OTHER LIGANDS FOR THE BENZODIAZEPINE RECEPTOR Among the early indications that the benzodiazepines were not the only compounds to bind to the benzodiazepine receptor were findings that emerged from a search for an endogenous ligand for this receptor site 5mg finast with visa. This effort produced a non-benzodiazepine ligand 5mg finast for sale, ethyl-b-carboline-3-carboxylate (b-CCE) order 5 mg finast fast delivery, and this pointed the way to a whole family of compounds that are high-affinity ligands for this receptor buy finast 5mg on line. However, not all turned out to share the properties of the protypical benzodiazepines (anti-anxiety, anticonvulsant, etc. THE BENZODIAZEPINE RECEPTOR AGONIST/INVERSE AGONIST SPECTRUM The rich portfolio of compounds that bind to the benzodiazepine receptor includes many compounds which, despite not being benzodiazepines, share the properties of the prototypical benzodiazepines, chlordiazepoxide and diazepam. However, all these groups of compounds, including the benzodiazepines themselves, span the activity spectrum: from full inverse agonist to full agonist. In between these extremes are compounds which have either partial agonist or partial inverse agonist activity and some are antagonists (Fig. This spectrum of actions reflects the overall effects of these drugs on native receptors and is usually assessed in whole animals. However, the synthesis of receptors comprising different combinations of subunits has shown that the activity of these drugs depends greatly on subunit composition. For instance, GABAA receptors have been characterised to which diazepam does not bind at all (see Chapter 11). The first antagonist to be developed was the (imidazo)benzodiazepine, flumazenil. This compound blocks the actions of both agonists and inverse agonists in vitro. The subunit composition of the GABAA receptor could be one confounding factor in resolving this question. For instance, flumazenil has been reported to augment the action of GABA at cloned receptors comprising a4 b2 g2 subunits. Apparent effects of the antagonist in vivo could also depend on whether there is any tonic activation of the benzodiazepine receptor by an endogenous ligand. Flumazenil is available in the clinic for intravenous infusion to reverse benzodiazepine-induced sedation (e. However, because it has a half-life of only 1 h in humans, it is only of realistic benefit in reversing the actions of agonist benzodiazepines with a short half-life, such as midazolam. The potential benefits of benzodiazepine partial agonists are as non-sedative, anti- anxiety agents. Because of their low efficacy, it was predicted that a partial agonist should not induce sedation even if their receptor occupancy exceeds that normally required for an anti-anxiety effect when using a full agonist. One such compound, bretazenil, has been developed but failed to reach the clinic because it displayed some sedative activity and, more problematic, there were end-of-dose rebound effects that were undoubtedly exacerbated by its short half-life. Currently, the partial agonist, abecarnil (a b-carboline), is undergoing clinical trials. For the current status of the development of partial agonists and other promising benzodiazepine receptor ligands see Cheetham and Heal (2000). Even benzodiazepine inverse agonists might yet find some useful applications such as in the relief of cognitive deficits (which are increased by benzodiazepine full agonists) (Abe, Takeyama and Yoshimura 1998). With the rapidly expanding understanding of different combinations of subunits that comprise the GABAA receptor, it is hoped to develop compounds that target specific subunit combinations and improve cognitive function in dementia but which lack any proconvulsant or anxiogenic actions. However, three candidates have been given prominent attention, albeit for different reasons, and are worthy of mention. Although subsequently found to be an artefact of the extraction process, this compound turned out to be a ligand for the benzodiazepine receptor, nonetheless, and was the first inverse agonist to be identified. The anxiogenic effects in humans of its more stable congener, FG 7142, are described graphically in a report by Dorow et al. Both these peptides are neuroactive and ODN turns out to have inverse agonist activity at GABAA receptors both in vivo and in vitro and to have marked effects on behaviour (e. However, there is scepticism as to whether the brain can manufacture sufficient peptide to regulate the ubiquitous GABAA receptor on a moment-to-moment basis. Currently, the binding of TTN to the peripheral benzodiazepine site, and its effect on neurosteroid synthesis, is attracting greater interest (Do Rego et al. Finally, the presence in human post-mortem brain tissue of the active metabolite of diazepam, desmethyldiazepam, raised some curiosity and frank alarm (Sangameswaran et al.

