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These include nicotinic receptors (increase release from striatal synaptosomes) purchase actoplus met 500mg otc diabetes symptoms nausea dizziness, a2A-adrenoceptors (depress cortical release) and H3-receptors (cortical depression) actoplus met 500 mg low cost diabetic diet quiz. This compound inhibits 5-HT uptake but its metabolite, d-norfenfluramine, increases 5-HT release as do high doses of d-amphetamine. It is important to realise that this 5-HT release is independent of nerve impulses and the action of such compounds rests on their effects on the 5-HT transporters on the storage vesicles and terminal membrane. Once these drugs have been taken up into 5-HT neurons by the transporter, they cause 5-HT to leak out of its storage vesicles and, ultimately, to be extruded from the neuron by retrotransport (see below and Chapter 4 for further details). Until recently, d-fenfluramine was used to control appetite, in preference to d-amphetamine, because it has a lower affinity for the catecholamine transporter and so its uptake into noradrenergic and dopaminergic neurons is much less than that of amphetamine. This is thought to explain why, at anorectic doses, this compound lacks the psychotropic effects and dependence-liability that are real problems with d-amphetamine. Unfortunately, despite this therapeutic advantage, this compound has had to be withdrawn from the clinic because of worries that it might cause primary pulmonary hypertension, valvular heart disease and even long-term neuropathy. INACTIVATION As with other monoamines, the actions of 5-HT are terminated by its reuptake from the synapse by another member of the family of Na‡/Cl7-dependent transporters. The 5-HT transporter has many features in common with its catecholamine equivalent (described fully in Chapter 8; see Fig. However, the cloned 5-HT transporter has a Km for 5-HT of about 450 nM whereas its Ki for both noradrenaline and dopamine is some ten thousand-fold greater (Povlock and Amara 1997) which means that it is relatively selective for uptake 5-HYDROXYTRYPTAMINE 195 of 5-HT. The uptake process itself requires the inward co-transport of one Na‡ ion and one Cl7 ion while K‡ (or H‡) is carried in the opposite direction. The energy required to maintain the ionic gradients that drive this process is provided by a Na‡/K‡-dependent ATPase. As might be expected, mRNA for the 5-HT transporter is found in high concentrations in the Raphe nuclei but it is also found in other brain regions. Whether this means that non-5-HT neurons can synthesise this protein is unknown but there is some evidence that it is synthesised in astrocytes, at least. One complication is that there are multiple forms of mRNA for the 5-HT transporter, but there is, as yet, no evidence for transporter subtypes in the CNS. However, it must also be remembered that 5-HT transporters are found in the peripheral tissues, notably platelets, mast cells, the placental brush-border and adrenal chromaffin cells and it is possible that these are not all identical. Inhibitors of 5-HT uptake include the tricyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs, which are discussed in detail in Chapter 20) as well as compounds like cocaine and d-amphetamine. Because cocaine is not transported into the neuron it is thought to bind to a site on the transporter protein. This has a negative allosteric effect on the protein and prevents binding of 5-HT to its domain. It has even been suggested that there could be an endogenous ligand for this site which regulates 5-HT uptake. By contrast, d-amphetamine is transported into neurons and so acts as a competitive inhibitor of 5-HT reuptake. Other inhibitors that are transported into the neuron, and which are thought to bind to the same site, include p-chloroamphetamine, MDMA and fenfluramine. Of course, all these transporter inhibitors release 5-HT (see above) but exactly how they do this is uncertain. One suggestion is that, because they can also penetrate the cell membrane directly, they recycle continuously through their active transport into the cell and passive outward diffusion. This is thought gradually to dissipate the ionic gradient that is needed for the transporter to take up 5-HT into the neuron and so culminates in the outward transport of 5-HT into the synapse (Rudnick 1997). This action is compounded by their disruption of the vesicular transporters (VMATs) since, once they gain access to the neuron, they diminish the proton gradient required for the VMATs to function properly, possibly because they are weak bases (see Chapter 8; Fig. This leads to leakage of 5-HT into the cytoplasm where its ensuing increased concentration ensures that a large pool is available for its retrotransport into the synapse. Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Vmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking.

