Ebselen does not improve oxidative stress and vascular function in patients with diabetes: a randomized, crossover trial.

Oxidative stress is a key driver of vascular dysfunction in diabetes mellitus. Ebselen is a glutathione peroxidase mimetic. A single-site, randomized, double-masked, placebo-controlled, crossover trial was carried out in 26 patients with type 1 or type 2 diabetes to evaluate effects of high-dose ebselen (150 mg po twice daily) administration on oxidative stress and endothelium-dependent vasodilation. Treatment periods were in random order of 4 wk duration, with a 4-wk washout between treatments. Measures of oxidative stress included nitrotyrosine, plasma 8-isoprostanes, and the ratio of reduced to oxidized glutathione. Vascular ultrasound of the brachial artery and plethysmographic measurement of blood flow were used to assess flow-mediated and methacholine-induced endothelium-dependent vasodilation of conduit and resistance vessels, respectively. Ebselen administration did not affect parameters of oxidative stress or conduit artery or forearm arteriolar vascular function compared with placebo treatment. There was no difference in outcome by diabetes type. Ebselen, at the dose and duration evaluated, does not improve the oxidative stress profile, nor does it affect endothelium-dependent vasodilation in patients with diabetes mellitus.

Effect of orally administered cisapride, bethanechol, and erythromycin on the apparent efficiency of colostral IgG absorption in neonatal Holstein-Friesian calves.

OBJECTIVE: To evaluate the effect of orally administered cisapride, bethanechol, and erythromycin on the absorption of colostral IgG in dairy calves. ANIMALS: Twenty-four healthy neonatal Holstein-Friesian calves. PROCEDURES: Calves were randomly assigned to one of the following treatments: 0.9% NaCl solution (2 mL, p.o.; negative control); erythromycin lactobionate (20 mg/kg BW, p.o.; anticipated to be a positive control); cisapride (0.5 mg/kg BW, p.o.); bethanechol chloride (0.5 mg/kg BW, p.o.). Calves were fed 3 L of pooled bovine colostrum containing acetaminophen (50 mg/kg) by suckling and oroesophageal intubation 30 minutes after each treatment was administered. Jugular venous blood samples were obtained periodically after the start of feeding and plasma total IgG, protein, acetaminophen, and glucose concentrations determined. Abomasal emptying rate was assessed by the time to maximal plasma acetaminophen concentration. RESULTS: Oral administration of cisapride facilitated the absorption of colostral IgG and protein. The effect of cisapride on abomasal emptying rate could not be evaluated because cisapride appeared to interfere with acetaminophen metabolism. Based on the total IgG and total protein concentration-time relationships, the beneficial effects of cisapride appeared to occur early after oral administration and were transient. CONCLUSIONS AND CLINICAL IMPORTANCE: Additional studies appear indicated to characterize the effect of cisapride dose on the magnitude and duration of its effect on facilitating the absorption of colostral IgG and protein. Identification of a nonantimicrobial method for increasing abomasal emptying rate, such as cisapride, will potentially provide a practical and effective method for facilitating transfer of passive immunity in colostrum-fed dairy calves.

Parasympathomimetic effect of shilajit accounts for relaxation of rat corpus cavernosum.

