Change in Intracellular Cyclic Nucleotide Content Accompanies Relaxation of the Isolated Canine Internal Anal Sphincter

Changes in cyclic nucleotide content arc associated with relaxation of lower esophageal sphincter (LES) smooth muscle. Although agents that increase cyclic AMP (cAMP) or cyclic CMP (cGMP) can relax the LES, relaxation produced by activation of enteric neurons is associated with, an increase in intracellular cGMP. To evaluate these changes in another sphincteric area of the gut, ice determined the effects of electrical field stimulation (EFS) (65 V, I ms) and of several relaxant agents that alter cyclic nucleotide content in isolated strips of canine internal anal sphincter. Each strip was contracted with norepinephrine (3 μM). During maximum contraction, tissues were relaxed by EFS or by addition of relaxant agents. EFS produced, a frequency-related relaxation, accompanied by a significant, increase, in cGMP; however, cAMP increased only slightly at the maximum frequency tested (8 Hz). Both EFS-induced relaxation and increased cGMP content were blocked 1 μM tetrodotoxin. Cumulative addition of sodium nitroprusside, forskolin, 8-bromoguanosine 3',5'-cylic monophosphate, or 8-bromoadenosine 3',5'-cyclic monophosphate relaxed the internal anal sphincter in a concentration-dependent manner. Sodium nitroprusside-induced relaxations were accompanied by concentration-dependent increases in cGMP content, whereas forskolin-induced relaxations were accompanied by concentration-dependent increases in cAMP content. In conclusion, both cAMP and cCMP appear to be intracellular mediators of relaxation in the canine internal anal sphincter. In addition, relaxation produced by activation of intrinsic inhibitory neurons is associated with an elevation of intracellular cGMP. Together with our previous findings in the LES, these results suggest that cCMP may be the intracellular mediator of neuronally induced, relaxation of gut sphincteric regions.     

Sodium azide induces relaxation of the canine gastric body by activating a guanylate cyclase-dependent pathway

In order to study the inhibitory mechanism by which sodium azide eliminates smooth muscle contraction in vivo and in vitro, gastrointestinal motility was monitored via chronically implanted force transducers in the stomach and duodenum of conscious dogs. Circular smooth muscle strips with myenteric plexus from the canine gastric body were used for in vitro measurement of isometric tension. In conscious dogs, sodium azide (50 μg kg⁻¹, i.v.) abolished both the spontaneously occurring phase III contractions and postprandial motility. Exogenous motilin (100 ng kg⁻¹)- and bethanechol (50 μg kg⁻¹)-induced contractions were also abolished by sodium azide. In vitro, sodium azide and electrical field stimulation (EFS) caused a concentration- or frequency-dependent nonadrenergic noncholinergic relaxation in the gastric body strips. The relaxation induced by EFS, but not sodium azide, was abolished by tetrodotoxin. N^G-nitro- l -arginine and oxyhaemoglobin failed to attenuate the relaxant effect of sodium azide, but strongly inhibited EFS-induced relaxation. Methylene blue inhibited both sodium azide- and EFS-induced relaxation. cGMP concentrations in muscle strips were markedly increased by sodium azide. These findings indicate that sodium azide induces relaxation in the canine gastric body through a direct action on smooth muscle, by activating a guanylate cyclase-dependent pathway; endogenous NO synthesis does not participate in this inhibitory mechanism.     

Response of Smooth Muscle from Proximal and Distal Human Colon

Regional differences in colonic motility may be responsible for the orderly transit of intraluminal contents through the colon. The aims of this study were to compare the effect of stretch on active and passive stress development in colonic muscle from the proximal and distal colon and to compare the responses of these tissues to KC1 or bethanechol stimulation. Strips of taenia or circular smooth muscle were obtained from the disease-free segment of the colon removed for adenocarcinoma. Passive, active, and total isometric stress were measured on full-thickness strips of circular or longitudinal taenial muscle stimulated with bethanechol (10⁻⁴ M) as the muscles were stretched to 120% of the length of optimum tension ( L _o.) The tissues then were stimulated with increasing concentrations of KCI and bethanechol while being stretched at L _o. The active stress in the proximal circular muscle was greater at all levels of stretch than in distal circular or longitudinal muscle ( p <.001). The resting and passive stress were greater in distal circular and longitudinal taenial muscle than in proximal circular muscle ( p < .05). There was a dose-dependent increase in stress development to bethanechol and KCl in each type of muscle. Proximal circular muscle had the greatest response. The EDSO was shifted to the right in distal circular muscle (2.6 ± 0.1 × 10⁻⁵ M) compared to proximal circular muscle (1.1 ± 0.1 × 10⁻⁵ M) ( p < .001). These studies suggest that muscle stress differs in different locations of the colon and the role of active and passive stress development must be considered in models explaining in vivo colonic motility disturbances.     