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Dust buy actoplus met 500 mg with visa diabetes type 2 cdc, pollen actoplus met 500 mg visa blood glucose scale, smoke, and other fine particles are trapped • The nasal epithelium covering the conchae serves to warm, along the moist mucous membrane lining the nasal cavity. The nasal epithelium is highly vascular and covers an extensive surface • The olfactory epithelium in the upper medial portion of area. This is important for warming the air but unfortu- the nasal cavity is concerned with the sense of smell. Respiratory System © The McGraw−Hill Anatomy, Sixth Edition Body Companies, 2001 Chapter 17 Respiratory System 607 FIGURE 17. There are several drainage openings into the nasal cavity (see Pharynx fig. An excessive secretion of tears causes the nose to run as the tears drain into the nasal cavity. The supporting walls of the pharynx are com- accessory connections, it is no wonder that infections can spread so posed of skeletal muscle, and the lumen is lined with a mucous easily from one chamber to another throughout the facial area. To avoid causing damage or spreading infections to other areas, one membrane. Within the pharynx are several paired lymphoid or- must be careful not to blow the nose too forcefully. Commonly referred to as the “throat” or “gul- let,” the pharynx has both respiratory and digestive functions. Paranasal Sinuses The pharynx is divided on the basis of location and function into three regions (see fig. Paired air spaces in certain bones of the skull are called paranasal • The nasopharynx serves only as a passageway for air, be- sinuses. These sinuses are named according to the bones in cause it is located above the point of food entry into the which they are found; thus, there are the maxillary, frontal, body (the mouth). It is the uppermost portion of the phar- sphenoidal, and ethmoidal sinuses (fig. Each sinus com- ynx, positioned directly behind the nasal cavity and above municates via drainage ducts within the nasal cavity on its own the soft palate. These sinuses are responsible ditory (eustachian) tubes connect the nasopharynx with for some sound resonance, but most important, they function to the tympanic cavities. The pharyngeal tonsils, or ade- decrease the weight of the skull while providing structural noids, are situated in the posterior wall of the nasal cavity. During the act of swallowing, the soft palate and uvula You can observe your own paranasal sinuses. Face a mirror are elevated to block the nasal cavity and prevent food from in a darkened room and shine a small flashlight into your entering. The frontal sinuses will be illuminated by directing the light just below the eyebrow. The maxillary sinuses are illuminated by shining the light into the oral cavity and closing your mouth around the flashlight. Respiratory System © The McGraw−Hill Anatomy, Sixth Edition Body Companies, 2001 608 Unit 6 Maintenance of the Body FIGURE 17. The larynx has two func- occurs before the uvula effectively blocks the nasopharynx, tions. Its primary function is to prevent food or fluid from entering fluid will be discharged through the nasal cavity. Both Laryngitis is the inflammation of the mucosal epithelium of the swallowed food and fluid and inhaled air pass through it. Laryngitis may result from overuse of the voice, inhalation of an irritating chemical, or oropharynx. Paired palatine tonsils are located on the pos- a bacterial or viral infection. Mild cases are temporary and seldom of terior lateral wall, and the lingual tonsils are found on the major concern.

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Adrenal hyperplasia is usually due to defects in cortisol roid disease runs in families buy 500 mg actoplus met diabetes kidney failure, the family history suggests production buy actoplus met 500mg on-line can glucosamine cause diabetes in dogs. Therefore, the serum concentrations of precur- that the thyroiditis might be due to an autoimmune re- sors of cortisol biosythesis such as progesterone, 17 -hy- sponse. The laboratory should determine the blood levels of thyroid In addition, serum ACTH would be elevated as a result of hormones (T4 and T3) and TSH. Thyroid hormones should the lack of negative feedback from the absent cortisol. Genetic defects in the gene for 11 -hydroxylase, resulting in gression of Hashimoto’s disease or decreased if the patient a reduction in the activity of this enzyme, would result in in- has Graves’ disease. The laboratory should measure antibodies to TSH receptor, ylase, which impair the activity of the enzyme, would not thyroid peroxidase, and thyroglobulin. Since 11-deoxy- peroxidase are elevated to the greatest extent in cortisol has significant mineralocorticoid activity, excess Hashimoto’s disease. Antibodies to TSH receptor, thyroid peroxidase, and thy- tension, rather than the volume depletion and hypotension roglobulin can all be elevated in Graves’ disease. Treatment would be directed toward replacement of gluco- 648 PART IX ENDOCRINE PHYSIOLOGY corticoids and mineralocorticoids. Exercise not only helps to control weight, it stimulates glu- place the missing cortisol and also suppress ACTH secre- cose uptake in skeletal muscle, lessening the requirements tion. With less ACTH stimulation of steroid production from for injected insulin. Mineralocorticoids are given to treat the “salt wasting” that CASE STUDY FOR CHAPTER 36 occurs in the absence of aldosterone. Bone Fractures CASE STUDY FOR CHAPTER 35 A 38-year-old Caucasian man recently came to the atten- tion of his physician when he suffered the second of two Type 2 Diabetes bone fractures in the past year and a half. He previously A 65-year-old semi-retired college professor was diag- was in relatively good health, was not a smoker, and used nosed with type 2 diabetes about 4 years ago during a alcohol only moderately. However, his only form of exer- routine physical examination at his family doctor’s of- cise was cutting the lawn on weekends during the sum- fice. He has not required any major surgeries tablet daily of an oral antidiabetic drug of the sulfony- during his lifetime, and had only minor bouts of the typi- lurea class and two daily injections of insulin. However, at age eight he was di- tient’s doctor also recommended modest weight loss agnosed with asthma after he suffered severe respiratory and a regular exercise program. With diligence to the problems during a baseball game on a hot summer day. For The fractures that the patient experienced were to the about one week after the surgery, the patient had to in- left wrist and the right forearm. In both cases, the trauma crease his insulin dosage to maintain normal blood glu- that caused the fracture was relatively minor. He gradually returned to his presurgery in- that there may be an underlying problem, his physician sulin dose. Results of these Because of the surgery, the patient vows to take better studies show that the patient has a considerable reduc- care of himself. He increases his physical activity and be- tion in bone mass compared with other men of the same gins a diet that results in loss of 7 kg in 3 months. What is the most probable underlying cause for the pa- Questions tient’s problem? Osteoporosis and, perhaps, glucocorticoid-induced osteo- gain the weight he lost after surgery? Because the patient is young and has a relatively healthy for type 2 diabetes? Glucocorticoids increase bone loss by inhibiting os- epinephrine and norepinephrine, both of which inhibit in- teoblasts, stimulating bone resorption, impairing intestinal sulin secretion. The patient’s pancreas will produce less in- calcium absorption, increasing urinary calcium loss, inhibit- sulin, and thus, more exogenous insulin will need to be pro- ing secretion of sex hormones, and other effects. If the patient were to regain weight, he would most likely hol intake, and being female. He does appear, however, to have to go back to taking insulin injections.