Previous studies have reported an enhancement of central cholinergic signal cascade by shilajit. For the present study, it was hypothesized that parasympathomimetic effect of shilajit accounting for relaxation of rat corpus cavernosum may be one of the major mechanisms attributing to its traditional role as an aphrodisiac. To test this hypothesis, the acute peripheral effect of standard acetylcholine (ACh), shilajit, and their combination was evaluated on cardiorespiratory parameters such as mean arterial blood pressure (MABP), heart rate (HR), respiratory rate (RR), and neuromuscular transmission (NMT). Furthermore, in vitro effect of standard ACh, shilajit, and their combination was tested on the rat corpus cavernosum. Six groups were used for the in vivo study (N = 5): Group I (control-saline), Group II (ACh), Group III (Sh), Group IV (Sh followed by ACh), Group V (Atropine followed by ACh), and Group VI (Atropine followed by Sh). The in vitro study included four groups: Group I (control-saline), Group II (ACh), Group III (Sh), and Group IV (Sh followed by ACh). The results of the in vivo study confirmed the peripheral parasympathomimetic effect of shilajit (400 µg/mL). The in vitro results revealed that shilajit (400 and 800 µg/mL) relaxed cavernous strips' concentration dependently and enhanced ACh-mediated relaxations. The peripheral parasympathomimetic effects of shilajit were confirmed by blockade of shilajit-induced relaxations (in vitro) and shilajit-induced lowering of MABP and HR (in vivo) by atropine.

Effects of St John's wort and its active constituents, hypericin and hyperforin, on isolated rat urinary bladder.

OBJECTIVES: To investigate the effect of St John's wort (SJW) and its active constituents hypericin and hyperforin on detrusor smooth muscle contractility and their possible neuroprotective role against ischaemic-like conditions, which could arise during overactive bladder disease. METHODS: In whole bladders, intrinsic nerves underwent electrical field stimulation (EFS). The effect of drugs on the contractile response and its recovery in reperfusion phase (R) was monitored at different concentrations during 1 or 2 h of anoxia-glucopenia (A-G) and the first 30 min of R. The effects of the drugs were also investigated on rat detrusor muscle strips contracted with carbachol, KCl and electrically. KEY FINDINGS: SJW has spasmolytic activity, which increases with increasing concentration and it worsens the damage induced by A-G/R on rat urinary bladder. Hypericin and hyperforin had no effect during ischemic-like conditions but they both exert a dual modulation of rat detrusor strips contraction. At high micromolar concentrations they showed a relaxing effect, but at submicromolar range hypericin increased the plasma membrane depolarisation and hyperforin showed a stimulatory effect on the cholinergic system. CONCLUSIONS: The results of our study showed that SJW and its constituents could modulate urinary bladder contractility and even worsen A-G/R injury.

Role of arginase in impairing relaxation of lung parenchyma of hyperoxia-exposed neonatal rats.

BACKGROUND: Prolonged exposure of immature lungs to hyperoxia contributes to neonatal lung injury and airway hyperreactivity. We have previously demonstrated that neonatal exposure of rat pups to ≥95% O2 impairs airway relaxation due to disruption of nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling. OBJECTIVE: We now hypothesize that these impaired relaxation responses are secondary to hyperoxia-induced upregulation of arginase, which competes with NO synthase for L-arginine. METHODS: Rat pups were exposed to moderate neonatal hyperoxia (50% O2) or room air for 7 days from birth. In additional hyperoxic and room air groups, exogenous L-arginine (300 mg/kg/day i.p.) or arginase inhibitor (Nω-hydroxy-nor-arginine, 30 mg/kg/day i.p.) were administered daily. After 7 days, animals were anesthetized and sacrificed either for preparation of lung parenchymal strips or lung perfusion. RESULTS: In response to electrical field stimulation (EFS), bethanechol-preconstricted lung parenchymal strips from hyperoxic pups exhibited significantly reduced relaxation compared to room air controls. Supplementation of L-arginine or arginase blockade restored hyperoxia-induced impairment of relaxation. Expression of arginase I in airway epithelium was increased in response to hyperoxia but reduced by arginase blockade. Arginase activity was also significantly increased in hyperoxic lungs as compared to room air controls and reduced following arginase blockade. EFS-induced production of NO was decreased in hyperoxia-exposed airway smooth muscle and restored by arginase blockade. CONCLUSION: These data suggest that NO-cGMP signaling is disrupted in neonatal rat pups exposed to even moderate hyperoxia due to increased arginase activity and consequent decreased bioavailability of the substrate L-arginine. We speculate that supplementation of arginine and/or inhibition of arginase may be a useful therapeutic tool to prevent or treat neonatal lung injury.

