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acetylcholine chloride [keywords]
- Individual synaptic vesicles from the electroplaque of Torpedo californica, a classic cholinergic synapse, also contain transporters for glutamate and ATP. [Journal Article]
- Physiol Rep 2014 Jan 1; 2(1):e00206.
The type of neurotransmitter secreted by a neuron is a product of the vesicular transporters present on its synaptic vesicle membranes and the available transmitters in the local cytosolic environment where the synaptic vesicles reside. Synaptic vesicles isolated from electroplaques of the marine ray, Torpedo californica, have served as model vesicles for cholinergic neurotransmission. Many lines of evidence support the idea that in addition to acetylcholine, additional neurotransmitters and/or neuromodulators are also released from cholinergic synapses. We identified the types of vesicular neurotransmitter transporters present at the electroplaque using immunoblot and immunofluoresence techniques with antibodies against the vesicle acetylcholine transporter (VAChT), the vesicular glutamate transporters (VGLUT1, 2, and 3), and the vesicular nucleotide transporter (VNUT). We found that VAChT, VNUT, VGLUT 1 and 2, but not 3 were present by immunoblot, and confirmed that the antibodies were specific to proteins of the axons and terminals of the electroplaque. We used a single-vesicle imaging technique to determine whether these neurotransmitter transporters were present on the same or different populations of synaptic vesicles. We found that greater than 85% of vesicles that labeled for VAChT colabeled with VGLUT1 or VGLUT2, and approximately 70% colabeled with VNUT. Based upon confidence intervals, at least 52% of cholinergic vesicles isolated are likely to contain all four transporters. The presence of multiple types of neurotransmitter transporters - and potentially neurotransmitters - in individual synaptic vesicles raises fundamental questions about the role of cotransmitter release and neurotransmitter synergy at cholinergic synapses.
- Characterization of blood pressure and endothelial function in TRPV4-deficient mice with l-NAME- and angiotensin II-induced hypertension. [Journal Article]
- Physiol Rep 2014 Jan 1; 2(1):e00199.
Transient receptor potential vanilloid type 4 (TRPV4) is an endothelial Ca(2+) entry channel contributing to endothelium-mediated dilation in conduit and resistance arteries. We investigated the role of TRPV4 in the regulation of blood pressure and endothelial function under hypertensive conditions. TRPV4-deficient (TRPV4(-/-)) and wild-type (WT) control mice were given l-NAME (0.5 g/L) in drinking water for 7 days or subcutaneously infused with angiotensin (Ang) II (600 ng/kg per minute) for 14 days, and blood pressure measured by radiotelemetry. TRPV4(-/-) mice had a lower baseline mean arterial pressure (MAP) (12-h daytime MAP, 94 ± 2 vs. 99 ± 2 mmHg in WT controls). l-NAME treatment induced a slightly greater increase in MAP in TRPV4(-/-) mice (day 7, 13 ± 4%) compared to WT controls (6 ± 2%), but Ang II-induced increases in MAP were similar in TRPV4(-/-) and WT mice (day 14, 53 ± 6% and 37 ± 11%, respectively, P < 0.05). Chronic infusion of WT mice with Ang II reduced both acetylcholine (ACh)-induced dilation (dilation to 10(-5) mol/L ACh, 71 ± 5% vs. 92 ± 2% of controls) and the TRPV4 agonist GSK1016790A-induced dilation of small mesenteric arteries (10(-8) mol/L GSK1016790A, 14 ± 5% vs. 77 ± 7% of controls). However, Ang II treatment did not affect ACh dilation in TRPV4(-/-) mice. Mechanistically, Ang II did not significantly alter either TRPV4 total protein expression in mesenteric arteries or TRPV4 agonist-induced Ca(2+) response in mesenteric endothelial cells in situ. These results suggest that TRPV4 channels play a minor role in blood pressure regulation in l-NAME- but not Ang II-induced hypertension, but may be importantly involved in Ang II-induced endothelial dysfunction.
- Evidence for a prosurvival role of alpha-7 nicotinic acetylcholine receptor in alternatively (M2)-activated macrophages. [Journal Article]
- Physiol Rep 2013 Dec 1; 1(7):e00189.
