation were investigated in nine anesthetized open-chest dogs in sinus rhythm. Supramaximal stimulation of acutely decentralized left stellate ganglia augmented heart rate, LV systolic pressure, and rate of LV pressure rise (maximum +dP/dt, 1,809 +/- 191 to 6,304 +/- 725 mmHg/s) and fall (maximum -dP/dt, -2,392 +/- 230 to -4,458 +/- 482 mmHg/s). It also reduced the time constant of isovolumic relaxation, tau (36.5 +/- 4.8 to 14.9 +/- 1.1 ms). Simultaneous two-dimensional echocardiography recorded reductions in end-diastolic and end-systolic LV cross-sectional chamber areas (23 and 31%, respectively), an increase in area ejection fraction (32%), and increases in end-diastolic and end-systolic wall thicknesses (14 and 13%, respectively). End-systolic and end-diastolic wall stresses were unchanged by stellate ganglion stimulation (98 +/- 12 to 95 +/- 9 dyn x 10(3)/cm2; 6.4 +/- 2.4 to 2.4 +/- 0.3 dyn x 10(3)/cm2, respectively). Atrial pacing to similar heart rates did not alter monitored indexes of contractility. Dobutamine and isoproterenol induced changes similar to those resulting from sympathetic neuronal stimulation. These data indicate that when the efferent sympathetic nervous system increases left ventricular contractility and relaxation, concomitant reductions in systolic and diastolic dimensions of that chamber occur that are associated with increasing wall thickness such that LV wall stress changes are minimized.

Animals↗

PubMed1985

Possible inhibitory role of endogenous gamma-aminobutyric acid in the nonnicotinic functions of the dog cardiac sympathetic ganglia.

Participation of endogenous gamma-aminobutyric acid (GABA) in the functions of dog cardiac ganglia was investigated. The ganglionic stimulants as well as agents affecting GABA system were given directly into the cardiac sympathetic ganglia through the right subclavian artery (i.a.), unless otherwise mentioned. Inhibition of endogenous GABA degradation by the GABA-transaminase inhibitor, aminooxyacetic acid (AOAA) administered 10 mg/kg i.v. 2 hr before completion of surgical procedures did not alter the positive chronotropic responses to bethanecol (25 and 50 micrograms) and acetylcholine (25, 50 and 100 micrograms) but reduced markedly those to angiotensin II (1 and 2 micrograms). This reduction was antagonized by picrotoxin (5 mg). Diazepam given 10 mg/kg i.v. also inhibited the ganglionic responses to angiotensin II in both untreated and AOAA-pretreated dogs, this inhibition by diazepam being more marked in the AOAA-pretreated than in the untreated dogs. The same dose of diazepam did not affect the responses to acetylcholine but reduced to a certain degree of responses to bethanechol in the AOAA-pretreated dogs. These inhibitions by diazepam were also reversed by picrotoxin. After i.v. treatment with the glutamic acid decarboxylase inhibitors, 3-mercaptopropionic acid (50 mg/kg) or isoniazid (200 mg/kg), the ganglionic responses to angiotensin II were not altered, but inhibitory effects of diazepam on the responses to angiotensin II were eliminated after 3-mercaptopropionic acid but not after isoniazid. These results suggest that endogenous GABA may play an inhibitory role in the nonnicotinic ganglionic pathways and that diazepam probably exerts a ganglionic action through endogenous GABAergic mechanisms.

3-Mercaptopropionic Acid↗

PubMed1995

Pressor and tachycardic responses to intravenous substance P in anesthetized rats.

Intravenous injection of 3-33 nmol/kg of substance P (SP) caused pressor and tachycardic responses in anesthetized rats. The responses were not blocked by a ganglion nicotinic receptor antagonist or by pithing. Pretreatment with reserpine blocked both responses. beta-Adrenoceptor blockade attenuated only the tachycardic response, and alpha-adrenoceptor blockade attenuated only the pressor response. These findings indicated that the effects of SP to increase blood pressure and heart rate are due to sympathetic ganglion stimulation. Studies with adrenalectomized rats showed that stimulation of the adrenals by SP contributes to both responses but makes a greater contribution to the tachycardic response. These observations raise the possibility that the tachykinin innervation of sympathetic ganglia and the adrenal medulla may be involved in the local regulation of blood pressure and heart rate.

Adrenal Glands↗

PubMed1985

Dual effects of clonidine on micturition reflex in urethane anesthetized rats.