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The placenta is also an endocrine gland; it secretes summarized in table 14 cheap finast 5 mg mastercard. Endocrine System © The McGraw−Hill Anatomy 5 mg finast sale, Sixth Edition Coordination Companies discount finast 5mg otc, 2001 EXHIBIT II The embryonic development of the thyroid gland generic finast 5 mg line. Detection of hCG in urine is an indication of pregnancy and is the basis of home 22. Describe the location of the pineal gland and the action of pregnancy tests. Endocrine System © The McGraw−Hill Anatomy, Sixth Edition Coordination Companies, 2001 480 Unit 5 Integration and Coordination Basal metabolism rate (BMR) and thyroid scans (see CLINICAL CONSIDERATIONS fig. Radiographs and electrocardiograms also may be helpful system and the consequences of glandular dysfunctions. Hypersecretion of an endocrine gland is generally Disorders of the Pituitary Gland caused by hyperplasia (increase in size) of the gland, whereas The pituitary is a remarkable gland. It simultaneously carries out hyposecretion of hormones is the consequence of a damaged or several functions, yet more than 90% of the gland must be de- atrophied gland. The diagnosis and treatment of endocrine problems can be difficult because of three complex physiological effects of Panhypopituitarism hormones. Total pituitary impairment, termed panhypopitu- Thus, the clinical symptoms obscure the source of the prob- itarism, brings about a progressive and general loss of hormonal lem. For example, the gonads stop functioning and the per- bolic problems because the primary action of hormones is to son suffers from amenorrhea (lack of menstruation) or aspermia regulate metabolism. The Common diagnostic methods will be discussed in this sec- thyroid and adrenals also eventually stop functioning. People tion, along with the more important endocrine disorders that af- with this condition and those who have had their pituitary sur- fect the major endocrine glands. Diagnosis of Endocrine Disorders Certain endocrine disorders affect the patient’s physical appearance Abnormal Growth Hormone Secretion and behavior; therefore, observation is very important in diagnosis. Inadequate growth hormone secretion during childhood causes The patient’s clinical history is also important in evaluating the pituitary dwarfism (fig. Hyposecretion of growth hor- rate of progress and stage of development of an endocrine disorder. One of the symptoms tory tests, particularly of blood and urine samples. These samples of this disease is premature aging caused by tissue atrophy. By are important because hormones are distributed via the blood, contrast, oversecretion of growth hormone during childhood and urine is produced from the metabolic wastes filtered from the causes gigantism (fig. A radioimmunoassay (RIA) is a laboratory test to deter- length of long bones. Excessive growth hormone secretion in an mine the concentration of hormones in blood and urine. Other adult does not cause further growth in bone length because the blood tests include the protein-bound iodine (PBI) test to deter- epiphyseal plates have already ossified. A urinalysis can be important in the diagnosis of several en- docrine disorders. A high level of glucose in a fasting patient in- dicates diabetes mellitus. A patient who has diabetes insipidus will produce a large volume (5–10 L per day) of dilute urine of low specific gravity. Certain diseases of the adrenal glands can also be detected by examining for changes in urine samples col- Simmonds’ disease: from Morris Simmonds, German physician, 1855–1925 lected over a 24-hour period. Endocrine System © The McGraw−Hill Anatomy, Sixth Edition Coordination Companies, 2001 Chapter 14 Endocrine System 481 (a) (b) (c) FIGURE 14. This disorder affects body fluids, causing edema and increasing Symptoms of this disease include polyuria (excessive urination), blood volume, hence increasing blood pressure.

