Showing papers on "Atropine published in 2019"

DARK Classics in Chemical Neuroscience: Atropine, Scopolamine, and Other Anticholinergic Deliriant Hallucinogens.

Abstract: Anticholinergic drugs based on tropane alkaloids, including atropine, scopolamine, and hyoscyamine, have been used for various medicinal and toxic purposes for millennia. These drugs are competitive antagonists of acetylcholine muscarinic (M-) receptors that potently modulate the central nervous system (CNS). Currently used clinically to treat vomiting, nausea, and bradycardia, as well as alongside other anesthetics to avoid vagal inhibition, these drugs also evoke potent psychotropic effects, including characteristic delirium-like states with hallucinations, altered mood, and cognitive deficits. Given the growing clinical importance of anti-M deliriant hallucinogens, here we discuss their use and abuse, clinical importance, and the growing value in preclinical (experimental) animal models relevant to modeling CNS functions and dysfunctions.

Sudden Heart Rate Reduction Upon Optogenetic Release of Acetylcholine From Cardiac Parasympathetic Neurons in Perfused Hearts.

Abstract: The balance of sympathetic and parasympathetic tone provides exquisite control of heart rate and contractility and has also been shown to modulate coronary flow and inflammation. Understanding how autonomic balance is altered by cardiac disease is an active area of research, and developing new ways to control this balance provides insights into disease therapies. However, achieving acute neuron-specific stimulation of autonomic neurons can be difficult in experiments that measure the acute effects of nerve stimulation on the heart. Conventional electrical and pharmacological approaches can be spatially and temporally non-selective. Cell-specific expression of light-activated channels (channelrhodopsin, ChR2) is a powerful approach that enables control of the timing and distribution of cellular stimulation using light. We present such an optogenetic approach where parasympathetic cardiac neurons are selectively photoactivated at high temporal precision to initiate cholinergic-mediated slowing of heart rate. Mice were crossbred to express ChR2 in peripheral cholinergic neurons using Cre-Lox recombination driven by a choline acetyltransferase (ChAT) promoter. Hearts from adult mice were excised, perfused, and the epicardium was illuminated (peak 460-465 nm) to photoactivate ChR2. In one set of studies, hearts were illuminated using a large-field LED light source. In other studies, a micro LED was placed on the right atrium to selectively illuminate the junction of the superior vena cava (SVC) and right atrium. The ECG was acquired before, during, and after tissue illumination to measure changes in heart rate. Upon illumination, hearts exhibited sudden and dramatic reductions in heart rate with restoration of normal heart rate after cessation of illumination. Delays in atrioventricular conduction were also observed. Heart rate reductions at the highest irradiance levels were similar to heart rate reductions caused by application of bethanechol (10 μM) or acetylcholine (800 μM). Atropine (50 nM) completely blocked the effect of ChR2 photoactivation, confirming cholinergic mediation. Optogenetic activation of intrinsic parasympathetic neurons reduced heart rate in an immediate, dose-dependent fashion, resembling the slowing of sinus rate in response to acetylcholine. Our results demonstrate a new approach for controlling parasympathetic modulation of cardiac function by selectively activating the endogenous release of acetylcholine from intrinsic cardiac cholinergic neurons. Key Message: Optogenetic photoactivation of intrinsic cardiac neurons provides immediate, tissue-specific stimulation with minimal cross-reactivity. Our results demonstrate that selective expression of channelrhodopsin within cardiac cholinergic neurons enables photoactivated release of acetylcholine, thereby instantaneously slowing sinus rate and altering atrioventricular conduction. This provides for in-depth examination of the endogenous interplay between cardiac autonomic neurons and the functional outcomes of downstream post-synaptic receptor activation.

