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The kidney is the primary site of excretion of VM A— vanillylmandelic acid purchase 250 mg cefuroxime visa. Such paroxysm s can be spontaneous or associated with pheochrom ocytom a during am bulatory blood pressure with activity of m any sorts discount cefuroxime master card. W hereas m ost levels were within the norm al; with perm ission trusted 250 mg cefuroxime. These light-brown- colored (coffee- with-cream -colored) lesions order cefuroxime 250 mg line, som etim es seen in patients with pheochrom ocytom a, usually are larger than 3 cm in the largest dim ension. In this particular patient, neurofibro- m as also are present FIGURE 4-27 (see Color Plate) and can be seen in N eurofibrom a associated with pheochrom ocytom a. These lesions are soft, fluctuant, and nontender and can appear anywhere on the surface of the skin. These lesions can be seen in profile in Figure 4-28. In addition to the neurofibrom as and PHEOCHROM OCYTOM A café au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnorm al- ities have been reported in patients with pheochrom ocytom a. Note that severe hyperten- sive retinopathy, Test Sensitivity, % Specificity, % Patients, % indicative of intense vasoconstriction, Elevated 24-h urinary catecholamines, ≈85 ≈80 Symptoms frequently is vanillylmandelic acid, homovanillic Severe headache 82 acid, metanephrines observed. Drugs, incom - Weight loss 15 plete urine collection, and episodic secretion of catecholam ines can Dyspnea 15 influence the tests based on 24-hour urine collections in a patient W armth, heat intolerance 15 with a pheochromocytoma. The clonidine suppression test is fraught with false-negative and false-positive results that are unacceptably Visual disturbances 12 high for the exclusion of this potentially fatal tum or. The “sleep” Dizziness, faintness 7 norepinephrine test eliminates the problems of incomplete 24-hour Constipation 7 urine collection because the patient discards all urine before retiring; Finding saves all urine voided through the sleep period, including the first Hypertension: specimen on arising; and notes the elapsed (sleep) time. The sleep Sustained 61 period is typically a time of basal activity of the sympathetic nervous Paroxysmal 24 system, except in patients with pheochromocytoma (see Fig. Pallor 44 Retinopathy: Grades I and II 40 Grades III and IV 53 Abdominal mass 9 Associated multiple endocrine 6 adenomatosis 4. The values for urinary excretion of norepinephrine are shown for norm al persons and 1000 patients with essential hypertension as m ean plus or m inus SD. Values for patients with pheochrom ocytom a are indicated by sym bols. N ote that the scale is logarithm ic and the highest value for patients with norm al or essential hypertension was less than 30 Patient I µg, whereas the lowest value for a patient with pheochrom ocytom a Patient II was about 75 µg. M ost patients with pheochrom ocytom as had val- Patient III ues an order of m agnitude higher than the highest value for Patient IV Patient V patients with essential hypertension. N ote the Test Sensitivity, % Specificity, % displacem ent of the left kidney (right) by Abdominal plain radiograph ≈40 ≈50 a suprarenal m ass. Intravenous pyelogram ≈60 ≈75 Adrenal isotopic scan ≈85 ≈85 (meta-iodobenzoylguanidine) Adrenal computed tomographic scan >95 >95 FIGURE 4-33 Localization of pheochrom ocytom a. O nce the diagnosis of pheochrom ocytom a has been m ade it is very im portant to localize the tum or preoperatively so that the surgeon m ay rem ove it with a m inim um of physical m anipulation. Com puted tom ographic scan or M RI appears to be the most effective and safest techniques for this purpose. The patient should be treated with -adrenergic blocking agents for 7 to 10 days before surgery so that the contracted extracellular fluid volume can be expanded by vasodilation. Three patients have left adrenal tum ors, and in m ocytom a. The black arrows identify the adrenal tum or in one patient (panel B) the tum or is on the right adrenal. A B FIGURE 4-36 (see Color Plates) A and B, Pathologic appearance of pheochrom ocytom a before tum or had gross areas of hem orrhage noted by the dark areas (panel A) and after (panel B) sectioning. Netter FH: Endocrine system and selected metabolic diseases. In Ciba 7: Lifton RP, Dluhy RG, Powers M : H ereditary hypertension caused by Collection of M