[3H]Nitrendipine Binding to Rabbit Colonic Smooth Muscle

We used [³H] nitrendipine binding to isolated smooth muscle cells and isometric tension studies of muscle strips to characterize the calcium channels from rabbit proximal and distal colon. At 25°C [³H] nitrendipine binding was rapid, saturable, reversible, specific, and linearly proportional to cell number. The affinity of the ligand for its receptor was similar in proximal and distal colon (K_D 129 ± 21 pM and 124 ± 17 pM, respectively). In the proximal colon there were 68,000 receptors per cell, compared to 58,000 receptors per cell in the distal colon (p > .1). The Hill coefficient for nitrendipine was close to unity, suggesting binding to a single receptor. Although nitrendipine and nifedipine competitively inhibited [³H]nitrendipine binding, verapamil did not alter [³H] nitrendipine binding, suggesting the presence of at least two discrete, noninteracting sites for the binding of drugs that block calcium channels. In studies with muscle strips nitrendipine competitively inhibited isometric tension stimulated by both bethanechol and high extracellular potassium concentration. There were no significant differences in response from proximal and distal colon. These results suggest that calcium antagonist binding characteristics to calcium channels are similar in proximal and distal colon, and do not explain previously observed differences in the function of muscle in these tissues.     

Regional Comparison of Rat Colon Mechanics

The purpose of this study was to examine the force-velocity characteristics of colonie muscle and to determine whether these factors contribute to regional specialization of the colon observed in adult Fischer rats. Four measurements were obtained from circular colon muscle strips: maximum shortening velocity, a reflection of crossbridge cycling rate; extension of the parallel elastic component, a measure of passive muscle properties of relaxed muscle; the series elastic component, a measure of passive muscle properties of contracted muscle; and peak isometric force, which is equal to the product of the number of activated crossbridges and the strength of individual crossbridges. Muscle length (L) was expressed in terms of the length of optimal tension development (L_o). Peak isometric force and maximum shortening velocity were 848.9 ± 114.7 g/cm² and 0.082 ± 0.012 L_o/s for muscle strips from the proximal colon, and 948.0 ± 138.2 g/cm² and 0.083 ± 0.014 L_o/s for muscle strips from the distal colon. Shortening velocity, isometric force, and load extension properties of the parallel elastic component and the series elastic component are similar in proximal and distal rat colon. This suggests that regional specialization is not determined at the myofibril level but is most likely determined by extrinsic regulatory factors at the neural or receptor level.     

5-HT4 receptors located on cholinergic nerves in human colon circular muscle

5-Hydroxytryptamine 4 (5-HT4) receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5-HT4 receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5-HT4 receptor-mediated stimulation of human colon CM contractile activity. 5-HT4 receptor ligands were tested on electrical field stimulation (EFS)-induced contractions of human colonic muscle strips cut in the circular direction (called 'whole tissue' strips). Additionally, after incubation of tissues with [3H]-choline these compounds were tested on EFS-induced release of tritium in whole tissue strips and in 'isolated' CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS-induced contractions of whole tissue CM strips. Prucalopride (0.3 micromol L-1) evoked a heterogenous response on EFS-induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS-induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS-induced tritium and [3H]-acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5-HT4 receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5-HT4 receptors on cholinergic nerves within the CM of human colon.     