The penetration and distribution of topical atropine in animal ocular tissues

Abstract: PURPOSE To conduct a multi-tissue investigation on the penetration and distribution of topical atropine in myopia treatment, and determine if atropine is detectable in the untreated contralateral eye after uniocular instillation. METHODS Nine mature New Zealand white rabbits were evenly divided into three groups. Each group was killed at 5, 24 and 72 hr, respectively, following uniocular instillation of 0.05 ml of 1% atropine. Tissues were sampled after enucleation: conjunctiva, sclera, cornea, iris, ciliary body, lens, retina, aqueous, and vitreous humors. The assay for atropine was performed using liquid chromatography-mass spectrometry (LC-MS), and molecular tissue distribution was illustrated using matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) via an independent experiment on murine eyes. RESULTS At 5 hr, the highest (mean ± SEM) concentration of atropine was detected in the conjunctiva (19.05 ± 5.57 ng/mg, p < 0.05) with a concentration gradient established anteriorly to posteriorly, as supported by MALDI-IMS. At 24 hr, preferential binding of atropine to posterior ocular tissues occurred, demonstrating a reversal of the initial concentration gradient. Atropine has good ocular bioavailability with concentrations of two magnitudes higher than its binding affinity in most tissues at 3 days. Crossing-over of atropine to the untreated eye occurred within 5 hr post-administration. CONCLUSION Both transcorneal and transconjunctival-scleral routes are key in atropine absorption. Posterior ocular tissues could be important sites of action by atropine in myopic reduction. In uniocular atropine trials, cross-over effects on the placebo eye should be adjusted to enhance results reliability. Combining the use of LC-MS and MALDI-IMS can be a viable approach in the study of the ocular pharmacokinetics of atropine.

Alpha2 -adrenoceptor agonists inhibit form-deprivation myopia in the chick.

Abstract: The putative myopia‐controlling receptor is thought to be muscarinic acetylcholine receptor subtype M4, because mamba toxin‐3 can inhibit form‐deprivation myopia in chicks at a far lower concentrat...

Intrinsic Adaptation of SHR Right Atrium Reduces Heart Rate.

Abstract: Hypertension represents an autonomic dysfunction, characterized by increased sympathetic and decreased parasympathetic cardiovascular tone leading to resting tachycardia. Therefore, studies assessing hypertension-associated changes in isolated cardiac tissues were conducted under electric field stimulation to stimulate the neurons. Herein, we characterize the influence of the autonomic neurotransmitter on the baseline atrial chronotropism of unpaced isolated right atria of normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). Our results revealed a resting bradycardia in tissues from SHR in comparison to NWR. The release of autonomic neurotransmitters, acetylcholine or norepinephrine, still occurs in the electrically unstimulated right atrium, after excision of the sympathetic nerve, which could explain differences in basal heart rate between NWR and SHR. Nicotine and the acetylcholinesterase inhibitor physostigmine reduced the chronotropism of right atria from either NWR or SHR. Conversely, the muscarinic receptor antagonist atropine did not affect the basal chronotropism of tissues from both strains. Furthermore, tyramine increased the chronotropism of NWR and SHR atria indicating availability of the neuronal stocks of noradrenaline. Although the monoamine uptake inhibitor cocaine increased right atrium chronotropism in both strains, the basal heart rate was not affected by the β-adrenoceptor antagonist propranolol. In summary, after acute section of the sympathetic nerve, autonomic neurotransmitters are still released either in resting conditions or upon pharmacological stimulation of right atria from both strains. Nevertheless, autonomic neurotransmission does not affect resting chronotropism, nor is the responsible for reduced basal heart rate of the isolated right atrium of hypertensive rats.

Electro convulsive therapy: Modification of its effect on the autonomic nervous system using anti-cholinergic drugs.