edical Illustrations, vol. Lifton RP, Dluhy RG, Powers M : A glucocorticoid-rem ediable aldos- 3. W einberger M H , Fineberg N S: The diagnosis of prim ary aldosteronism Springer-Verlag; 1977:97. Grim CE, W einberger M H : Fam ilial, dexam ethasone-suppressible pheochrom ocytom a: detection by m easurem ent of urinary norepineph- norm okalem ic hyperaldosteronism. Kem DC, W einberger M H , M ayes D, N ugent CA: Saline suppression of plasm a aldosterone and plasm a renin activity in hypertension. Bauer his chapter reviews the currently available classes of drugs used in the treatment of hypertension. To best appreciate the com- Tplexity of selecting an antihypertensive agent, an understanding of the pathophysiology of hypertension and the pharmacology of the various drug classes used to treat it is required. A thorough under- standing of these mechanisms is necessary to appreciate more fully the workings of specific antihypertensive agents. Among the factors that modulate high blood pressure, there is considerable overlap. The drug treatment of hypertension takes advantage of these integrated mecha- nisms to alter favorably the hemodynamic pattern associated with high blood pressure. There are a large num ber of control m echanism s involved product of cardiac output (CO ) and peripheral vascular resistance in every type of hypertension. M any hypertensive patients appear to be sodium sensitive, as first suggested by studies in 19 hypertensive subjects who were observed after “norm al” (109 m m ol/d), “low” (9 m m ol/d), and “high” (249 m m ol/d) sodium intake. This figure shows the percent increase in m ean blood pressure in salt-sensitive (SS) and non–salt-sensi- 20 tive (N SS) patients with hypertension when their diet was changed from low sodium to high sodium. An increase in cardiac output has been suggested 19 as a m echanism for hypertension, particularly in its early border- 18 line phase [3,4]. Sodium and water retention have been theorized 17 to be the initiating events. Sequential changes following salt load- 16 4 % ing are depicted. The resultant high cardiac output perfuses the 15 peripheral tissues in excess of their m etabolic requirem ents, result- 20 % ing in a norm al autoregulatory (vasoconstrictor) pressure. Shown here are segm ental changes in the im portant cardiovascular hem odynam ic variables in the first 16 60 % few weeks following the onset of short-term salt-loading hyperten- 14 sion. N ote especially that the arterial pressure increases ahead of 20 % 12 the increase in total peripheral resistance. M ost established cases of hypertension dashed line indicates results after 10 years; dotted line indicates results are associated with an increase in peripheral vascular resistance. BP— blood pressure; CI— cardiac index; DAP— diastolic These alterations m ay be related to a functional constriction, the arterial blood pressure; HR— heart rate; M AP— mean arterial pressure; type observed under the influence of circulating or tissue-generated SAP— systolic arterial blood pressure; SI— stroke index; TPRI— total vasoconstrictors, or m ay be a result of structural alterations in the peripheral resistance index; VO2— oxygen consumption. Solid line indicates values at start of the study; Johansen; with perm ission. There are 12 currently available classes of antihypertensive agents. Diuretics: benzothiadiazides, loop, and potassium-sparing -adrenergic and 1/ -adrenergic antagonists Central 2-adrenergic agonists Central/peripheral adrenergic neuronal-blocking agent Peripheral 1-adrenergic antagonists Moderately selective peripheral 1-adrenergic antagonist Peripheral adrenergic neuronal blocking agents Direct-acting vasodilators Calcium antagonists Angiotensin-converting enzyme inhibitors Tyrosine hydroxylase inhibitor Angiotensin II receptor antagonists FIGURE 7-6 H em odynam ic response to diuretics. Diuretics reduce m ean arterial BP pressure by their initial natriuretic effect. Acutely, this is achieved by a reduction in cardiac output m ediated by a reduction in plasm a and extracellular fluid volum es. Initially, peripheral vascular resistance is increased, m ediated in part by stim ulation of the renin- PV angiotensin system. During sustained diuretic therapy, cardiac output returns to pretreatm ent levels, probably reflecting restoration of ISF plasma volume. Chronic blood pressure control now correlates with a reduction in peripheral vascular