Norepinephrine storage

The answer is b. (Hardman, p 790.) Neuronal uptake is necessary for the hypotensive action of guanethidine. It competes for the norepinephrine storage site and, in time, replaces the natural neurotransmitter. This is the basis of its hypotensive effect. Drugs that prevent reuptake by the neurons, such as cocaine, would destroy the effectiveness of guanethidine... 

DRUGS THAT INTERFERE WITH NOREPINEPHRINE STORAGE ... 

Reserpine (Serpasil) is the prototypical drug interfering with norepinephrine storage. Reserpine lowers blood pressure by reducing norepinephrine concentrations in the noradrenergic nerves in such a way that less norepinephrine is released during neuron activation. Reserpine does not interfere with the release process per se as does guanethidine. 

In addition to impairing norepinephrine storage and thereby enhancing its catabolism, reserpine impairs the vesicular uptake of dopamine, the immediate precursor of norepinephrine. Since dopamine must be taken up into the adrenergic vesicles to undergo hydroxylation and form norepinephrine, reserpine administration impairs norepinephrine synthesis. The combined effects of the blockade of dopamine and norepinephrine vesicular uptake lead to transmitter depletion. 

The pharmacologic effects of direct agonists depend on the route of administration, their relative affinity for adrenoreceptor subtypes, and the relative expression of these receptor subtypes in target tissues. The pharmacologic effects of indirect sympathomimetics are greater under conditions of increased sympathetic activity and norepinephrine storage and release. 

Ephedrine, which is not a catecholamine, has weak oral activity as a bronchodilator and although it has some direct action at adrenergic receptors, its predominant mode of action is by displacing norepinephrine from storage vesicules. 2"Agonists which are in use or are under investigation are the result of quests for improved selectivity, retention of potency, oral activity, and longer duration of action. 

The sympathetic or adrenergic nervous system operates in juxtaposition to the parasympathetic nervous system to maintain homeostasis in response to physical activity and physical or psychological stress. Sympathomimetic neurotransmission is generally mediated by norepinephrine [51-41 -2] (1), CgH NO, released from presynaptic storage granules upon stimulation. A second endogenous sympathomimetic agent, epinephrine [51-43-4] (2),... 

The answers are 318-d, 319-c, 320-a. (Hardman, pp 120-1220 Norepinephrine is synthesized from dopamine by dopamine-p-oxidase, which hydnoxylates the p-carbon This enzyme is localized in the amine storage granules. Norepinephrine is found in adrenergic fibers, the adrenal medulla, and in neurons in the locus ceruleus and lateral ventral tegmental fields of the CNS. 

Ordinarily, low concentrations of catecholamines are free in the cytosol, where they may be metabolized by enzymes including monoamine oxidase (MAO). Thus, conversion of tyrosine to l-DOPA and l-DOPA to dopamine occurs in the cytosol dopamine then is taken up into the storage vesicles. In norepinephrine-containing neurons, the final P-hydroxylation occurs within the vesicles. In the adrenal gland, norepinephrine is N-methylated by PNMT in the cytoplasm. Epinephrine is then transported back into chromaffin granules for storage. 

Reserpine depletes norepinephrine from sympathetic nerve endings and blocks the transport of norepinephrine into its storage granules. When the nerve is stimulated, less than the usual amount of norepinephrine is released into the synapse. This reduces sympathetic tone, decreasing peripheral vascular resistance and BP. 

Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake indicated for depression and painful diabetic neuropathy, is expected to become first-line therapy for SUI. Duloxetine is thought to facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase. 

The Rauwolfia alkaloid reserpine, due to its strong central component of activity, is excluded from this review, even though it has the peripheral effect of releasing norepinephrine from storage sites where it can be metabolized by monoamine oxidase. This results in neurotransmitter depletion and it appears that good blood pressure control would be achieved by a drug which has this peripheral mechanism but lacks the central component. The Mead-Johnson compound MJ-10459-2 (LXI) shows activity in... 

When norepinephrine is substituted in the storage sites by amines of similar structure which are less agonistic, these agents are called "false transmitters." Until its central... 

Several of the neurotransmitters are small-molecule amines such as dopamine, serotonin, epinephrine, and norepinephrine. These neurotransmitters are synthesized in the cytoplasm of the axon terminal and subsequently transported into and stored within the synaptic vesicles. The amino acids glycine and glutamic acid are normal constituents of proteins and are present in abundance in the axons. These are also stored in synaptic vesicles. Each electrical impulse that arrives at the presynaptic side of a synapse will cause only a small minority of the synaptic vesicles to fuse with the plasma membrane and discharge their contents. The remaining synaptic vesicles remain, waiting for subsequent electrical impulses. At the same time, neurotransmitter synthesis continues, as does their storage in synaptic vesicles. This tends to restore the full complement of amine neurotransmitters at the axon terminal. 

The effect of released norepinephrine wanes quickly, because approx. 90% is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by the enzyme catechol-0-methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normeta-nephrine), and monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-dihydroxymandelic acid). 

Conventionally called adrenergic neuron blockers, the last group of adrenoblockers are drugs that suppress synthesis, storage, and release of biogenic amines (norepinephrine, dopamine, or serotonin) in nerve endings. 

Adrenergic neuron blockers cause degradation of biogenic amines in neuron endings. These drugs can interfere with the synthesis, storage and release of norepinephrine, dopamine, and serotonin. 

Pharmacology These drugs are non-selective MAOIs and cause an increase in the concentration of endogenous epinephrine, norepinephrine, and serotonin (5HT) in storage sites throughout the nervous system. 

Several mechanisms exist to explain the etiology of affective disorders all based on the hypothesis that certain levels of amine neurotransmitters (e.g., norepinephrine - NE, serotonin - 5-HT) and receptor sensitivity are necessary for normal mood. There is ample evidence that depression occms if receptors are insensitive or if amine synthesis, storage or... 

Varicosity of a noradrenergic neuron showing synthesis and storage of norepinephrine. Also shown Is the release of norepinephrine (NE) and multiple routes for degradation. COMT, catechol-O-methyltransferase MAO, monoamine oxidase. 

Synthesis of norepinephrine begins with the amino acid tyrosine, which enters the neuron by active transport, perhaps facilitated by a permease. In the neuronal cytosol, tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa), which is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase, sometimes termed dopa-decarboxylase. The dopamine is actively transported into storage vesicles, where it is converted to norepinephrine (the transmitter) by dopamine (3-hydroxylase, an enzyme within the storage vesicle. 

Since the enzyme that converts dopamine to norepinephrine (dopamine (3-hydroxylase) is located only within the vesicles, the transport of dopamine into the vesicle is an essential step in the synthesis of norepinephrine. This same transport system is essential for the storage of norepinephrine. There is a tendency for norepinephrine to leak from the vesicles into the cytosol. If norepinephrine remains in the cytosol, much of it will be destroyed by a mitochondrial enzyme, monoamine oxidase MAO). However, most of the norepinephrine that leaks out of the vesicle is rapidly returned to the storage vesicles by the same transport system that carries dopamine into the storage vesicles. It is important for a proper understanding of drug action to remember that this single transport system, called vesicular transport, is an essential element of both synthesis and storage of norepinephrine. 

Transport back into the noradrenergic neuron (reup-take), followed by either vesicular storage or by enzymatic inactivation by mitochondrial MAO. The transport of norepinephrine into the neurons is a sodium-facilitated process similar to that for choline transport. 

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