Recent observations in endothelial cells and macrophages indicate that nicotinic acetylcholine receptors (nAChRs) are potential novel players in mechanisms linked to atherogenesis. In macrophages, α7nAChR mediates anti-inflammatory actions and contributes to regulation of cholesterol flux and phagocytosis. Considering that macrophage apoptosis is a key process throughout all stages of atherosclerotic lesion development, in the present study, we examined for the first time the impact of α7nAChR expression and function in macrophage survival and apoptosis using in vitro polarized (M1 and M2) bone marrow-derived macrophages (BMDMs) from wild-type and α7nAChR knockout mice. Our findings show that stimulation of α7nAChR results in activation of the STAT3 prosurvival pathway and protection of macrophages from endoplasmic reticulum (ER) stress-induced apoptosis. These actions are rather selective for M2 BMDMs and are associated to activation of the JAK2/STAT3 axis. Remarkably, these effects are completely lost in M2 macrophages lacking α7nAChR.
- Novel features on the regulation by mitochondria of calcium and secretion transients in chromaffin cells challenged with acetylcholine at 37°C. [Journal Article]
- Physiol Rep 2013 Dec 1; 1(7):e00182.
From experiments performed at room temperature, we know that the buffering of Ca(2+) by mitochondria contributes to the shaping of the bulk cytosolic calcium transient ([Ca(2+)]c) and secretion transients of chromaffin cells stimulated with depolarizing pulses. We also know that the mitochondrial Ca(2+) transporters and the release of catecholamine are faster at 37°C with respect to room temperature. Therefore, we planned this investigation to gain further insight into the contribution of mitochondrial Ca(2+) buffering to the shaping of [Ca(2+)]c and catecholamine release transients, using some novel experimental conditions that have not been yet explored namely: (1) perifusion of bovine chromaffin cells (BCCs) with saline at 37°C and their repeated challenging with the physiological neurotransmitter acetylcholine (ACh); (2) separate blockade of mitochondrial Ca(2+) uniporter (mCUP) with Ru360 or the mitochondrial Na(+)/Ca(2+) exchanger (mNCX) with CGP37157; (3) full blockade of the mitochondrial Ca(2+) cycling (mCC) by the simultaneous inhibition of the mCUP and the mNCX. Ru360 caused a pronounced delay of [Ca(2+)]c clearance and augmented secretion. In contrast, CGP37157 only caused a tiny delay of [Ca(2+)]c clearance and a mild decrease in secretion. The mCC resulting in continued Ca(2+) uptake and its release back into the cytosol was interrupted by combined Ru360 + CGP37157 (Ru/CGP), the protonophore carbonyl cyanide-p-trifluoromethoxyphenylhydrazone, or combined oligomycin + rotenone (O/R); these three treatments caused a mild but sustained elevation of basal [Ca(2+)]c that, however, was not accompanied by a parallel increase in basal secretion. Nevertheless, all treatments caused a pronounced augmentation of ACh-induced secretion, with minor changes of the ACh-induced [Ca(2+)]c transients. Combined Ru/CGP did not alter the resting membrane potential in current-clamped cells. Additionally, Ru/CGP did not increase basal [Ca(2+)]c near subplasmalemmal sites and caused a mild decrease in the size of the readily releasable vesicle pool. Our results provide new functional features in support of the view that in BCCs there are two subpopulations of mitochondria, M1 underneath the plasmalemma nearby exocytotic sites and M2 at the core cell nearby vesicle transport sites. While M1 serves to shape the ACh-elicited exocytotic response through its efficient Ca(2+) removal by the mCUP, M2 shapes the lower [Ca(2+)]c elevations required for new vesicle supply to the exocytotic machinery, from the large reserve vesicle pool at the cell core. The mCUP of the M1 pool seems to play a more prominent role in controlling the ACh responses, in comparison with the mNCX.
- Pharmacology of the lower urinary tract. [Journal Article]
- Indian J Urol 2014 Apr; 30(2):181-8.