Spasmogenic and spasmolytic activities of Onosma griffithii Vatke.

Methanolic extract of Onosma griffithii and its fractions were evaluated for possible effects on rabbits' jejunum preparations. Rabbits of either sex (weight 1.5-2.0 kg) were used in experiments. Studies were carried out on rabbits' jejunum preparations. Crude methanolic extract of Onosma griffithii (Meth.OG) was tried in concentrations of 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, 5.0 and 10.0 mg/ml on rabbits' jejunum preparations. Meth.OG was also tried on KCl-induced contractions to explain its possible mode of actions in the presence and absence of atropine (0.03 µM). Fractions of Meth.OG were tried in similar manner. Calcium chloride curves were constructed for Meth.OG treated tissues that were compared with curves constructed for verapamil in same fashion. Preliminary phytochemical screening of the plant was also performed. Meth.OG increased the amplitude of spontaneous activity of rabbits' jejunum preparations at concentrations of 0.1, 0.3 and 1.0 mg/ml. However, spasmolytic effects were observed at higher concentrations 3.0, 5.0 and 10.0 mg/ml. Mean EC(50) values (mg/ml), respectively, in absence and presence of atropine were 7.5 ± 0.25 (6.9-8.4, n=6) and 3.0 ± 0.17 (2.3-3.5, n=6, p<0.05). Mean EC(50) values, respectively, for effects on spontaneous and KCl-induced contractions were 7.5 ± 0.25 (6.9-8.4, n=6) and 7.3 ± 0.35 (6.25-8.2, n=6, p<0.05). n-Hexane, chloroform and ethyl acetate fractions showed their respective EC(50) values (mg/ml) 9.7 ± 0.25 (8.6-10.2, n=6), 4.0 ± 0.2 (3.5-4.6, n=6) and 1.07 ± 0.093 (0.78-1.5, n=6). EC(50) values for calcium chloride curves in presence of 0.3 mg/ml Meth.OG were - 2.27 ± 0.038 (- 2.4 to - 2.10, n=6) vs. control - 2.78 ±0.04 (-2.9 to - 2.6, n=6, p<0.05) Log [Ca(++)]M. Comparing with curves of calcium chloride constructed in presence of 0.1 µM verapamil, the EC(50) (log [Ca(++)] M) values were - 1.82 ± 0.087 (- 2.0 to - 1.65, n=6) vs. control - 2.64 ± 0.089 (- 2.9 to - 2.4, n=6) demonstrated a right shift (p<0.05). Meth.OG tested positive for terpenes, saponins, sterols, flavonoids and carbohydrates. We concluded that the relaxant effect of Meth.OG is exerted through blocking of calcium channels. However, n-butanolic and aqueous fractions produced spasmogenic effects that require further work for isolation of pharmacologically active substances.

Electroacupuncture improves rectal distension-induced delay in solid gastric emptying in dogs.

The aim of this study was to investigate the effects and mechanisms of electroacupuncture (EA) on rectal distension (RD)-induced delay in solid gastric emptying in dogs. Gastric emptying of solids was assessed in 12 dogs chronically implanted with a duodenal cannula by collecting samples at different time points from the cannula and measuring the dried weights of the samples. Bethanechol and atropine were used to qualitatively validate the method. In separate experiments, gastric emptying of solids was measured in a number of sessions: control, RD, RD + sham-EA, RD + EA of 6 mA, RD + EA of 3 mA, and RD + EA + naloxone. The method of gastric emptying by collecting and drying gastric chyme from the duodenal cannula was found to be accurate and reliable. Using the method, we found gastric emptying to be accelerated with bethanechol (70.01 ± 8.10% vs. 82.61 ± 4.15%, P = 0.04, vs. control) and delayed with atropine (4.31 ± 1.57%, P < 0.001, vs. control). RD substantially and significantly delayed gastric emptying. EA, but not sham-EA, attenuated delayed gastric emptying induced by RD (sham-EA: 48.79 ± 9.47% vs. EA: 74.28 ± 5.96%, P < 0.01). The effect was more potent with EA of 6 mA than EA of 3 mA and blocked by naloxone. EA is able to attenuate RD-induced delay in gastric emptying of solids, and this ameliorating effect may be mediated via the opioid pathway. EA may have a therapeutic potential for treating delayed gastric emptying attributed to lower gut distension.