The voltage at which the net membrane current regenerative local currents similar to those in a nonmyeli- would become zero is called the reversal potential of the nated nerve fiber 500mg actoplus met with amex diabetic diet bananas. If some circumstance causes reduced ACh release buy actoplus met 500mg overnight delivery metabolic disease related to carbohydrates, the To complete the circuit, the current flowing inward at amount of depolarization at the endplate could be corre- the postsynaptic membrane must be matched by a return spondingly reduced. This current flows through the local muscle cyto- ever, the endplate potential is much more than sufficient to plasm (myoplasm), out across the adjacent muscle mem- produce a muscle action potential; this reserve, referred to brane and back through the extracellular fluid (Fig. As as a safety factor, can help preserve function under abnor- CHAPTER 9 Skeletal Muscle and Smooth Muscle 155 A receptors. This binding does not result in opening of the Motor axon action potential C ion channels, however, and the endplate potential is re- Muscle action duced in proportion to the number of receptors occupied potential by curare. Although the muscle can be directly stimulated electrically, nerve stimulation is ineffective. External muscular junction in a slightly different way; this molecule transmitter release return current binds to the receptors and causes the channels to open. Be- cause it is hydrolyzed very slowly by AChE, its action is long lasting and the channels remain open. This prevents resetting of the inactivation gates of muscle membrane sodium channels near the endplate region and blocks sub- 4. Drugs that produce extremely current long-lasting endplate potentials are referred to as depolar- 2. In carefully controlled doses, they can temporarily alleviate symptoms of myasthenia gravis, an autoimmune condition that results in a loss of postsynaptic ACh receptors. Longitudinal principal symptom is muscular weakness caused by end- B myoplasmic current plate potentials of insufficient amplitude. Partial inhibition Endplate potential of the enzymatic degradation of ACh allows ACh to remain effective longer and, thus, to compensate for the loss of re- ceptor molecules. A, The inward membrane current is car- to the endplate region of a muscle. If accidental denerva- ried by sodium ions through the channels associated with ACh tion occurs (e. The other currents are nonspecific and are carried by tire muscle becomes sensitive to direct application of ACh appropriately charged ions in the myoplasm and extracellular fluid. B, The endplate potential is localized to the endplate re- within several weeks. C, The muscle action potential is propagated along the sur- to the synthesis of new ACh receptors, a process normally face of the muscle. Arti- ficial electrical stimulation has been shown experimentally to prevent the synthesis of new receptors, by regulating mal conditions. The rate of rise of the endplate potential is transcription of the genes involved. If reinnervation occurs, determined largely by the rate at which ACh binds to the the extrasynaptic receptors gradually disappear. Muscle at- receptors, and indirect clinical measurements of the size rophy also occurs in the absence of functional innervation, and rise time of the endplate potential are of considerable which also can be at least partially reversed with artificial diagnostic importance. OF SKELETAL MUSCLE The variety of controlled muscular movements that humans Neuromuscular Transmission Can Be can make is remarkable, ranging from the powerful con- Altered by Toxins, Drugs, and Trauma tractions of a weightlifter’s biceps to the delicate move- ments of the muscles that position our eyes as we follow a The complex series of events making up neuromuscular moving object. In spite of this diversity, the fundamental transmission is subject to interference at several steps. The drug hemicholinium interferes with choline up- take by the presynaptic terminal and, thus, results in the de- The Timing of Muscle Stimulation Is a pletion of ACh. Botulinum toxin interferes with ACh Critical Determinant of Contractile Function release. This bacterial toxin is used to treat focal dystonias (see Clinical Focus Box 9. A skeletal muscle must be activated by the nervous system Postsynaptic blockade can result from a variety of cir- before it can begin contracting. Drugs that partially mimic the action of ACh processes previously described, a single nerve action po- can be effective blockers.

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