Pharmacology of the lower urinary tract provides the basis for medical treatment of lower urinary tract symptoms (LUTS). Therapy of LUTS addresses obstructive symptoms (frequently explained by increased prostate smooth muscle tone and prostate enlargement) in patients with benign prostate hyperplasia (BPH) and storage symptoms in patients with overactive bladder (OAB). Targets for medical treatment include G protein-coupled receptors (α1-adrenoceptors, muscarinic acetylcholine receptors, β3-adrenoceptors) or intracellular enzymes (5α-reductase; phosphodiesterase-5, PDE5). Established therapies of obstructive symptoms aim to induce prostate smooth muscle relaxation by α1-blockers or PDE5 inhibitors, or to reduce prostate growth and volume with 5α-reductase inhibitors. Available options for treatment of OAB comprise anitmuscarinics, β3-adrenoceptor agonists, and botulinum toxin A, which improve storage symptoms by inhibition of bladder smooth muscle contraction. With the recent approval of β3-antagonists, PDE inhibitors, and silodosin for therapy of LUTS, progress from basic research of lower urinary tract pharmacology was translated into new clinical applications. Further targets are in preclinical stages of examination, including modulators of the endocannabinoid system and transient receptor potential (TRP) channels.
- Tomosyn-2 is required for normal motor performance in mice and sustains neurotransmission at motor endplates. [JOURNAL ARTICLE]
- Brain Struct Funct 2014 Apr 18.
Tomosyn-1 (STXBP5) is a soluble NSF attachment protein receptor complex-binding protein that inhibits vesicle fusion, but the role of tomosyn-2 (STXBP5L) in the mammalian nervous system is still unclear. Here we generated tomosyn-2 null (Tom2(KO/KO)) mice, which showed impaired motor performance. This was accompanied by synaptic changes at the neuromuscular junction, including enhanced spontaneous acetylcholine release frequency and faster depression of muscle motor endplate potentials during repetitive stimulation. The postsynaptic geometric arrangement and function of acetylcholine receptors were normal. We conclude that tomosyn-2 supports motor performance by regulation of transmitter release willingness to sustain synaptic strength during high-frequency transmission, which makes this gene a candidate for involvement in neuromuscular disorders.
- [Resected thymic hyperplasia with myasthenia gravis and lambert-eaton myasthenic syndrome]. [English Abstract, Journal Article]
- Kyobu Geka 2014 Mar; 67(3):194-7.
A 61-year-old male who noticed muscular weakness of his extremities, diplopia and slur his words was found to have a thymic tumor on computed tomography. The immunological examination showed incremental of anti Acetylcholine receptor antibody titer and anti P/Q-type voltage-gated calcium channels antibody titer. Electromyography showed decremental response to low frequency stimulations, andincremental response to high frequency stimulations. So he was diagnosed with thymic tumor combined with myasthenia gravis and Lambert-Eaton myasthenic syndrome. He treated with extended thymomectomy resulting in the improvement of his neurological symptoms. Five years after operation, the patient is well without any malignant diseases.
- Remodeling of aorta extracellular matrix as a result of transient high oxygen exposure in newborn rats: implication for arterial rigidity and hypertension risk. [Journal Article]
- PLoS One 2014; 9(4):e92287.
Neonatal high-oxygen exposure leads to elevated blood pressure, microvascular rarefaction, vascular dysfunction and arterial (aorta) rigidity in adult rats. Whether structural changes are present in the matrix of aorta wall is unknown. Considering that elastin synthesis peaks in late fetal life in humans, and early postnatal life in rodents, we postulated that transient neonatal high-oxygen exposure can trigger premature vascular remodelling. Sprague Dawley rat pups were exposed from days 3 to 10 after birth to 80% oxygen (vs. room air control) and were studied at 4 weeks. Blood pressure and vasomotor response of the aorta to angiotensin II and to the acetylcholine analogue carbachol were not different between groups. Vascular superoxide anion production was similar between groups. There was no difference between groups in aortic cross sectional area, smooth muscle cell number or media/lumen ratio. In oxygen-exposed rats, aorta elastin/collagen content ratio was significantly decreased, the expression of elastinolytic cathepsin S was increased whereas collagenolytic cathepsin K was decreased. By immunofluorescence we observed an increase in MMP-2 and TIMP-1 staining in aortas of oxygen-exposed rats whereas TIMP-2 staining was reduced, indicating a shift in the balance towards degradation of the extra-cellular matrix and increased deposition of collagen. There was no significant difference in MMP-2 activity between groups as determined by gelatin zymography. Overall, these findings indicate that transient neonatal high oxygen exposure leads to vascular wall alterations (decreased elastin/collagen ratio and a shift in the balance towards increased deposition of collagen) which are associated with increased rigidity. Importantly, these changes are present prior to the elevation of blood pressure and vascular dysfunction in this model, and may therefore be contributory.