The effects of clonidine (CLO) on reflexly activated bladder motility have been examined in urethane-anesthetized rats and compared to its effects on field stimulation-induced contractions of isolated urinary bladder. Intravenous CLO suppressed micturition reflex transiently in a yohimbine-sensitive manner. The suppressive effect of i.v. CLO was greater after surgical sympathectomy (bilateral section of the hypogastric nerves). Intracisternal CLO was more effective than topical (on the bladder dome) or intracerebroventricular CLO in suppressing micturition. When tested in experimental conditions involving activation of both excitatory and inhibitory reflexes to the bladder CLO produced either inhibitory and/or excitatory effects on bladder motility in dependence of factors such as dose, route of administration and integrity of the sympathetic (inhibitory) innervation to the bladder. CLO suppressed bladder contractions produced by dimethylphenilpiperazinium, a ganglionic stimulant, and reduced those produced by postganglionic nerve stimulation. CLO inhibited, in a yohimbine-sensitive manner, amplitude of field stimulation-induced contractions of isolated rat bladder, and its effectiveness was inversely related to the frequency of stimulation. Our findings are suggestive that the inhibitory action of CLO on micturition reflex is counteracted, in normal animals, by a negative feedback on sympathetic inhibitory influences carried out through the hypogastric nerves.

Anesthesia↗

PubMed1999

The chronic infusion of hexamethonium and phenylephrine to effectively clamp sympathetic vasomotor tone. A novel approach.

There are several ways to assess the sympathetic nervous system (i.e. , nerve recording, sympathectomy, etc.), each of which has its own limitations. The present study was conducted to establish a standard, testable chronic ganglionic blockade protocol with a fixed level of adrenergic vasomotor tone. Rats were instrumented with radio telemetry pressure transducers and venous catheters for continuous measurement of arterial pressure and infusion of pharmacologic agents, respectively. After 3 days of control measurements, rats were infused for 9 days with a continuous dose of the ganglionic blocking agent, hexamethonium and the alpha-adrenergic agonist, phenylephrine. In this way, sympathetic tone was effectively "clamped," which maintained a normal level of arterial pressure. Control pressure between hexamethonium + phenylephrine (HEX + PE) treated rats (101+/-2 mm Hg) and saline (VEHICLE) treated rats (101+/-2 mmHg) was not different. By day 9 of the infusion, there was no difference in arterial pressure between groups (VEHICLE: 101+/-3 mm Hg, HEX + PE: 103+/-3 mm Hg) or from the control period, although heart rate was significantly less in HEX + PE rats (VEHICLE: 406+/-9 beats/min vs. HEX + PE: 343+/-6 beats/min). The effectiveness of this technique was validated by measuring cardiac baroreceptor reflex sensitivity, as well as the pressor response to the direct ganglionic stimulating agent, 1, 1-dimethyl-4-phenylpiperazinium iodide (DMPP). Compared to VEHICLE rats, HEX + PE rats showed no tachycardic response to depressor stimuli and an absence of a pressor response to DMPP. We conclude that this protocol is a useful technique to chronically, yet reversibly, block the sympathetic nervous system in experimental settings.

Adrenergic alpha-Agonists↗

PubMed2000

Implantation of retina stimulation electrodes and recording of electrical stimulation responses in the visual cortex of the cat.

BACKGROUND: Simple basic visual perception may be restored by epiretinal electrical stimulation in patients that are blind due to photoreceptor loss. To stimulate ganglion cells, epiretinally flat platinum microelectrodes embedded in thin polyimide film were developed and tested in the cat. METHODS: After removal of the lens and the vitreous body a thin microfilm electrode array was implanted through a corneoscleral incision in the cat eye (n = 4). In two eyes no further attempt was made to fixate the tip of the electrode, which was pressed onto the retinal surface due to the tension of the curved polyimide film. In two eyes the tip of the electrode was fixed with cyanoacrylate adhesive. The exterior part of the microelectrode film was directed under the skin towards the forehead which allowed fixation of the microplug to a head fixation bolt. Retinal stimulation experiments were performed within 1 week after implantation. Success of stimulation was assessed by recording neuronal activities from areas 17 and 18. Retinal microelectrodes were removed 2 weeks or longer after implantation. RESULTS: Intraocular inflammation or retinal detachment were not observed after implantation of the microelectrode film. In two eyes the tip of the microelectrodes dislocated spontaneously within the first few days. The lowest threshold of electrical stimulation was 35 microA, corresponding to a charge transfer of 14 nC per phase. These values were ten times higher than those obtained by needle electrodes used in prior experiments. CONCLUSIONS: Intraocular implanted flat microelectrodes made of platinum and polyimide were well tolerated. Because of the flat configuration of the microelectrodes higher stimulation thresholds than for needle electrodes were found, indicating insufficient contact to the retinal surface. An alternative shape and fixation technique is required to minimise electrodes' threshold of stimulation.