Abstract: The antidepressant efficacy of electroconvulsive therapy (ECT) is correlated to the quality of the seizure as measured by EEG but has also been linked to the magnitude of changes in hemodynamic variables. Muscarinic receptor antagonists are frequently used in the treatment, and are known to affect the hemodynamic response. We hypothesized that atropine and glycopyrrolate alter the hemodynamic and autonomic hormonal response to ECT. In a randomized, cross-over study design 23 patients received either atropine, glycopyrrolate or placebo before ECT. Hemodynamic variable, EEG and EMG, and blood adrenaline, noradrenaline and pancreatic polypeptide was determined. No geriatric patients were included. Hemodynamic changes with ECT can be divided into three phases: Drop in blood pressure and pulse rate in 1st post-stimulus phase was less when using 1 mg atropine. In 2nd post-stimulus phase atropine gave a higher systolic blood pressure. No differences were seen in hormone levels after ECT in the three interventions. A significant longer tonic clonic seizure was seen in the glycopyrrolate group and a tendency of the same was seen with atropine. The study found that the changes in hemodynamic variables induced by ECT can be altered by concomitant administration of muscarinic receptor antagonist.

Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects.

Abstract: The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2 mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.

Targeted disruption of glycogen synthase kinase-3β in cardiomyocytes attenuates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice.

Abstract: Type 1 diabetic Akita mice develop severe cardiac parasympathetic dysfunction that we have previously demonstrated is due at least in part to an abnormality in the response of the end organ to parasympathetic stimulation. Specifically, we had shown that hypoinsulinemia in the diabetic heart results in attenuation of the G-protein coupled inward rectifying K channel (GIRK) which mediates the negative chronotropic response to parasympathetic stimulation due at least in part to decreased expression of the GIRK1 and GIRK4 subunits of the channel. We further demonstrated that the expression of GIRK1 and GIRK4 is under the control of the Sterol Regulatory element Binding Protein (SREBP-1), which is also decreased in response to hypoinsulinemia. Finally, given that hyperactivity of Glycogen Synthase Kinase (GSK)3β, had been demonstrated in the diabetic heart, we demonstrated that treatment of Akita mice with Li+, an inhibitor of GSK3β, increased parasympathetic responsiveness and SREBP-1 levels consistent with the conclusion that GSK3β might regulate IKACh via an effect on SREBP-1. However, inhibitor studies were complicated by lack of specificity for GSK3β. Here we generated an Akita mouse with cardiac specific inducible knockout of GSK3β. Using this mouse, we demonstrate that attenuation of GSK3β expression is associated with an increase in parasympathetic responsiveness measured as an increase in the heart rate response to atropine from 17.3 ± 3.5% (n = 8) prior to 41.2 ± 5.4% (n = 8, P = 0.017), an increase in the duration of carbamylcholine mediated bradycardia from 8.43 ± 1.60 min (n = 7) to 12.71 ± 2.26 min (n = 7, P = 0.028) and an increase in HRV as measured by an increase in the high frequency fraction from 40.78 ± 3.86% to 65.04 ± 5.64 (n = 10, P = 0.005). Furthermore, patch clamp measurements demonstrated a 3-fold increase in acetylcholine stimulated peak IKACh in atrial myocytes from GSK3β deficiency mice compared with control. Finally, western blot analysis of atrial extracts from knockout mice demonstrated increased levels of SREBP-1, GIRK1 and GIRK4 compared with control. Taken together with our prior observations, these data establish a role of increased GSK3β activity in the pathogenesis of parasympathetic dysfunction in type 1 diabetes via the regulation of IKACh and GIRK1/4 expression.

Effect of pregnancy on the cholinergic responses of the bladder: role of acetylcholinesterase.