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Initially purchase 5mg finast free shipping, pulsatility is results from the combined effects of the act of suckling most prominent at night cheap 5mg finast amex, entrained by deep sleep; later it and elevated PRL levels generic finast 5 mg with mastercard. PRL suppresses ovulation by in- becomes established throughout the 24-hour period buy discount finast 5mg on-line. It is also possible that PRL may (up-regulation) and augments the synthesis, storage, and inhibit the action of the low circulating levels of go- secretion of the gonadotropins. Thus, follicular develop- ness of FSH to GnRH in females occurs earlier than that of ment would be suppressed by a direct inhibitory action of LH, accounting for a higher FSH/LH ratio at the onset of PRL on the ovary. Although fertility is reduced by lacta- puberty than during late puberty and adulthood. A reversal tion, there are numerous other methods of contraception of the ratio is seen again after menopause. The sensitivity of gonadotrophs to GnRH is in- creased, the secretion of LH and FSH is augmented, the go- The Onset of Puberty Depends on Maturation nads become more responsive to the gonadotropins, and of the Hypothalamic GnRH Pulse Generator the secretion of gonadal hormones is stimulated. The rising The onset of puberty depends on a sequence of matura- circulating levels of gonadal steroids induce progressive de- tional processes that begin during fetal life. The hypothal- velopment of the secondary sex characteristics and estab- amic-pituitary-gonadal axis undergoes a prolonged and lish an adult pattern of negative feedback on the hypothal- multiphasic activation-inactivation process. Activation of the positive-feedback tion, LH and FSH levels in fetal blood are elevated, reach- mechanism in females and the capacity to exhibit an estro- ing near adult values. Experimental evidence suggests that gen-induced LH surge is a late event, expressed in midpu- the hypothalamic GnRH pulse generator is operative at this berty to late puberty. The levels of FSH are lower in males than in females, prob- Lasting 3 to 5 years, the process involves the development ably because of suppression by fetal testosterone at midges- of secondary sex characteristics, a growth spurt, and the ac- tation. As the levels of placental steroids increase, they ex- ert negative feedback on GnRH release, lowering LH and FSH to very low levels toward the end of gestation. Ovulation Girls After birth, the newborn is deprived of maternal and pla- Breast bud begins cental steroids. The reduction in steroidal negative feed- back stimulates gonadotropin secretion, which stimulates Pubic hair begins the gonads, resulting in transient increases in serum testos- terone in male infants and estradiol in females. FSH levels Peak height spurt in females are usually higher than those in males. At ap- proximately 3 months of age, the levels of both go- Menarche nadotropins and gonadal steroids are in the low-normal adult range. Circulating gonadotropins decline to low lev- Pubic hair adult els by 6 to 7 months in males and 1 to 2 years in females and remain suppressed until the onset of puberty. Breast adult Throughout childhood, the gonads are quiescent and plasma steroid levels are low. The prepubertal restraint of gonadotropin secre- Genital development begins Boys tion is explained by two mechanisms, both of which affect the hypothalamic GnRH pulse generator. One is a sex steroid-de- Pubic hair begins pendent mechanism that renders the pulse generator ex- tremely sensitive to negative feedback by steroids. The other Peak height spurt is an intrinsic central nervous system (CNS) inhibition of the GnRH pulse generator. Together, they suppress the ampli- Genitalia adult tude, and probably the frequency, of GnRH pulses, resulting Spermatogenesis begins in diminished secretion of LH, FSH, and gonadal steroids. Pubic hair adult Throughout this period of quiescence, the pituitary and the gonads can respond to exogenous GnRH and gonadotropins, but at a relatively low sensitivity. Age (years) The hypothalamic-pituitary axis becomes reactivated during the late prepubertal period. The principal mediator of GH is in- by genetic, nutritional, climatic, and geographic factors. Plasma concentration of Over the last 150 years, the age of puberty has declined by IGF-I increases significantly during puberty, with peak lev- 2 to 3 months per decade; this pattern appears to correlate els observed earlier in girls than in boys.

Because the pulmonary arterial PO2 is re- In Lung Disease order finast 5 mg without a prescription, Respiratory Limitations May Be duced in exercise buy finast 5mg cheap, blood shunted past ventilated areas can Evidenced by Shortness of Breath or Decreased profoundly depress systemic arterial oxygen content discount finast 5 mg on-line. Oxygen Content of Arterial Blood Other than having a diminished oxygen content finast 5mg lowest price, pul- monary arterial blood flow (cardiac output) rises during Any compromise of lung or chest wall function is much exercise. In compensation, ventilation rises faster than more apparent during exercise than at rest. One hallmark of cardiac output: The ventilation-perfusion ratio of the lung disease is dyspnea (difficult or labored breathing) dur- lung rises from near 1 at rest to greater than 4 with stren- ing exertion, when this exertion previously was unprob- uous exercise (see Table 30. Restrictive lung diseases limit tidal volume, reduc- nearly constant arterial PO2 with acute exercise, although ing the ventilatory reserve volumes and exercise capacity. This in- Obstructive lung diseases increase the work of breathing, crease shows that, despite the increase in the ventilation- exaggerating dyspnea and limiting work output. Lung dis- perfusion ratio, areas of relative