Rat Colonic Motor Responses to Inflammatory Mediators In Vitro: A Poor Model for the Human Colon

There is evidence that the rat colon exposed to trinitrobenzenesulfonic acid (TNBS) develops a colitis-like inflammation which may be a model for inflammatory bowel disease (IBD) in humans. The aim of this study was to determine if the pharmacologic responses of the normal rat distal colon to several IBD-associated inflammatory mediators were sufficiently similar to those of the normal human colon for the rat with TNBS-induced colitis to provide an appropriate model for their effects on human colonic motility in IBD. Longitudinal and circular muscle mechanical properties were also investigated. Longitudinal muscle responded with concentration-dependent contractions to histamine, leukotriene D₄, and prostaglandins E₂ and F-₂α, which were mediated by a direct action. In general, circular muscle responses to these mediators were smaller, and in the cases of leukotriene D₄ and prostaglandin F₂α, these were modulated by the concurrent activation of intrinsic inhibitory neurons. The mechanical properties of rat distal colonic longitudinal and circular muscle differed significantly from the equivalent human muscles. In most aspects studied normal rat distal colonic smooth muscles were at variance with previously reported properties of the equivalent human muscles. Thus the rat colon would be inappropriate as a model to study potential inflammatory mediator-induced alterations of colonic motility in IBD.     

A missing sphincteric component of the gastro-oesophageal junction in patients with GORD

Abstract  It was recently shown that the tonic pressure contribution to the high-pressure zone of the oesophago-gastric segment (OGS) contains the contributions from three distinct components, two of which are smooth muscle intrinsic sphincter components, a proximal and a distal component [ J Physiol 2007; 580.3 : 961 ]. The aim of this study was to compare the pressure contributions from the three sphincteric components in normal subjects with those in gastro-oesophageal reflux disease (GORD) patients. A simultaneous endoluminal ultrasound and manometry catheter was pulled through the OGS in 15 healthy volunteers and seven patients with symptomatic GORD, before and after administration of atropine. Pre-atropine (complete muscle tone), postatropine (non-muscarinic muscle tone plus residual muscarinic tone) and subtracted (pure muscarinic muscle tone) pressure contributions to the sphincter were averaged after referencing spatially to the right crural diaphragm and the pull-through start position. In the normal group, the atropine-resistant and atropine-attenuated pressures identified the crural and two smooth muscle sphincteric components respectively. The subtraction pressure curve contained proximal and distal peaks. The proximal component moved with the crural sling between full inspiration and full expiration and the distal component coincided with the gastric sling-clasp fibre muscle complex. The subtraction curve in the GORD patients contained only a single pressure peak that moved with the crural sphincter, while the distal pressure peak of the intrinsic muscle component, which was previously recognized in the normal subjects, was absent. We hypothesize that the distal muscarinic smooth muscle pressure component (gastric sling/clasp muscle fibre component) is defective in GORD patients.     

5-HT receptors on interstitial cells of Cajal, smooth muscle and enteric nerves

Abstract  The majority of the body's serotonin (5-HT) is produced by the gastrointestinal tract. 5-HT has several functions in the gastrointestinal tract. 5-HT is a paracrine signalling molecule released from enterochromaffin cells, a survival and proliferating factor and a neurotransmitter. The actions of 5-HT are transduced by a large family of 5-HT receptors, several of which are expressed on different gastrointestinal cell types including enteric nerves, smooth muscle and interstitial cells of Cajal (ICC). This review will summarize recent advances in understanding the role of 5-HT in regulating function of ICC, and the expression and function of 5-HT receptors on muscle and enteric nerves in human tissue. Rodent ICC express several 5-HT receptors including 5-HT_2B receptors which regulate ICC survival and proliferation. Human smooth muscle and enteric neurons also express several 5-HT receptor subtypes. Expression and function of these receptors is significantly different from small laboratory animals. 5-HT₇ receptor activation causes relaxation of muscle, whereas 5-HT_2B receptors increase muscle activity. The 5-HT₄ receptor appears to mediate both inhibition and activation of smooth muscle involving myogenic as well as neural actions. Despite the abundant expression of 5-HT₃ receptors in the human enteric nervous system no functional correlate has been as yet demonstrated.     

