Rat ileum consists of longitudinal and circular smooth muscle. The rat ileal smooth muscles express five isoforms of muscarinic acetylcholine receptor MAchR (M1-M5)(Yuan et al., 2011), and seven classes of 5-hydroxytryptamine (5-HT, serotonin) receptors (5-HT1-5-HT7)(Briejer et al., 1997). These receptors are major drug targets and belong to the family of G protein-coupled receptor (GPCR) consisting of seven transmembrane spanning domains (Hannon & Hoyer, 2008; Yuan et al., 2011). Both MAchR and 5-HT receptors are essential in the regulations of smooth muscle contraction in gastrointestinal tracts (Yuan et al., 2011). M2 receptors are more abundantly found in the ileal smooth muscle compared to M3 receptor (Tanahashi et al., 2013). Both M2 and M3 …show more content…
receptors are responsible for contractile activity with M3 receptors primarily contributing to muscle contractions (Yuan et al., 2011; Tanahashi et al., 2013). M3 receptor evokes a direct contractile response through mobilization of Ca2+ , whereas the contractile effect of M2 receptor is conditional as it depends on Ca2+ mobilization by another receptor such as the M3 receptor (Ehlert, 2003). Rat ileum contracts in response to exogenously administered agonist acetylcholine (Ach). Ach interacts with structurally specific M3 receptor coupled to heterotrimeric Gq proteins, activating enzyme phospholipase C (PLC) by altering its shape and activity, followed by the production of second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) via phosphatidylinositol (PI) hydrolysis (Ehlert, 2003). DAG then activates protein kinase C (PKC) which goes on phosphorylating various proteins while IP3 binds to IP3-gated calcium channels in the sacroplasmic reticulum, causing an increase in cytosolic Ca2+ level (Unno et al., 2005). Binding of free Ca2+ to calmodulin increases concentration of Ca2+/calmodulin, activating myosin light chain kinase (MLCK) which is essential to phosphorylate myosin light chain (MLC)(Stull et al., 1993). This in turn leads to the cross-bridge formation between actin and myosin, thus eliciting maximal muscle contraction in rat ileum (Stull et al., 1993). Besides, M2 receptor triggers contraction indirectly by opening cationic channels when bound by Ach, resulting in an influx of calcium ions into the cell, in fact, this mechanism is greatly modulated by M3 receptor (Unno et al., 2005). The mechanism of action of agonist 5-HT on longitudinal muscles of rat ileum is the same as that of Ach described previously. 5-HT binds to 5-HT2A serotonergic receptors coupled to Gq/G11 subunit, activating enzyme PLC, mediating the IP3/PKC/Ca2+ pathway and therefore triggering smooth muscle contraction (Briejer et al., 1997; Hannon & Hoyer, 2008). However, the effect of agonists on contractile activity is reduced or inhibited when antagonists are administered.
Atropine is a non-selective muscarinic cholinergic antagonist and it functions by directly blocking the M3 receptor (Bhattacharjee et al., 2013). This is an example of pharmacological antagonism whereby atropine competitively inhibits Ach, antagonizing the action of Ach at postganglionic muscarinic sites (Bhattacharjee et al., 2013). The inhibition effect of atropine is concentration-dependent (Wali et al., 1987). In high concentrations, atropine reduces Ach-induced contractions by blocking ion channels present at the postsynaptic membrane of the smooth muscle cells (Wali et al., 1987).
Another antagonist, adrenaline, promotes longitudinal smooth muscle relaxation by interacting with B2-adrenergic receptor coupled to Gs protein (Kosterlitz et al., 1970). This is known as the physiological antagonism. Consequently, the binding of adrenaline depresses the Ach-induced contractions in the muscle (Kosterlitz et al., 1970) besides activating enzyme adenylyl cyclase which then leads to the production of cyclic adenosine monophosphate (cAMP), thus decreasing motility in smooth
muscles. Apart from that, metergoline is a potent and selective 5-HT antagonist (Sastry & Phillis, 1977). Metergoline directly blocks the access of agonist 5-HT to the 5-HT2A receptor-binding site and reduces agonist-receptor complexes formed (Briejer et al., 1997). Metergoline uses the same mechanism as atropine but instead, it binds irreversibly to the receptor (Briejer et al., 1997). In conclusion, one of the aims of this experiment is to investigate the effect of agonists Ach and 5-HT on the contractile activity of rat ileum. A concentration-response curve is plotted for each agonist and the EC50 value is then determined from the curves. The second aim is to investigate the effect of Ach and 5-HT on rat ileal smooth muscle contraction in the presence of different antagonists (atropine, adrenaline and metergoline) at fixed concentrations. The findings from this experiment are useful in determining the potential drugs to treat gastrointestinal disorders by regulating the contraction of gastrointestinal smooth muscles (Tanahashi et al., 2013).