Abstract: Pregnancy is associated with many functional changes of the urinary bladder. It was reported that most of healthy women complain from urinary symptoms during pregnancy. The parasympathetic system is mainly mediating bladder emptying. The aim of the study is to investigate the cholinergic effect and the role of acetylcholinesterase in the bladder during pregnancy. Sixteen rats were used in the present study as control group (non-pregnant) and pregnant group (18–20 days pregnant). Isolated urinary smooth muscle strips were suspended in organ baths filled with Krebs’ solution for isometric tension recording. Electric field stimulation (EFS), (0.1–40 Hz), of the control and pregnant bladder preparations produced frequency-dependent contractions. Atropine (1 µM) inhibited EFS-induced contractions in the two groups by 65% and 50% respectively indicating the response of cholinergic innervation. Neostigmine significantly enhanced EFS responses, confirming its selectivity for inhibiting acetylcholinesterase which is responsible for termination of acetylcholine. Concentration–response curves for acetylcholine were reduced in pregnant group than control. Concentration–response curves for ATP were increased in pregnant group than control. Neostigmine augmented concentration–response curves for acetylcholine in control and pregnant groups. The effect of neostigmine on acetylcholine contractile responses in pregnancy group was higher than in control. Urinary bladder dysfunction during pregnancy might be due to augmentation of acetylcholinesterase effect. This will lead to the decrease in response to cholinergic stimuli. New pharmaceutical drugs specifically affecting the enzyme in the bladder can help in avoiding the unpleasant urinary symptoms during pregnancy.

Role of Muscarinic M1, M2, and M3 Receptors in the Regulation of Electrical Activity of Myocardial Tissue of Caval Veins during the Early Postnatal Ontogeny.

Abstract: We studied the influence of blockers of muscarinic M1, M2, and M3 receptors on the effect of acetylcholine in the myocardial tissue of caval veins in rats at the early stage of ontogeny. The experiments were performed on isolated preparations of the right superior vena cava working under their own rhythm. Action potentials were recorded using the standard microelectrode technique. Acetylcholine (1 μM) suppressed automatic activity in the superior vena cava myocardium. Preliminary perfusion of the preparation with non-selective blocker atropine (1 μM) completely abolished the effect of acetylcholine, treatment with M2 receptor blocker AQ-RA 741 (1 μM) led to partial suppression of the effect of acetylcholine. Blockers of M1 and M3 receptors pirenzepine (1 μM) and 4DAMP (0.1 μM) did not suppress the effect of acetylcholine. Thus, the effect of acetylcholine is predominantly realized via M2 receptors, but M3 receptors can also partially mediate its effect in the superior vena cava myocardium in rats at the early stages of ontogeny.

P4423Extreme bradycardia in athletes is due to intrinsic changes within the heart

Abstract: Background It is well known that athletes and in particular endurance athletes have lower resting heart rates than non-athletes. This has generally been considered a healthy adaptation. Traditionally this was thought be due to increased vagal tone. Several studies have shown that endurance athletes continue to have lower heart rates in the absence of autonomic influence suggesting bradycardia is due to intrinsic changes within the heart. A subset of endurance athletes have very low heart rates with Tour de France cyclists having described heart rates in the 30s. It is unclear whether in these elite athletes with very low heart rates the profound bradycardia is due to autonomic influence or intrinsic changes within the heart. Aim The aim of this study was to determine if extreme bradycardia in athletes is due to excess vagal tone or more profound intrinsic changes within the heart. Methods We recruited three cohorts for this study: non-athlete controls (NA), endurance athletes with a documented resting heart rate >40 (EA) and endurance athletes with a resting heart rate <40 (BA). All participants underwent baseline testing including ECG, echocardiography and VO2 max testing. All participants came back on a second occasion for treatment with dual autonomic blockade (DAB) to determine intrinsic heart rate in the following manner. After resting supine for five minutes resting heart rate was measured. Participants were then administered 0.04mg/kg of intravenous atropine. After five minutes participants were then administered 0.05mg/kg of intravenous metoprolol. This was repeated every five minutes until there was no further drop in heart rate or 0.2mg/kg had been administered. The resting heart rate at this stage was recorded as the intrinsic heart rate. Parasympathetic blockade was confirmed by lack of response to Valsalva manoeuvre and sympathetic blockade was confirmed by lack of response to metoprolol. VO2 max testing was then performed to determine maximum heart rate. Results 9 NA (7 male), 10 EA (8 male) and 5 BA (4 male) participated in this study. The average age was similar in all groups (NA 32.9y, EA 32.4y, BA 31.4y). The average resting heart rate was 71.7 in the NA group, 48.3 in the EA group and 41.6 in the BA group (p<0.05 for comparisons between all three groups). Following dual autonomic blockade resting heart rate was 86.0 in the NA group, 76.9 in the EA group and 64.4 in the BA group (p<0.05 for comparisons between all three groups). Maximum heart rate under DAB was 140.1 in the NA group, 138.0 in the EA group and 140.4 in the BA group. These differences were not significant. Conclusion In athletes with very low heart rates, bradycardia is due to more profound intrinsic changes within the heart. Acknowledgement/Funding NHMRC Project Grant