Regulation of smooth muscle excitation and contraction

Abstract  Smooth muscle cells (SMC) make up the muscular portion of the gastrointestinal (GI) tract from the distal oesophagus to the internal anal sphincter. Coordinated contractions of these cells produce the motor patterns of GI motility. Considerable progress was made during the last 20 years to understand the basic mechanisms controlling excitation-contraction (E-C) coupling. The smooth muscle motor is now understood in great molecular detail, and much has been learned about the mechanisms that deliver and recover Ca²⁺ during contractions. The majority of Ca²⁺ that initiates contractions comes from the external solution and is supplied by voltage-dependent Ca²⁺ channels (VDCC). VDCC are regulated largely by the effects of K⁺ and non-selective cation conductances (NSCC) on cell membrane potential and excitability. Ca²⁺ entry is supplemented by release of Ca²⁺ from IP₃ receptor-operated stores and by mechanisms that alter the sensitivity of the contractile apparatus to changes in cytoplasmic Ca²⁺. Molecular studies of the regulation of smooth muscle have been complicated by the plasticity of SMC and difficulties in culturing these cells without dramatic phenotypic changes. Major questions remain to be resolved regarding the details of E-C coupling in human GI smooth muscles. New discoveries regarding molecular expression that give GI smooth muscle their unique properties, the phenotypic changes that occur in SMC in GI motor disorders, tissue engineering approaches to repair or replace defective muscular regions, and molecular manipulations of GI smooth muscles in animals models and in cell culture will be topics for exciting investigations in the future.     

Cyclic Nucleotide-gated Channels in Identified Human Olfactory Receptor Neurons

Patch-clamp recordings revealed the presence of a non-desensitizing cyclic nucleotide-gated channel on human olfactory receptor neurons and a fast-desensitizing non-specific cation channel activated by nucleotides on human supporting cells. Cyclic nucleotide-gated channels on olfactory receptor neurons showed selective channel activation by cAMP (K_1/2= 5 μM) and cGMP (K_1/2= 2 μM), a unitary conductance of ∼20 pS, a reversal potential of single-channel currents close to 0 mV, a linear current-voltage relationship over the range of −80 to 80 mV and a strong extracellular but a weaker intracellular blocking effect of Ca²⁺. The channel activity outlasted the cyclic nucleotide pulses for hundreds of milliseconds when higher agonist concentrations (>50 μM cAMP) were applied. The duration of the response was longer than in cyclic nucleotide-gated channels from other species studied so far. The plateau duration and the decay remained constant for pulses with a length of 50−150 ms, whereas pulses shorter than 50 ms successively reduced the time required by shortening the plateau phase. A larger difference for the K_1/2 values of cAMP (K_1/2= 22 μM) and cGMP (K_1/2= 2.5 μM) were found for a small group (n = 3) of cyclic nucleotide-gated channels, pointing to the selective expression of the a-subunit in a small subgroup of olfactory receptor neurons.     

Oxytocin receptor expressed on the smooth muscle mediates the excitatory effect of oxytocin on gastric motility in rats

Abstract  The aim of this study was to localize oxytocin receptor (OTR) in the stomach and to investigate the effect of OT on gastric motility in rats. Western blot and immunohistochemistry methods were used to localize OTR in stomach. The motility of stomach was recorded in vivo (recording of the intragastric pressure), in vitro (recording of the contraction of muscle strips) and on isolated smooth muscle cells. OTR was expressed on cells of both circular and longitudinal muscle of stomach. Systemic administration of OT induced an early transient decrease and a subsequent increase on intragastric pressure. Devazepide (1 mg kg⁻¹, i.v.), a cholecystokinin-1 (CCK₁) receptor antagonist, completely abolished the transient response but did not influence the subsequent one. OT (10⁻⁹–10⁻⁶ mol L⁻¹) dose-dependently increased the contraction of the muscle strips of gastric body, antrum, and pyloric sphincter, and decreased the average cell length of isolated smooth muscle cells. Tetrodotoxin and atropine did not influence the effect of OT on muscle strips. Pretreatment with atosiban, an OTR antagonist, inhibited the spontaneous contraction of muscle strips and abolished the excitatory effect of OT on the muscle strips and the isolated cells. These results suggest that the OTR is expressed on the smooth muscle of the stomach and mediates excitatory effect of OT on gastric motility.     