Animals↗

PubMed1963

THE SITE OF THE 5-HYDROXYTRYPTAMINE RECEPTOR ON THE INTRAMURAL NERVOUS PLEXUS OF THE GUINEA-PIG ISOLATED ILEUM.

Dose/response measurements were made on the guinea-pig isolated ileum with six agonists, acetylcholine, 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium, choline phenyl ether and histamine. The dose effects were repeated in the presence of each of twelve antagonists and one anticholinesterase. Acetylcholine and histamine were chosen because of their direct mode of action on smooth muscle, nicotine, dimethylphenylpiperazinium and choline phenyl ether were used as examples of drugs that act at the ganglionic acetylcholine receptor. 5-Hydroxytryptamine was the drug investigated. Hyoscine blocked the contractions caused by acetylcholine, 5-hydroxytryptamine and the ganglion-stimulants but left the responses to histamine unchanged. The anticholinesterase N,N'-diisopropylphosphorodiamidic fluoride (mipafox) potentiated all the agonists except histamine. The strength of potentiation decreased in the order 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium and choline phenyl ether, and acetylcholine. The local anaesthetic procaine inhibited to the same extent contractions elicited by 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium and choline phenyl ether. These results showed that 5-hydroxytryptamine, like nicotine, choline phenyl ether and dimethylphenylpiperazinium, mediated its response through the nervous plexus. Of those tested 5-hydroxytryptamine was the only specific antagonist to 5-hydroxytryptamine; lysergic acid derivatives produced spasm and prolonged changes in tone; phenoxybenzamine caused non-specific block. The diverse modes of action of a number of ganglion-blocking agents were selectively used. Thus hexamethonium, pentolinium, and nicotine in its competitive phase, blocked contractions due to nicotine, dimethylphenylpiperazinium and choline phenyl ether and left those due to 5-hydroxytryptamine, acetylcholine and histamine unchanged. The depolarizing ganglion-blocking agents, dimethylphenylpiperazinium and nicotine, inhibited the responses to all the indirectly acting drugs. Furthermore, mecamylamine, a drug with a less well-defined mode of action, partially inhibited contractions due to 5-hydroxytryptamine in a concentration that blocked those due to nicotine, dimethylphenylpiperazinium and choline phenyl ether. Pempidine, known to act like mecamylamine, did not antagonize 5-hydroxytryptamine. It is concluded that 5-hydroxytryptamine activates specific receptors sited at the intramural parasympathetic ganglion cells.

Acetylcholine↗

PubMed1992

General pharmacology of the new quinolone antibacterial agent levofloxacin.

The general pharmacological properties of (-)-(S)-9-fluoro-2,3-dihydro-3- methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4] benzoxazine-6-carboxylic acid hemihydrate (levofloxacin, DR-3355, CAS 100986-85-4), an optically active isomer of ofloxacin, were examined. 1. Central nervous system (CNS): DR-3355 at 200-600 mg/kg p.o. showed depressant activity on the CNS, as was indicated by the depressant syndrome (mice), decreased spontaneous motor activity (mice) and hypothermia (mice and rabbits). In the cat behavior and EEG experiments, it had both stimulant and depressant effects at 30-100 mg/kg i.p., and caused transient slow waves followed by seizures at 20-30 mg/kg i.v. DR-3355 had no effect on convulsion, hexobarbital anesthesia, pain reaction to a tail pinch, or conditioned avoidance response, except that it showed mild analgesic activity in acetic acid writhing at 600 mg/kg p.o. 2. Respiratory and cardiovascular system: DR-3355 produced a hypotensive and a bradycardiac effect after the rapid i.v. injection of 6 mg/kg or more in anesthetized dogs, accompanied by an increase in plasma histamine concentration. Both changes were markedly reduced when the test drug was administered by continuous i.v. infusion. 3. Autonomic nervous system: DR-3355 inhibited nictitating membrane contraction induced by both pre- and post-ganglionic stimulation, and inhibited the depressor response to acetylcholine at 20 mg/kg i.v. It had no influence on pupil size or on pressor response to norepinephrine. 4. Gastrointestinal system: DR-3355 at 600 mg/kg p.o. inhibited gastric secretion. Dog gastrointestinal motility was slightly inhibited, and was then stimulated over the dose range of 2-20 mg/kg i.v. It had no influence on gastrointestinal propulsion, the gastric emptying rate or the gastric mucosa. 5. Isolated smooth muscle: At a concentration of 5 x 10(-4) g/ml, DR-3355 was devoid of spasmogenic or smasmolytic activity, except for showing a slight relaxation effect (trachea), inhibition of nicotine-induced contraction (ileum) and spontaneous or oxytocin-induced motility (pregnant uterus). 6. Miscellaneous: DR-3355 inhibited the urine output and carrageenin-induced paw edema at 600 mg/kg p.o. It had no effect on skeletal muscle contraction or the corneal reflex.

