Released acetylcholine

The Class I agents decrease excitability, slow conduction velocity, inhibit diastoHc depolarization (decrease automaticity), and prolong the refractory period of cardiac tissues (1,2). These agents have anticholinergic effects that may contribute to the observed electrophysiologic effects. Heart rates may become faster by increasing phase 4 diastoHc depolarization in SA and AV nodal cells. This results from inhibition of the action of vagaHy released acetylcholine [S1-84-3] which, allows sympathetically released norepinephrine [51-41-2] (NE) to act on these stmctures (1,2). 

The two most common neurotransmitters released by neurons of the ANS are acetylcholine (Ach) and norepinephrine (NE). Several distinguishing features of these neurotransmitters are summarized in Table 9.3. Nerve fibers that release acetylcholine are referred to as cholinergic fibers and include all preganglionic fibers of the ANS — sympathetic and parasympathetic systems all postganglionic fibers of the parasympathetic system and sympathetic postganglionic... 

Figure 9.2 Autonomic nerve pathways. All preganglionic neurons release acetylcholine (Ach), which binds to nicotinic receptors (N) on the postganglionic neurons. All postganglionic neurons in the parasympathetic system and some sympathetic postganglionic neurons innervating sweat glands release Ach that binds to muscarinic (M) receptors on the cells of the effector tissue. The remaining postganglionic neurons of the sympathetic system release norepinephrine (NE), which binds to alpha (a) or beta (P) receptors on cells of the effector tissue. The cells of the adrenal medulla, which are modified postganglionic neurons in the sympathetic system, release epinephrine (EPI) and NE into the circulation.

Neurotransmission in autonomic ganglia is more complex than depolarization mediated by a single transmitter 190 Muscarinic receptors are widely distributed at postsynaptic parasympathetic effector sites 190 Stimulation of the motoneuron releases acetylcholine onto the muscle endplate and results in contraction of the muscle fiber 191 Competitive blocking agents cause muscle paralysis by preventing access of acetylcholine to its binding site on the receptor 191... 

Stimulation of the motoneuron releases acetylcholine onto the muscle endplate and results in contraction of the muscle fiber. Contraction and associated electrical events can be produced by intra-arterial injection of ACh close to the muscle. Since skeletal muscle does not possess inherent myogenic tone, the tone of apparently resting muscle is maintained by spontaneous and intermittent release of ACh. The consequences of spontaneous release at the motor endplate of skeletal muscle are small depolarizations from the quantized release of ACh, termed miniature endplate potentials (MEPPs) [15] (seeCh. 10). Decay times for the MEPPs range between l and 2 ms, a duration similar to the mean channel open time seen with ACh stimulation of individual receptor molecules. Stimulation of the motoneuron results in the release of several hundred quanta of ACh. The summation of MEPPs gives rise to a postsynaptic excitatory potential (PSEP),... 

Sanders They release acetylcholine to the same extent. We measured the output of acetylcholine from the nerves, and this was the same in wild-type and mutant animals. It appears that the close association between the nerve terminals and the interstitial cells is very important. As acetylcholine is released, it is broken down by the esterase. If the esterase is inhibited, a response in the smooth muscle can be seen, but this is not physiological. 

Sanders-. But the nerves can still be stimulated and they still release acetylcholine, so they are not non-functional. 

Hirst We can demonstrate that the nerves are releasing acetylcholine. If we block the esterases we get a slow response in the muscle. The acetylcholine can get there it just doesn t normally get there. 

Stimulation of the parasympathetic system releases acetylcholine at the neuromuscular junction in the sinoatrial node. The binding of acetylcholine to its receptor inhibits adenylate cyclase activity and hence decreases the cyclic AMP level. This reduces the heart rate and hence reduces cardiac output. This explains why jumping into very cold water can sometimes stop the heart for a short period of time intense stimulation of the vagus nerve (a parasympathetic nerve) markedly increases the level of... 

Each neuron usually releases only one type of neurotransmitter. Neurons that release dopamine are referred to as dopaminergic, for example, while those that release acetylcholine are cholinergic, etc. The transmitters that are released diffuse through the synaptic cleft and bind on the other side to receptors on the postsynaptic membrane. These receptors are integral membrane proteins that have binding sites for neurotransmitters on their exterior (see p. 224). 

The airway effects of released acetylcholine are mediated via activation of three distinct muscarinic receptor subtypes Mj, in parasympathetic ganglia, mucous glands and alveolar walls autoinhibitory M2, in parasympathetic nerve terminals and M3, in airway smooth muscle, mucus glands, and airway epithelium. 

Schematic diagram comparing some anatomic and neurotransmitter features of autonomic and somatic motor nerves. Only the primary transmitter substances are shown. Parasympathetic ganglia are not shown because most are in or near the wall of the organ innervated. Cholinergic nerves are shown in blue noradrenergic in red and dopaminergic in green. Note that some sympathetic postganglionic fibers release acetylcholine or dopamine rather than norepinephrine. The adrenal medulla, a modified sympathetic ganglion, receives sympathetic preganglionic fibers and releases epinephrine and norepinephrine into the blood. ACh, acetylcholine D, dopamine Epi, epinephrine M, muscarinic receptors N, nicotinic receptors NE, norepinephrine.