The ACB technique: a biomagentic tool for monitoring gastrointestinal contraction directly from smooth muscle in dogs.

The aim of this paper was to verify whether AC biosusceptometry (ACB) is suitable for monitoring gastrointestinal (GI) contraction directly from smooth muscle in dogs, comparing with electrical recordings simultaneously. All experiments were performed in dogs with magnetic markers implanted under the serosa of the right colon and distal stomach, and their movements were recorded by ACB. Monopolar electrodes were implanted close to the magnetic markers and their electric potentials were recorded by electromyography (EMG). The effects of neostigmine, hyoscine butylbromide and meal on gastric and colonic parameters were studied. The ACB signal from the distal stomach was very similar to EMG; in the colonic recordings, however, within the same low-frequency band, ACB and EMG signals were characterized by simultaneity or a widely changeable frequency profile with time. ACB recordings were capable of demonstrating the changes in gastric and colonic motility determined by pharmacological interventions as well as by feeding. Our results reinforce the importance of evaluating the mechanical and electrical components of motility and show a temporal association between them. ACB and EMG are complementary for studying motility, with special emphasis on the colon. ACB offers an accurate method for monitoring in vivo GI motility.

Hypertensive effects of oral administration of the aqueous extract of Solanum torvum fruits in L-NAME treated rats: evidence from in vivo and in vitro studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Solanum torvum fruits are commonly used in Cameroonian traditional medicine for treatment of arterial hypertension. It has been previously shown that intravenous administration of aqueous extract from dried fruits (AEST) reduced blood pressure. AIM: The present work evaluates acute toxicity and effects of oral administration of AEST in chronic arterial hypertension induced by L-NAME. Effects of AEST were also evaluated on isolated aorta. MATERIALS AND METHODS: AEST (200 mg/kg/day, p.o.) was given solely or concomitantly with L-NAME (40 mg/kg/day, p.o.) for 30 consecutive days. Animal body weight, systolic blood pressure and heart rate were measured before stating the treatment and at the end of each week. Urinary volume and urinary sodium and potassium contents were quantified before and at days 1, 15 and 30 of the treatment. Aorta from treated animals was tested for their sensitivity to noradrenaline and carbachol. Aorta from normal untreated rats was used to evaluate the in vitro vascular effect of AEST. RESULTS: The results showed that AEST did induce neither mortality nor visible signs of toxicity. When given solely or in co-administration with L-NAME, AEST significantly reduced animal's body weight. It amplified the hypertensive and cardiac hypertrophy effect of L-NAME and did not affect these parameters in normotensive animals. AEST increased the sensitivity to noradrenaline in normotensive and significantly reduced it in hypertensive animals. AEST significantly increased urinary volume and sodium excretion in L-NAME treated animals while reducing the sodium excretion in normotensive. In vitro, AEST induced a potent partial endothelium-dependent contraction of aortic ring; contractions that were partially antagonized by prazosin and verapamil and were not relaxed by carbachol. CONCLUSION: These results suggest that oral chronic administration of AEST induced potentiation of arterial hypertension and cardiac hypertrophy in L-NAME treated rats. These effects may result from a reduction in sensitivity to vasorelaxant agents and increase in hypersensitivity to contractile factors. AEST possess potent in vitro vasocontractile activity that may result from activation of both alpha(1)-adrenergic pathway and calcium influx.

Cardio-selective inhibitory effect of the betel nut extract: possible explanation.