Animals↗

PubMed1998

Effects of SR140333, a selective non-peptide NK1 receptor antagonist, on trigemino-thalamic nociceptive pathways in the rat.

Trigeminal stimulation of C-fibers increased c-fos expression within the trigeminal nucleus caudalis (NtV) and thalamic neuronal activity which both reflect the transmission of a nociceptive message. We examined the effects on both these phenomena of the selective NK1 and NK2 receptor antagonists, SR140333 and SR48968. SR140333 (0.3, 1 and 3 micrograms/kg intravenously [i.v.]) dose-dependently, reversibly and stereoselectively antagonized the increase of contralateral thalamic activity. This compound, when given i.v. (30 micrograms/kg) or orally (10 mg/kg), also reduced the number of Fos-like immunoreactive cells particularly at the medial and caudal level of the NtV. In contrast, SR48968 did not exert any antagonistic effect either on thalamic activity or on Fos-like immunoreactivity. The data strongly suggest a preferential involvement of NK1 vs NK2 receptors in nociceptive transmission following trigeminal ganglion stimulation. Taken together, our results indicate that SR140333 could provide a potent drug for the relief of pain occurring under excessive activity of sensory trigeminal fibers.

Administration, Oral↗

PubMed1992

Acetylcholine released from guinea-pig submucosal neurones dilates arterioles by releasing nitric oxide from endothelium.

1. The role of the endothelium as an effector of the neurogenic cholinergic vasodilatation in submucosal arterioles of the guinea-pig ileum was investigated by measuring changes in arteriolar diameter in response to exogenous application of muscarine or electrical stimulation of the submucosal ganglia. 2. NG-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, competitively inhibited the vasodilatation produced by muscarine in arterioles which had been preconstricted with the prostaglandin analogue U46619. L-Arginine (10 mM), but not D-arginine (10 mM), prevented the inhibition by L-NMMA. 3. Neither tetrodotoxin (TTX, 1 microM), nor the cyclo-oxygenase inhibitor, indomethacin (10 microM), altered the muscarinic vasodilatation or the inhibitory effect of L-NMMA. 4. Sodium nitroprusside (SNP), an activator of the soluble guanylate cyclase, dilated the arterioles in a concentration-dependent manner. This vasodilatation was unaffected by L-NMMA but was abolished by the guanylate cyclase inhibitor, methylene blue (10 microM). In addition, methylene blue antagonized the muscarinic vasodilatation to a similar degree as did L-NMMA. 5. The vasodilatation produced by ganglionic stimulation (10 Hz, 10 s) was blocked by TTX and the muscarinic receptor antagonist, 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP, 1 microM). The neurally evoked vasodilatation was inhibited by 70% in the presence of L-NMMA; this inhibition was prevented by L-arginine. Methylene blue inhibited the neurogenic vasodilatation to the same extent as did L-NMMA. 6. These results show that arteriolar vasodilatation by muscarine is mediated mainly through the release of NO formed from L-arginine; the origin of the L-arginine appears to be the endothelium. These results also demonstrate that acetylcholine released from submucosal nerves onto submucosal blood vessels reaches the endothelium to cause the release of NO formed from L-arginine; the endothelial-derived NO dilates the arteriole.

Acetylcholine↗

PubMed1992

Distinct activation patterns of idioventricular rhythms and sympathetically-induced ventricular tachycardias in dogs with atrioventricular block.