- Protective effects of bajijiasu in a rat model of Aβ25-35-induced neurotoxicity. [JOURNAL ARTICLE]
- J Ethnopharmacol 2014 Apr 14.
Neurodegenerative diseases (NDs) caused by neurons and/or myelin loss lead to devastating effects on patients' lives. Although the causes of such complex diseases have not yet been fully elucidated, oxidative stress, mitochondrial and energy metabolism dysfunction, excitotoxicity, inflammation, and apoptosis have been recognized as influential factors. Current therapies that were designed to address only a single target are unable to mitigate or prevent disease progression, and disease-modifying drugs are desperately needed, and Chinese herbs will be a good choice for screening the potential drugs. Previous studies have shown that bajijiasu, a dimeric fructose isolated from Morinda officinalis radix which was used frequently as a tonifying and replenishing natural herb medicine in traditional Chinese medicine clinic practice, can prevent ischemia-induced neuronal damage or death.In order to investigate whether bajijiasu protects against beta-amyloid (Aβ25-35)-induced neurotoxicity in rats and explore the underlying mechanisms of bajijiasu in vivo, we prepared an Alzheimer's disease (AD) model by injecting Aβ25-35 into the bilateral CA1 region of rat hippocampus and treated a subset with oral bajijiasu. We observed the effects on learning and memory, antioxidant levels, energy metabolism, neurotransmitter levels, and neuronal apoptosis.Bajijiasu ameliorated Aβ-induced learning and memory dysfunction, enhanced antioxidative activity and energy metabolism, and attenuated cholinergic system damage. Our findings suggest that bajijiasu can enhance antioxidant capacity and prevent free radical damage. It can also enhance energy metabolism and monoamine neurotransmitter levels and inhibit neuronal apoptosis.The results provide a scientific foundation for the use of Morinda officinalis and its constituents in the treatment of various AD. Future studies will assess the multi-target activity of the drug for the treatment of AD.
- [The selective dilatation effects of iptakalim on basilar and pulmonary arterioles in high-altitude hypoxic rats]. [English Abstract, Journal Article]
- Zhongguo Ying Yong Sheng Li Xue Za Zhi 2014 Jan; 30(1):1-3.
To study the selective dilatation effects of iptakalim (Ipt) on basilar and pulmonary arterioles, and endothelial cell function of these arterioles in hypoxic rats.SD male rats were divided into 2 groups:control and hypoxic group fed in normobaric hypoxic environment (O2 7.8%, 8 h). Arteriole rings about (204 + 5) pm were isolated and the tension of hypoxic arterioles pre-contracted by 6 nmol/L endothelin-1 (ET-1) was observed with wire myograph system model (DMT 610 m). The relaxing response of hypoxic arterioles induced by different concentration of Ipt were detected and endothelial activity was also tested by acetylcholine.10(5) mol/L acetylcholine (ACh)-mediated vasodilatation of basilar and pulmonary arterioles was greatly reduced in the hypoxic group than those in control group (P < 0.05). Compared with normal group, a novel ATP-sensitive potassium channel opener Ipt at the concentration ranging from 10(-11) mol/L to 10(3) mol/L, caused stronger dose dependent vasodilatation on hypoxic pulmonary arterioles, and there was no significant difference between control and hypoxic basilar arterioles.The endothelial function of basilar and pulmonary arterioles was damaged under hypoxic state, and Ipt selectively increased dilatation effects on hypoxic pulmonary arterioles, but not on hypoxic basilar arterioles which could improve high altitude pulmonary edema pathological state and be the novel drug in the treatment of pulmonary hypertension.