pulmonary underventila- eases that compromise oxygen diffusion from alveolus to tion and, possibly, some mild diffusion limitation exist blood exaggerate exercise-induced widening of the alveo- even in highly trained, healthy individuals. Second, Normally, the respiratory system does not limit exercise their primary complaint is usually shortness of breath, or tolerance. In fact, patients with chronic obstructive pul- tion with oxygen, which averages 98% at rest, is main- monary disease often first seek medical evaluation be- tained at or near 98% in even the most strenuous dy- cause of dyspnea experienced during such routine activi- namic or isometric exercise. In healthy people, includes the ability to augment ventilation more than car- exhaustion is rarely associated solely with dyspnea. In em- diac output; the resulting rise in the ventilation-perfusion physematous patients, exercise-induced dyspnea results, ratio counterbalances the falling oxygen content of in part, from respiratory muscle fatigue exacerbated by di- mixed venous blood. Third, in emphysematous patients, arterial oxygen exercise occur long before ceilings are imposed by either saturation will characteristically fall steeply and progres- skeletal muscle oxidative capacity or by the ability of the sively with increasing exercise, sometimes reaching dan- cardiovascular system to deliver oxygen to exercising gerously low levels. These limitations are manifest during a stress test oxygenate blood at rest is compounded during exercise by on the basis of three primary measurements. First, patients increased pulmonary blood flow, and by increased exer- with ventilatory limitations typically cease exercise at rela- cise oxygen extraction that more fully desaturates blood tively low heart rate, indicating that exhaustion is due to returning to the lungs. The signs and symptoms of a respiratory limitation to Although strenuous exercise can reduce intramuscular pH exercise include exercise cessation with low maximal heart to values as low as 6. The best correlate prospects of training-based rehabilitation are modest, al- of fatigue in healthy individuals is ADP accumulation in the though locomotor muscle-based adaptations can reduce face of normal or slightly reduced ATP, such that the lactate production and ventilatory demands in exercise. Because the complete oxida- Specific training of respiratory muscles to increase their tion of glucose, glycogen, or free fatty acids to carbon diox- strength and endurance is of minimal benefit to patients ide and water is the major source of energy in prolonged with compromised lung function. In healthy individuals, cate- of disorders exemplified by the various muscular dystro- cholamine release from the adrenal medulla and sympa- phies. In these illnesses, the loss of active muscle mass as a thetic nerves dilates the airways during exercise. Sympa- result of fat infiltration, cellular necrosis, or atrophy re- thetic bronchodilation in people with asthma is duces exercise tolerance despite normal capacities (in outweighed by constrictor influences, among them heat healthy fibers) for ATP production. It is unclear whether fa- loss from airways (cold, dry air is a potent bronchocon- tigue in health ever occurs centrally (pain from fatigued strictor), release of inflammatory mediators, and increases muscle may feed back to the brain to lower motivation and, in airway tissue osmolality. Leukotriene-receptor antago- possibly, to reduce motor cortical output) or at the level of nists block exercise-induced symptoms in most people. Individuals with exer- cise-induced bronchoconstriction are simply the most sen- Endurance Activity Enhances Muscle sitive people along a continuum; for example, breathing Oxidative Capacity high volumes of cold, dry air provokes at least mild bron- chospasm in everyone. Within skeletal muscle, adaptations to training are specific to the form of muscle contraction. Increased activity with low loads results in increased oxidative metabolic capacity without hypertrophy; increased activity with high loads MUSCLE AND BONE RESPONSES produces muscle hypertrophy. Increased activity without Events within exercising skeletal muscle are a primary fac- overload increases capillary and mitochondrial density, tor in fatigue. These same events, when repeated during myoglobin concentration, and virtually the entire enzy- training, lead to adaptations that increase exercise capacity matic machinery for energy production from oxygen and retard fatigue during similar work. Coordination of energy-producing and en- traction also increases stresses placed on bone, leading to ergy-utilizing systems in muscle ensures that even after at- specific bone adaptations. In fact, the easy fatigability of at- companied by an acute phase reaction that includes com- rophied muscle is due to the requirement that more motor plement activation, increases in circulating cytokines, neu- units be recruited for identical external force; the fatigabil- trophil mobilization, and increased monocyte cell adhesion ity per unit cross-sectional area is normal. Training adaptation to the eccentric components of the skeletal muscle endurance training response is lim- of exercise is efficient; soreness after a second episode is ited by factors outside the muscle, since cross-innervation minimal if it occurs within two weeks of a first episode. While standard resistance exercise in- Local adaptations of skeletal muscle to endurance activ- volves a mixture of contraction types, careful studies show ity reduce reliance on carbohydrate as a fuel and allow that when one limb works purely concentrically and the more metabolism of fat, prolonging endurance and de- other purely eccentrically at equivalent force, only the ec- creasing lactic acid accumulation.

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