Chewing of betel nut, the seed of Areca catechu, is associated with a host of physical and psychological effects while it is also traditionally used in constipation and hypertension. In this study, we report the cardio-selective cholinomimetic activity of the betel nut crude extract (Ac.Cr). Ac.Cr, that tested positive for saponins, tannins, phenols, alkaloids and terpenes, exhibited dose-dependent atropine-sensitive inhibition of isolated guinea-pig atrial contractility with an EC50 value of 0.93 microg/ml (0.57-1.51, 95% CI). In rabbit jejunum, Ac.Cr showed atropine-sensitive spasmogenicity with an EC50 of 7.31 microg/ml (5.41-9.88, 95% CI) showing that it is around 8 times more potent in the cardiac than the intestinal preparation. Both carbachol and physostigmine exhibited acetylcholine-like stimulant activity in jejunum with the latter being more potent in jejunum than in atrial tissues. Activity-directed fractionation of Ac.Cr yielded fractions with similar cholinergic activity in atria and jejunum except the aqueous fraction being 6 times more potent in the atria. Arecoline, the known betel nut compound with cholinergic activity showed similar potency in both tissues while catechin and tannic acid exhibited intestinal spasmolytic effect but were inactive in atria. The results show the cardio-selective inhibitory effect of Ac.Cr which might possibly be due to selective gut-spasmolytic behaviour of catechin and tannic acid thus reducing the cholinomimetic activity of Ac.Cr in the gut though the preferential binding of the constituents of betel nut extract at muscarinic receptor subtypes in heart cannot be ignored.

[The circadian effects of antiglaucomatous drugs]. / Effets nycthéméraux des molécules anti-glaucomateuses.

PURPOSE: To collect data reflecting the current knowledge on the interactions of medical antiglaucomatous therapy and circadian variations. METHOD: Review of the available literature published on this topic in common electronic databases. RESULTS: The IOP-reducing effect of a molecule throughout the day depends on many parameters and still remains poorly investigated. It is well known that beta-blockers have a poor efficacy at night, while prostaglandins prevent nocturnal IOP variations because of their original mechanism. DISCUSSION: The lack of a 24-hour IOP recording device limits our ability to track the effect of antiglaucomatous drugs over 24 hours, an important point because these antiglaucomatous drugs vary in terms of their capacity to reduce IOP over a 24-hour period. CONCLUSION: Assessing the effect of antiglaucomatous therapy on a 24-hour basis remains very difficult. However, in the next few Years, this could become an emerging focus point in the management of glaucoma.

The role of the cholinergic system of the sensorimotor cortex of the rat brain in controlling different types of movement.

The role of the cholinergic system of the sensorimotor cortex of the Wistar rat brain in controlling various types of movements was assessed by studying the effects of microinjections of carbachol and scopolamine into the representation area of the forelimb on the performance of two types of fore-limb food-procuring movements--with and without pressure on an obstacle--as well as on the animals' locomotion. These studies showed that administration of the cholinergic agonist carbachol (0.03-3 microg) leads to slowing of both types of procuring movements and acceleration of locomotor activity in an open field. Injections of the cholinergic antagonist scopolamine (0.3-3 microg) into the same area accelerated procuring movements, while the animals' locomotor activity remained unaltered. These data indicate that the cholinergic system of the sensorimotor cortex has different regulatory influences on movement activity (locomotion) and the performance of learned movements requiring forelimb muscle tone to be maintained for different periods of time (the usual rapid movements used for extracting food from a narrow horizontal tube versus slow movements with additional tactile and tonic components).

Retrospective study of neostigmine for the treatment of acute colonic pseudo-obstruction.