To investigate mechanisms of ventricular impulse formation in response to sympathetic stimulation in the healthy canine heart in situ, we compared the patterns of ventricular activation during the idioventricular rhythms arising after complete atrioventricular (AV) block and ventricular tachycardias induced by RSG or LSG stimulation. Isochronal maps were generated by computer from 116-127 unipolar electrograms recorded from the entire ventricular epicardium in 15 open chest, anesthetized dogs. In eight of these, bipolar electrograms were recorded with plunge electrodes from 11 selected endocardial sites located below epicardial breakthrough areas. Intracardiac recordings from the His-Purkinje system were made with electrode catheters. After electrograms were recorded during sinus rhythm, complete AV block was induced by injecting formaldehyde into the AV node and idioventricular rhythms occurred spontaneously at a rate of 37 +/- 12 beats/min (mean +/- SD, n = 25). During idioventricular rhythms, endocardial activation preceded the earliest epicardial breakthrough, which occurred in either the right anterior paraseptal region, antero-apical left ventricle, or postero-apical left ventricle. These sites were consistent with a focal origin in the subendocardial His-Purkinje system. Total epicardial activation times lasted for 47 +/- 13 msec (n = 40). Idioventricular rhythms were suppressed by overdrive pacing (intermittent trains of ten beats with decremental cycle length from 500 to 200 msec) or by intravenous calcium infusion (to plasma levels of 10.1-15.2 mM). Right or left stellate ganglion stimulation increased idioventricular rhythm rates (to 52 +/- 13 beats/min, n = 28) and also induced, in all preparations, ventricular tachycardias that had significantly faster rates (189 +/- 55 beats/min, n = 27, P less than 0.005). Ventricular fibrillation was induced after brief runs of ventricular tachycardia in five of the preparations. During ventricular tachycardias, epicardial activation occurred on the right ventricular outflow tract or the postero-lateral wall of the left ventricle, and preceded endocardial activation in 50% of cases. Total epicardial activation times (103 +/- 29 beats/min) were significantly longer than during idioventricular rhythms (P less than 0.005). Ventricular tachycardias displayed overdrive excitation at critical pacing cycle lengths (360-280 msec) and were not suppressed by calcium infusion. Thus, differential mechanisms of impulse formation with distinct localizations can be elicited from healthy ventricular myocardium.

Animals↗

PubMed1997

Compensation of muscarinic bronchial effects of talsaclidine by concomitant sympathetic activation in guinea pigs.

The aim of the present investigation was to determine the reasons why the muscarinic receptor agonist talsaclidine (WAL 2014 FU, 1-azabicyclo[2.2.2] octane,3-(2-propynyloxy)-, (R)-,(E)-2-butenedioate) is devoid of bronchospastic effects in anaesthetized guinea pigs but causes contracture in isolated tracheal muscle from this species. Effects on airway resistance were assessed with a modified Konzett-Rossler method in guinea pigs anaesthetized with urethane. Intravenous injection of 1-64 mg/kg talsaclidine did not cause substantial bronchospasm in control animals. After blockade of beta-adrenoceptors, the muscarinic receptor agonist induced dose-dependent bronchospasm which could be blocked by atropine. In despinalized animals and in animals with spinal transection, talsaclidine was bronchospastic but ED50 values were higher and maximal effects were smaller than in intact animals after beta-adrenoceptor blockade. In adrenalectomized guinea pigs, talsaclidine was nearly as bronchospastic as after blockade of beta-adrenoceptors. In contrast, the muscarinic ganglion stimulant McN-A-343, 4-(m-chlorophenylcarbamoyloxy)-2-butyn-trimethyl-ammonium chloride, (2-32 mg/kg i.v.), which has a muscarinic receptor profile similar to that of talsaclidine, i.e., full muscarinic agonism and highest affinity at muscarinic M1 receptors, partial agonism at muscarinic M3 receptors, but in contrast to talsaclidine does not penetrate the blood-brain barrier, caused dose-dependent bronchospasm in control animals. These results indicate that talsaclidine has bronchospastic potential which, however, does not become evident in vivo because of functional antagonism via beta-adrenoceptors resulting from concomitant activation of the sympathetic nervous system in general and the adrenals in particular. It can be concluded that the unique profile of action of talsaclidine is due to partial agonism at bronchial muscarinic M3 receptors, a prerequisite for susceptibility to functional antagonism, and to its ability to penetrate the blood-brain barrier readily and to induce sympathetic activation as a result of full agonism at peripheral ganglionic and adrenal as well as central muscarinic M1 receptors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