Vagal ganglionic and nonadrenergic noncholinergic neurotransmission to the ferret lower oesophageal sphincter

In the present study we aimed to discretely characterise ganglionic and neuroeffector transmission to the ferret lower oesophageal sphincter (LOS) using a novel preparation of LOS muscle with intact vagal innervation in conjunction with isolated LOS muscle strips. In this way we could compare vagally mediated LOS relaxation with that of enteric inhibitory motorneurones which were directly stimulated. Preparations of LOS muscle, with or without attached vagus nerves, were dissected from adult ferrets and maintained under preload in organ baths, where LOS muscle developed spontaneous tone. LOS relaxations in response to vagal stimulation (0.5-5 Hz, 30 V) were recorded, alone and following pretreatment with tetrodotoxin (TTX), hexamethonium (Hex), Hex and atropine and NG-nitro-L-arginine (L-NNA). Direct activation of enteric inhibitory motorneurones was performed via electrical field stimulation (EFS). Vagal stimulation elicited frequency-dependent relaxations of the LOS that were abolished by tetrodotoxin (1 microM) and markedly reduced following L-NNA pretreatment (100 microM), but unaltered following pretreatment with the selective VIP or PACAP receptor antagonists VIP (10-28) or PACAP (6-38), respectively (each at 5 microM). The potent NOS inhibitor S-methyl-L-thiocitrulline (100 microM) inhibited LOS relaxation to the same degree at 5 Hz. Hex alone (500 microM) reduced maximal relaxation by 50%; in combination with atropine (2 microM), relaxation was almost abolished. In isolated LOS muscle strips, neither VIP (10-28) nor PACAP (6-38) altered EFS-induced relaxation. Taken together, these results suggest ganglionic neurotransmission to the ferret LOS occurs mainly through a combination of nicotinic and muscarinic receptors and utilises nitroxidergic enteric inhibitory motorneurones to relax the LOS. Moreover, LOS relaxation due to direct activation of inhibitory motorneurones also utilises primarily nitric oxide and other as yet undefined neurotransmitters. Neither VIP nor PACAP are involved in vagally mediated or direct enteric neuronally stimulated LOS relaxation in the ferret.     

Superior laryngeal nerve stimulation in the cat: effect on oropharyngeal swallowing, oesophageal motility and lower oesophageal sphincter activity

Superior laryngeal nerve (SLN) stimulation can activate the brainstem swallowing mechanism to produce a complete swallowing sequence consisting of oropharyngeal, oesophageal and lower oesophageal sphincter (LOS) components. However, little is known of the effect of SLN stimulation (peripheral-sensory input from the pharynx) on the characteristics of oesophageal motor activity, especially in the smooth muscle portion. The present study examined the effect of varying stimulus train length and frequency on each of the three components of the reflex. Acute studies were performed in urethane anaesthetized cats. Oesophageal motility was monitored using conventional manometric techniques, and oropharyngeal swallowing by the mylohyoid electromyogram. SLN stimulus train length (1–10 sec) and frequency (5–30 Hz) were varied independently. Increased train length or frequency resulted in (1) an increase in oropharyngeal swallowing and incidence of the complete swallowing response, (2) an increase in latency to onset of the oesophageal peristaltic wave, (3) reduction of the amplitude of the evoked peristaltic contraction in the smooth muscle portion, without altering its velocity, (4) increased LOS relaxation, and increased LOS after-contraction. The LOS contraction was abolished by atropine (100 μg kg⁻¹). Therefore, increased SLN stimulation not only results in excitation of the central swallowing program and the oropharyngeal stage of swallowing, but has major effects on the oesophageal and LOS stages of swallowing. Afferent SLN stimuli can impact on the control mechanisms for each stage, to inhibit or excite the stages in different ways.     