Acute colonic pseudo-obstruction (ACPO) typically develops postoperatively or after severe illness. Studies suggest that pharmacologic manipulation with intravenous (i.v.) neostigmine (NSM) may be an effective and less invasive treatment modality for ACPO with minimal side effects. The purpose of this study was to retrospectively assess the efficacy and incidence of complications of an i.v. NSM bolus in patients with ACPO. Eight patients with ten episodes of ACPO were treated with a bolus dose of NSM. Rapid and effective decompression of the colon was achieved in six episodes after a single dose of NSM at a mean of 22.8 +/- 13.5 minutes. In three episodes decompression occurred after a second dose of NSM at a mean of 44.7 +/- 37.7 minutes. One patient failed NSM treatment but responded to a Cystografin enema. One patient experienced significant bradycardia. NSM is a simple, safe, and effective treatment for ACPO and based on result comparison of this study and previous studies both bolus and slow infusion dosing practices of NSM are effective. The NSM bolus dosing side effect profile has been shown to include significant bradycardia, whereas when NSM was infused over one hour significant bradycardic episodes requiring treatment have not been encountered. We propose that a prospective study evaluating NSM dosing as an i.v. bolus versus an i.v. infusion would be useful in determining whether NSM infusion can be proven safer than bolus dosing for the treatment of ACPO.

Rise in plasma leptin levels after stimulation of hypothalamic cholinoceptive neurons by neostigmine in rats.

To investigate the role of hypothalamic cholinergic neurons in the regulation of plasma leptin levels, we injected neostigmine, a cholinesterase inhibitor, or vehicle alone into the third cerebral ventricle in free moving male Wistar rats and then measured plasma leptin levels. The administration of neostigmine (5 x 10(-9) or 5 x 10(-8) mol) increased plasma leptin levels 3-6 h after stimulation in a dose-dependent manner, while intravenous injection of neostigmine (5 x 10(-8) mol) had no effect. Atropine (5 x 10(-8) mol) concomitantly injected with neostigmine (5 x 10(-8) mol) prevented neostigmine-induced increase in plasma leptin. The expression of leptin messenger ribonucleic acid (mRNA) in epididymal white adipose tissue was significantly increased at 4 and 6 h after neostigmine injection compared with that before the injection. Plasma levels of corticosterone were significantly increased at 30 min after stimulation with neostigmine and this increase was sustained for 6 h after stimulation. Furthermore, bilateral adrenalectomized rats showed no increase in plasma leptin levels after stimulation. In conclusion, stimulation of hypothalamic cholinoceptive neurons increased plasma leptin levels in rats by increasing leptin production in adipocytes. This increase may be due to an increase in glucocorticoids from the adrenal glands. These results suggest that plasma leptin levels can be regulated by hypothalamic cholinoceptive neurons.

Neuromuscular blocking effects of an alkaloidal extract from Inula royleana: contractile and electrical studies on amphibian skeletal muscle in vitro.

The neuromuscular blocking properties of an alkaloidal extract from the root of Inula royleana have been investigated in vitro using a combination of mechanical and electrophysiological approaches. Neurogenic twitches of the frog sartorius were profoundly inhibited by concentrations of the extract > or = 20 micrograms/ml, being reduced to 50% of control amplitude in approximately 90 s at a concentration of > or = 20 micrograms/ml. They were partially reversed by neostigmine (6 micrograms/ml), and by prolonged washout of the extract. Muscle surface action potentials, recorded with extracellular electrodes, also declined rapidly in amplitude in the presence of the extract. Direct muscle stimulation during inhibition by the extract elicited contractions and action potentials whose magnitudes were similar to control responses. Resting membrane potentials, and the intracellular input impedance of the skeletal muscle cells, were not significantly changed by the alkaloids. These results indicate that the extract has significant neuromuscular blocking activity of a partially or slowly reversible nature. The block appears to be exerted at the postjunctional end-plate nicotine receptors, thus offering promise for the identification of novel cholinergic receptor antagonist(s).

Activation of the cholinergic system of the striatum improves attention to conditioned reflex stimuli.