In vivo, ex vivo and in vitro evidence for atropine-mediated attenuation of glucagon-like peptide-1 secretion: findings from a systematic review

Abstract: Glucagon-like peptide-1 (GLP-1) is involved in postprandial glucose homeostasis. Secretion of which involves a cholinergic pathway. Anticholinergic agent like atropine could act as a competitive antagonist of acetylcholine at muscarinic receptors. This review explores studies that assess the role of atropine in GLP-1 secretion. We selected published original articles from PubMed, Science Direct, The Cochrane Library, Trip, Google and the reference lists of the selected articles. Reporting was done according to the PRISMA statement. Relevant standard and previously published tools were used to assess the risk of bias of the selected articles. Twelve articles out of 185 search results fulfilled the review criteria. Eight were in vivo studies (six animal and two human studies), three were ex vivo studies and one was an in vitro study. Animal studies had rats, mice, pigs and monkeys as the subjects. Human studies involved healthy men and women. Majority of the studies reported an atropine-mediated attenuation of GLP-1 secretion and postprandial secretion of GLP-1 was mainly affected. However, atropine failed to significantly affect GLP-1 secretion when dipeptidyl peptidase-4 (DPP-4) enzyme was inhibited.

How to Induce Arrhythmias with Atropine

Abstract: Atropine sulfate is the sulfate salt of atropine, which is an alkaloid found in its natural form together with scopolamine and hyoscyamine in the plant Atropa belladonna. The first synthesis of atropine was achieved by Richard Willstatter, a German organic chemist whose studies in the field of alkaloids brought him the 1915 Nobel Prize for Chemistry. Usual doses of atropine (>0.5 mg) abolish various types of vagal reflexmediated bradycardia or asystole and also prevent or abolish the negative chronotropic effect produced by other parasympathomimetic drugs. Atropine also ameliorates the AV conduction when an incomplete block is noted. In some patients with complete heart block, the resultant escape rhythm rate (junctional origin) may be accelerated by atropine.

Allergic reaction to intravenous atropine in a patient with organophosphate poisoning

Abstract: Atropine is a drug of choice for muscarinic effects in organophosphate (OP) poisoning. Allergic reaction to atropine is rare. Here, we report a case of a 17-year-old male who was admitted with clinical manifestations of acute OP poisoning. After intravenous atropine injection, cutaneous signs of hypersensitivity including erythema and urticarial were observed on his body. Atropine injection was stopped, and antihistamines and hydrocortisone were administered. His condition was improved, and he discharged with a good condition after 2 days hospitalization. Adverse allergic reaction to atropine should be in mind when managing OP poisoning cases.

Effect of Muscarinic Cholinergic Receptor Blockade on Heart Activity in Rat Fetuses.

Abstract: Cardiac activity parameters were analyzed in rat fetuses with preserved placental circulation on gestation days 17-20 after administration of muscarinic receptor blocker atropine either directly to the fetuses, or to the females. The obtained results attested to the absence of chronotropic effect from the cholinergic system in rats during the fetal period. At the same time, changes in heart rate variability observed after atropine injection showed that cholinergic receptors are involved into heart rhythm regulation in rat fetuses and that their role increases from the 17th to 20th day of the embryonic period.