In the beginning phases of muscle contraction, a “cocked” motor neuron in the spinal cord is activated to form a neuromuscular junction with each muscle fiber when it begins branching out to each cell. An action potential is passed down the nerve, releasing calcium, which simultaneously stimulates the release of acetylcholine onto the sarcolemma. As long as calcium and ATP are present, the contraction will continue. Acetylcholine then initiates the resting potential’s change under the motor end plate, stimulates the action potential, and passes along both directions on the surface of the muscle fiber. Sodium ions rush into the cell through the open channels to depolarize the sarcolemma. The depolarization spreads. The potassium channels open while the sodium channels close off, which repolarizes the entire cell. The action potential is dispersed throughout the cell through the transverse tubule, causing the sarcoplasmic reticulum to release
Nerve stimulation was induced for every fifteen seconds at an increment frequency of 0.5 pps (parts per seconds), 1.0 pps, 2.0 pps, 4.0 pps, 8.0 pps, 15 pps, and 25 pps. Every increment trial had a thirty-seconds waiting period. To witness the effects of tubocurare on muscle activity, the baseline was maintained between 20-30 grams and a control was established by turning the stimulator on repeat for 60-120 seconds. Then 0.25 ml of tubocurare was infused into the gastrocnemius muscle. The data was recorded for ten minutes.
...s to interfere with bonding to the receptors. The final possibility uses CNP, which downregulates the activation in MAP kinase pathways in the chondrocytes (4).
Muscle fatigue is a decline in ability of a muscle to generate force within any part of the body. Muscular fatigue is a particular response when it comes to an untrained athlete that is starting an intense workout program, and the muscles of the body is not able to respond in an orderly manner as it would respond to an elite athlete. This paper will focus and provide general information about recent studies on peripheral fatigue. Peripheral fatigue is one of the sites for possible fatigue and its where neural, mechanical, or energetic events can hamper tension development. Neural fatigue is a factor of peripheral fatigue, which occurs when the nerves are unable to generate a signal and this reduces the ability of the muscle fiber to contract which is considered to be metabolic fatigue. Neural factors deals with the movement of action potential going through a process to produce a muscle contraction and when this process does not go through the proper steps then fatigue set in because the muscles will not be able to contract. Neural fatigue has two main factors which is, a shortage of...
Myasthenia Gravis is an autoimmune disease in which the lymphocytes in the blood produce antibodies that destroy muscle-cell sites for the reception of acetylcholine molecules. Normally, acetylcholine is used in signal transmission between nerves and muscles, its goal is to provide muscle contractions.
Adenosine is a natural chemical found in the body which binds to respective adenosine receptors in the sinoatrial node and slows down the activity of the nerve cells. Caffeine also binds to these receptors which results in the activity of these nerve cells to increase.
Irritable Bowel Syndrome (IBS) is a gastrointestinal syndrome characterized by chronic pain and irregular bowl movement with the absence of organ cause. IBS could be diarrhea-predominate or constipation-predominate. One of the pathophysiology that thought to cause IBS diarrhea-predominate (IBS-D) is a high level of serotonin especially after the meals. There are two type of serotonin that involve in the gastrointestinal system, type 3 (HT3) and type 4 (HT4). The purpose of this study is to evaluate the efficacy of ondansetron, which is a selective 5-HT3-receptor antagonist that have been used as antiemitc agent, in the treatment IBS-D.
Acetylcholine (Ach) is a major transmitter found in the autonomic ganglia that allows neurons to communicate for sensory input and muscle control. Muscarinic receptors are vital in the control of the central nervous system (CNS) and also parasympathetic control of the heart, lungs, and gastrointestinal processes. By blocking the action of these receptors, a result is possible impaired central and peripheral nervous system functioning. Inhibiting this function could also cause tachycardia, which can lead to myocardial infarction (heart attack) or angina (chest pain). Scopolamine is also used as a pupil dilator, in pain management, and to treat symptoms associated with chemotherapy.... ...
For many years, the mechanism of caffeine was not yet clear. However, it was thought that the mechanism involves the re...
Muscle contraction is a long process. It goes through many different steps. First, an electrical signal, action potential, travels down a nerve cell, causing it to release a chemical message, known as neurotransmitter,into a small gap between the nerve cell and muscle cell. This gap is called the synapse.The chemical message, neurotransmitter, crosses the gap, and attaches to a protein called a receptor on the muscle-cell membrane and causes an electrical signal, action potential, in the muscle cell.The chemical signal, action potential, spreads quickly along the muscle cel...
Norepinephrine is the neurotransmitter released by sympathetic nerves (e.g., those innervating the heart and blood vessels) and, within the brain, those of the locus coe...
6. McFadzean I and Gibson A (2002) “The developing relationship between receptor-operated and store-operated calcium channels in smooth muscle”. British Journal of Pharmacology 135: 1-13. Online, available at http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0704468/pdf -Accessed 23/11/2013.
The second aspect of this presentation was the 5-HT Receptor Antagonist. These antagonists are capable of decreasing the effect of NPY levels within the body. One antagonist, in particular, was shown to have a great effect on NPY effect, known as DOI. It was found that DOI blocks NYP responses inside the brain. One specific part of DOI was signaled out as being responsible for the blockage of NPY, known as 2A. Even though the DOI is able to decrease the sense of hunger, it is not used in humans because it causes very bad after effects, especially great nausea.
Gastrin hormone has a role in controlling gastric secretion. Gastrin hormone functions by binding on the secretory cells ...
Exercise may serve as an effective tranquilizer. Studies in adults indicate that 30 min of aerobic exercise reduces muscle tension by as much as does a dose of 400 mg o...