Chronic experiments were performed on 16 dogs using a model of an operant defensive reflex associated with maintenance of a flexion pose to study the effects of uni- and bilateral microinjections of the acetylcholine agonist carbacholine (0.05-0.4 microg) and the choline receptor blocker scopolamine (0.5 microg) into the dorsolateral part of the head of the caudate nucleus and CM-Pf intralaminar thalamic nuclei. These experiments produced data showing that the cholinergic system of the striatum has an important role in realizing the sensory and motor components of the learned movement. Activation of the cholinergic system of the dorsal striatum led to general calming of behavior and inhibition of intersignal limb elevation and the phasic components of the movement, along with ordering and stabilizing of the pose and an increase in the tonic component of the operant response. This suggests that the cholinergic system of the striatum receives an indirect efferent output via motor structures and takes part in preparing the motor apparatus needed for transferring attention to significant stimuli. Microinjections of scopolamine had the opposite effects. Use of differential signals in the same behavioral model, along with special tests for attention, showed that the cholinergic system of the striatum plays an important role in the sensory control of attention. Activation of the striatal cholinergic system led to a significant improvement in responses to differential signals and defensive signals of intensity 2-3 times slower than normal signals, and these changes were accompanied by clearer responses in special tests for attention. Scopolamine microinjections had the opposite effects. Carbacholine microinjections into the intralaminar thalamic nuclei potentiated the effects of cholinergic activation of the striatum. These data indicate that the dorsal striatum can be regarded not only as a parallel level of information processing, but also as a control system for passing this information to various levels of both sensory and motor structures. One important result of this type of control may be that of improving attention to significant stimuli.

The monoterpene alkaloid cantleyine from Strychnos trinervis root and its spasmolytic properties.

Cantleyine, a monoterpene alkaloid isolated from the root bark of Strychnos trinervis, was submitted to a broad spectrum pharmacological screening, in which the principal effect observed was a nonspecific relaxation of isolated smooth muscles. Cantleyine relaxed (IC50 2.1 x 10(-4) M) the guinea-pig trachea, pre-contracted by carbachol and antagonized in a nonspecific manner; carbachol (IC50 2.1 x 10(-4) M) and histamine (IC50 1.4 x 10(-4) M) induced contractions in the guinea-pig ileum; and phenylephrine (IC50 3.8 x 10(-4) M) responses in the rat aorta. Cantleyine antagonized (pD'2, 3.82) cumulative concentration response curves to histamine in the ileum in a noncompetitive, reversible (slope, 4.84) and concentration dependent manner. The tonic contractions induced by histamine and KCl were also inhibited in a concentration-dependent and reversible manner (IC50 7.2 x 10(-5) and 1.8 x 10(-4) M, respectively), suggesting that cantleyine should be acting on voltage-dependent Ca2+ channels. This hypothesis was confirmed by the observation that cantleyine inhibited (pD'2, 3.35), in a concentration dependent manner, the CaCl2 induced contraction in depolarizing medium. These results suggest that cantleyine produces nonspecific spasmolytic effects in smooth muscle and that in guinea-pig ileum this effect is, in part, due to the inhibition of Ca+2 influx through voltage-dependent Ca2+ channels.

Prognostic value of the pilocarpine test to identify patients who may obtain long-term relief from xerostomia by acupuncture treatment.