Actions of morphine and enkephalins on the internal anal sphincter of the cat: relevance for the physiological role of opiates

The effects of Leu-enkephalin, Met-enkephalin and morphine on the electrical activity of the internal anal sphincter were studied in anesthetized spinalized cats and in vitro on sphincteric muscle strips. All the effects of enkephalins and morphine were antagonized by naloxone (2 mg/kg, i.v. in vivo and 10(-6)M in vitro). In vivo, the enkephalins (0.01 mg/kg i.v.) and morphine (2 mg/kg, i.v.) decreased the amplitude of the excitatory responses evoked in the sphincter by stimulation of the hypogastric nerves. Opiates presumably act on the sympathetic nerve endings by reducing the release of noradrenaline. In vitro, the enkephalins (10(-6)M) and morphine (10(-6)M) had a similar inhibitory effect, indicating that opiates act, at least partly, at intramural level. In vivo, the enkephalins and morphine produced an inhibition of the spontaneous electrical activity of the internal anal sphincter. This inhibition occurs also in vitro; it is thus due to a peripheral effect of opiates acting either directly on the sphincteric smooth muscle cells, or through the nervous structures controlling sphincteric motility. In addition, the distribution of nerves containing enkephalin-like immunoreactivity, using whole mount preparations of cat internal anal sphincter, indicates that this area is supplied with a dense Leu- and Met-enkephalinergic innervation. Met- and Leu-enkephalin-like immunoreactive axons were detected within the circular and longitudinal muscles.     

The antiepileptogenic effect of electrical stimulation at different low frequencies is accompanied with change in adenosine receptors gene expression in rats

Purpose:   Previous studies have shown that the anticonvulsant effects of low-frequency stimulation (LFS) can be affected by activation of adenosine receptors. In the present study, the effect of LFS at different frequencies on kindling rate and adenosine receptors gene expression was investigated.
Methods:   Animals were kindled by perforant path stimulation in a rapid kindling manner. LFS (0.5, 1, and 5 Hz) was applied after termination of each kindling stimulation. Seizure severity was measured according to behavioral and electrophysiologic parameters. At the end of the experiments, adenosine A₁ and A_2A receptor gene expression were measured.
Results:   The inhibitory effect of LFS on kindling acquisition was observed at all frequencies. In addition, the inhibitory action of LFS on enhancement of field excitatory postsynaptic potential slope and population spike amplitude during kindling acquisition was not affected by the LFS frequency. However, the effects of LFS on paired-pulse recordings were greater at frequency of 5 Hz. Application of LFS during kindling acquisition also prevented the kindling induced decrease in the A₁ receptor gene expression and attenuated the level of A_2A receptor gene expression in the dentate gyrus. These effects were also greater at the frequency of 5 Hz.
Discussion:   According to these data, it may be suggested that the antiepileptogenic effects of LFS, developed through inhibition of synaptic transmission in the dentate gyrus, is mediated somehow through preventing the decrease of A₁ receptor and through attenuating the A_2A receptor gene expression. These effects might be dependent on the frequency of LFS.     

5-HT receptor types in the rat ileum longitudinal muscle: focus on 5-HT2 receptors mediating contraction

The 5-hydroxytryptamine (5-HT) receptor(s) that mediate(s) contraction of the rat ileum longitudinal muscle was studied.
5-HT and α-methyl-5-HT equipotently induced contractions, whereas 5-methoxytryptamine and 2-methyl-5-HT (partial agonist) were less potent; this rank order of potency suggests involvement of a 5-HT₂ receptor. Neither tetrodotoxin nor atropine affected the contraction to 5-HT, suggesting a smooth muscle localization of these 5-HT₂ receptors. The presence of either a selective 5-HT_2B (SB 204741), 5-HT₃ (granisetron) or 5-HT₄ (SB 204070) antagonist, slightly affected the contractions to 5-HT. Thus, they were also included in the organ bath solution in all subsequent experiments in order to pharmacologically isolate the main contractile component. Using (if possible) 5-HT_2A receptor-selective concentrations, ketanserin, ritanserin, metergoline, spiperone, mianserin, methiothepin, mesulergine, methysergide and cisapride all inhibited the contractions to 5-HT, causing a depression of the curve to 5-HT (i.e. surmountable antagonism was not observed with any of the above agents). Comparison of the affinities of these compounds for the various 5-HT₂ receptor subtypes revealed that the receptor involved in the contractions to 5-HT most closely resembles the 5-HT_2A receptor. However, cinanserin at a concentration expected to inhibit 5-HT_2A receptor-mediated effects, failed to affect the contractions to 5-HT.
It is thus concluded that on the longitudinal smooth muscle of the rat ileum, at least a part of the contraction to 5-HT is mediated by 5-HT receptors resembling the 5-HT_2A receptor subtype.     