As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary transmitter. Some of the substances identified to date are listed in Table 6-1. Many of these substances are also primary transmitters in the nonadrenergic, noncholinergic nerves described in the text that follows. They appear to play several roles in the function of nerves that release acetylcholine or norepinephrine. In some cases, they provide a faster or slower action to supplement or modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals. 

The direct slowing of sinoatrial rate and atrioventricular conduction that is produced by muscarinic agonists is often opposed by reflex sympathetic discharge, elicited by the decrease in blood pressure (see Figure 6-7). The resultant sympathetic-parasympathetic interaction is complex because muscarinic modulation of sympathetic influences occurs by inhibition of norepinephrine release and by postjunctional cellular effects. Muscarinic receptors that are present on postganglionic parasympathetic nerve terminals allow neurally released acetylcholine to inhibit its own secretion. The neuronal muscarinic receptors need not be the same subtype as found on effector cells. Therefore, the net effect on heart rate depends on local concentrations of the agonist in the heart and in the vessels and on the level of reflex responsiveness. 

The cholinesterase inhibitors have important therapeutic and toxic effects at the skeletal muscle neuromuscular junction. Low (therapeutic) concentrations moderately prolong and intensify the actions of physiologically released acetylcholine. This increases the strength of contraction, especially in muscles weakened by curare-like neuromuscular blocking agents... 

At the end of an axon, where it meets another nerve cell or an effector cell (a cell such as a muscle or a gland cell), there is a gap or junction that is usually about 10 to 20 nm wide and this is known as a synapse. The passage of the nerve impulse across this synapse is chemical rather than electrical. When the nerve impulse reaches a synapse it causes the release of a chemical transmitter that is usually acetylcholine. Other transmitters have been identified and these include L-glutamate and y-aminobutyric acid (GABA). The released acetylcholine interacts with a receptor on the... 

Studies of neuromuscular junctions of the autonomic nervous system as early as 1904 led to the suggestion that adrenaline might be released at the nerve endings. Later it was shown that, while adrenaline does serve as a transmitter at neuromuscular junctions in amphibians, it is primarily a hormone in mammals. Nevertheless, it was through this proposal that the concept of chemical communication in synapses was formulated. By 1921, it was shown that acetylcholine is released at nerve endings of the parasympathetic system, and it later became clear the motor nerve endings of the somatic system also release acetylcholine. 

Around 1970, some clues as to individual channel action emerged. Katz and Miledi (1972) discovered that the end-plate membrane potential becomes markedly noisy in the presence of acetylcholine, and they interpreted this as a series of elementary events produced by the opening and closing of individual channels as they bound and released acetylcholine molecules. This led to a series of studies by Stevens and others using techniques of fluctuation analysis to gain information about the size and duration of these events. 

Figure. 2—4. The two major components of the ANS. The parasympathetic neurons release acetylcholine the sympathetic neurons release norepinephrine. These two systems provide a balance of control of the function of the organs and structures...

Adenosine is ubiquitous in the brain. Every cell can release it and does so rather continually while you are awake. It builds in concentration and slowly inhibits the activity of nearby neurons. Of particular concern is the inhibition of the attentioncontrolling acetylcholine neurons that project to the cortex. We need and want those neurons to be active so we consume drinks containing caffeine, a drug that quickly enters the brain and blocks the action of adenosine and releases acetylcholine neurons from the tyranny of inactivation once again, coffee comes to the rescue. 

Mechanism of action. The cellular actions of bot-ulinum toxin at the neuromuscular junction have recently been clarified.84 This toxin is attracted to glycoproteins located on the surface of the presynaptic terminal at the skeletal neuromuscular junction.33 Once attached to the membrane, the toxin enters the presynaptic terminal and inhibits proteins that are needed for acetylcholine release (Figure 13-4).84 Normally, certain proteins help fuse presynaptic vesicles with the inner surface of the presynaptic terminal, thereby allowing the vesicles to release acetylcholine via exocytosis. Botulinum toxin cleaves and destroys these fusion proteins, thus making it impossible for the neuron to release acetylcholine into the synaptic cleft.32,84 Local injection of botulinum toxin into specific muscles will therefore decrease muscle excitation by disrupting synaptic transmission at the neuromuscular junction. The affected muscle will invariably undergo some degree of paresis and subsequent... 

Receptor Class Mu (pi) Primary Therapeutic Effect(s) Spinal and supraspinal analgesia Other Effects Sedation respiratory depression constipation inhibits neurotransmitter release (acetylcholine, dopamine) increases hormonal release (prolactin growth hormone)... 

FIGURE 18-1 Autonomic neurotransmitters and receptors. Preganglionic neurons (solid lines] release acetylcholine [ACh], Postganglionic neurons [dashed lines] release ACh in the parasympathetic pathways and norepinephrine [NE] in the sympathetic pathways. 

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