BACKGROUND: Xerostomia (dry mouth) is a clinical symptom due to a number of factors, including Sjögren syndrome and radiation treatment to the head and neck region. It has been reported that acupuncture increases the salivary flow rate (SFR) in healthy subjects and in patients with xerostomia. A prognostic tool that would allow the care provider to identify patients who may respond to acupuncture treatment will aid in early intervention and thus lead to normalized SFR or relief of symptoms. OBJECTIVES: To determine the prognostic value of a test using pilocarpine chloride to identify those patients with xerostomia who may achieve a long-term increase in SFR in response to acupuncture. DESIGN: Cohort clinical study of 10 months' duration. SETTING: School of dentistry in a large, urban, research institute. PATIENTS: Thirty-two consecutive patients with xerostomia due to radiation treatment (n = 21) or Sjögren syndrome (n=11). INTERVENTION: Salivary flow rates for unstimulated whole saliva and paraffin-chewing stimulated whole saliva were measured before and after the administration of individualized doses of pilocarpine. All patients were then given 24 acupuncture treatments and followed up at 1 and 6 months. The effects of acupuncture treatment on SFR were recorded and response compared with the results of the pilocarpine test. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive value of the pilocarpine test based on changes in SFR, defined as a 20% increase or greater, following acupuncture treatment, compared with response to the pilocarpine test. RESULTS: At the 1-month follow-up, 18 (72%) of 25 patients with a positive pilocarpine test result had defined significant changes in SFR; 4 (67%) of 6 patients with a negative pilocarpine test result had an unchanged SFR. At this point, the sensitivity of the pilocarpine test was 0.90 (95% confidence interval [CI], 0.68-0.99) and the specificity was 0.36 (95% CI, 0.11-0.69). The positive predictive value was 0.72 (95% CI, 0.51-0.88), and the negative predictive value was 0.67 (95% CI, 0.22-0.96). At the 6-month follow-up, 17 (74%) of 23 patients with a positive pilocarpine test result had defined significant changes in SFR; 3 (60%) of 5 patients with a negative pilocarpine test result had an unchanged SFR. At this point, the sensitivity of the pilocarpine test was 0.89 (95% CI, 0.67-0.99), and the specificity was 0.33 (95% CI, 0.07-0.70). The positive predictive value was 0.74 (95% CI, 0.52-0.90), and the negative predictive value was 0.60 (95% CI, 0.15-0.95). CONCLUSION: The pilocarpine test was found to have a high sensitivity and good positive predictive value in identifying patients who may respond to acupuncture for the treatment of xerostomia.

Ionic mechanism of isoflurane's actions on thalamocortical neurons.

We studied the actions of isoflurane (IFL) applied in aqueous solutions on ventrobasal neurons from thalamic brain slices of juvenile rats. By using the whole cell, patch-clamp method with current- and voltage-clamp recording techniques, we found that IFL increased a noninactivating membrane conductance in a concentration-dependent reversible manner. In an eightfold concentration range that extended into equivalent in vivo lethal concentrations, IFL did not produce a maximal effect on the conductance; this is consistent with a nonreceptor-mediated mechanism of action. TTX eliminated action potential activity but did not alter IFL effects. The effects on the membrane potential and current induced by IFL were voltage independent but depended on the external [K+], reversing near the equilibrium potential for K+. External Ba2+ or internal Cs+ applications, which block K+ channels, suppressed the conductance increase caused by IFL. External applications of the Ca2+ channel blockers Co2+ or Cd2+ or internal application of the Ca2+ chelator 1,2-bis-(2-aminophenoxy)-ethane-N,N, N',N'-tetraacetic acid did not prevent the effects of IFL, implying little involvement of Ca2+-dependent K+ currents. A contribution of inwardly rectifying K+ channels to the increased steady-state conductance seemed unlikely because IFL decreased inward rectification. An involvement of ATP-mediated K+ channels also was unlikely because application of the ATP-mediated K+ channel blocker glibenclamide (1-80 microM) did not prevent IFL's actions. In contrast to spiking cells, IFL depolarized presumed glial cells, consistent with an efflux of K+ from thalamocortical neurons. The results imply that a leak K+ channel mediated the IFL-induced increase in postsynaptic membrane conductance in thalamic relay neurons. Thus a single nonreceptor-mediated mechanism of IFL action was responsible for the hyperpolarization and conductance shunt of voltage-dependent Na+ and Ca2+ spikes, as reported in the preceding paper. Although anesthetics influence various neurological systems, an enhanced K+ leak generalized in thalamocortical neurons alone could account for anesthesia in vivo.