Colonic and Cardiovascular Actions of the Atypical β-Adrenergic Agonist SR 58611A in Rats

Inhibition of colonic myoelectric activity by the new atypical β-adrenergic agonist SR 58611A and its cardiovascular effects were investigated in orally dosed unanesthetized rats. SR 58611A and the reference compound ritodrine caused dose-related reduction of the long spike burst frequency of the proximal colon (respective ED₅₀ values of 0.47 and 3.1 mg/kg); this was prevented by alprenolol but not by the β₁- or β₂-selective adrenergic antagonists CGP 20712A and ICI 118,551. The minimal effective doses of SR 58611A and ritodrine raising heart rate were about 20 and 3 times their respective ED₅₀ values for inhibition of colonie motility. Ritodrine, unlike SR 58611A, caused a dose-dependent increase in heart rate. Blood pressure was not affected by either drug. There was partial tolerance to the intestinal effects of SR 58611A and ritodrine, which fell by about half after 4 days' treatment but no further after 8 days. In the animal model investigated, SR 58611A was less liable than ritodrine to induce cardiovascular side effects. It should thus be of prospective therapeutic interest for intestinal hypermotility disorders.     

The effect of glucocorticoids in the normal cerebral hemisphere of brain tumour patients

Objectives – To study the potential effects of glucocorticoids (GC) in normal white matter (WM) of the contralateral cerebral hemisphere in brain tumour patients in a prospective protocol. Materials and methods – Using MR relaxation time (RT) imaging (T₁ and T₂-maps), 190 different scanning sessions were performed on 42 brain tumour patients before and after initiation of GC-treatment. RT imaging correlates closely with in vivo tissue water content (reported estimation accuracy error <4%). Repetitive studies were performed in order to study changes as a function of time. RTs were measured in the contralateral frontal and occipital white matter (WM). Results – The mean change in T₁ after initiation of GC treatment was 1.61.7% ( P =0.24), and 1.83.8% in T₂. The mean coefficient of variation for the pooled data in all patients was 1.4% for both T₁ and T₂. There were no differences in effect between different histological types of tumours or sex. Conclusion – GC treatment does not influence in vivo cerebral water content expressed as relaxation times of apparently normal WM. The neurological effects in brain tumour patients are normally evident within 24 h, but do not seem to correlate with changes in brain water content. The normal biological variation in RTs (and thereby in vivo tissue water content) in normal WM of brain tumour patients is very small and approaches the expected fluctuations in the MRI measurement technique.     

Influence of Selective α- and β-Adrenoceptor Antagonists on the Control of Motor Activity and Transmural Potential Differences in the Rabbit Ileum in Vitro

Although the sympathetic nervous system influences intestinal motility and intestinal fluid and electrolyte transport, the role of sympathetic nerves in the relationship between the two processes has not been characterized. We investigated the effect of sympathetic nerve stimulation of intestinal function by monitoring concurrently predominantly longitudinal smooth muscle activity and transmural potential difference as an on-line marker of intestinal ion transport. In a segment of rabbit small intestine in vitro, perivascular nerve stimulation inhibits spontaneous phasic motor activity and reduces transmural potential difference, which reflects enhanced absorption of fluids and electrolytes. The aim of this study was to investigate the particular adrenoceptors involved in both the smooth muscle and epithelial responses. Using the selective antagonists for the α₁-(prazonsin), α₂-(idazoxan), β₁-(atenolol), and β₂-adrenoceptors (butoxamine), we demonstrated that the enhanced fluid absorption, as shown by a fall in transmural potential difference, is α-mediated with both α₁-and α₂-adrenoceptors being involved. However, there was considerable variation with regard to the type of α-adrenoceptor subtype exerting the dominant effect. The sympathetically induced loss of spontaneous smooth muscle motor activity was found to be predominantly β₁-mediated, with the remainder of the response involving β₂-adrenoceptors.