resistance. BP— blood pressure; CO CO — cardiac output; ISF— interstitial fluid; PRA— plasm a renin CO activity; PV— plasma volume; Rx— treatment; TPR— total peripheral TPR TPR resistance. DIURETICS: BENZOTHIADIAZIDES (PARTIAL LIST) AND RELATED DIURETICS Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h Hydrochlorothiazide (G) 12. DIURETICS: LOOP Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h Bumetanide (G) 0. DIURETICS: POTASSIUM -SPARING DIURETICS Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h Spironolactone (G) 25 50–1 00 mg QD 400 48–72 (Aldactone) Amiloride (G) 5 5–10 mg QD 20 24 (Midamor) Triamterene (G) 50 50-100 mg bid 300 7–9 (Dyrenium) (G)— generic available. Diuretics: benzothiadiazides and related agents, loop diuretics, diuretics. Because of their steep dose-response curves and natri- and potassium -sparing agents.
APPENDIX 4 Study ID Reason for exclusion Fisher EB purchase cefuroxime 500 mg visa, Strunk RC purchase cefuroxime visa, Sussman LK order cefuroxime 250 mg online, Sykes RK purchase cefuroxime 500mg with amex, Walker MS. Community organization to No eligible health outcomes reduce the need for acute care for asthma among African American children in low-income neighborhoods: the Neighborhood Asthma Coalition. Pediatrics 2004;114:116–23 Forsander GA, Sundelin J, Persson B. Influence of the initial management regimen and No eligible health outcomes family social situation on glycemic control and medical care in children with type 1 diabetes mellitus. Acta Paediatr 2000;89:1462–8 Foster EM, Jones D, Conduct Problems Prevention Research Group. Can a costly Ineligible population intervention be cost-effective? Costs and effectiveness of the fast track intervention for antisocial behavior. Ineligible population J Ment Health Policy Econ 2010;13:101–19 Foulds JL, Vanderloo SE, Marks SD, Johnson JA. Healthcare costs for initial management No eligible health outcomes of children with new-onset type 1 diabetes mellitus in central and northern Alberta. Can J Diabetes 2012;36:128–32 Franklin BE, Crisler SC Jr, Shappley R, Armour MM, McCommon DT, Ferry RJ Jr. Real-time Ineligible intervention support of pediatric diabetes self-care by a transport team. Diabetes Care 2014;37:81–7 Garcia-Perez L, Perestelo-Perez L, Serrano-Aguilar P, Del Mar Trujillo-Martin M. Effectiveness No eligible health outcomes of a psychoeducative intervention in a summer camp for children with type 1 diabetes mellitus. Diabetes Educ 2010;36:310–17 Geist R, Heinmaa M, Stephens D, Davis R, Katzman DK. Comparison of family therapy and Absent/ineligible comparator family group psychoeducation in adolescents with anorexia nervosa. Can J Psychiatry 2000;45:173–8 Gerald LB, Redden D, Wittich AR, Hains C, Turner-Henson A, Hemstreet MP, et al. No eligible health outcomes Outcomes for a comprehensive school-based asthma management program. J Sch Health 2006;76:291–6 Gerald LB, Redden D, Wittich AR, Hains C, Turner-Henson A, Hemstreet MP, et al. Ineligible intervention Outcomes for a comprehensive school-based asthma management program. J Sch Health 2006;76:291–6 Gillies J, Barry D, Crane J, Jones D, MacLennan L, Pearce N, et al. A community trial of a Ineligible intervention written self management plant for children with asthma. N Z Med J 1996;109:30–3 Greer D, Grasso DJ, Cohen A, Webb C. Trauma-focused treatment in a state system of No eligible health outcomes care: is it worth the cost? Adm Policy Ment Health Ment Health Serv Res 2014;41:317–23 Greineder DK, Loane KC, Parks P. A randomized controlled trial of a pediatric asthma No eligible health outcomes outreach program. J Allergy Clin Immunol 1999;103:436–40 Grey M, Boland EA, Davidson M, Li J, Tamborlane WV. Coping skills training for youth with No eligible economic diabetes mellitus has long-lasting effects on metabolic control and quality of life. J Pediatr outcomes 2000;137:107–13 Griffiths JD, Martin PR. Clinical- versus home-based treatment formats for children with No eligible economic chronic headache. Br J Health Psychol 1996;1:151–66 outcomes Grimes KE, Schulz MF, Cohen SA, Mullin BO, Lehar SE, Tien S. Pursuing cost-effectiveness No eligible health outcomes in mental health service delivery for youth with complex needs. J Ment Health Policy Econ 2011;14:73–83 Guglani L, Havstad SL, Johnson CC, Ownby DR, Joseph CL. Effect of depressive symptoms No eligible economic on asthma intervention in urban teens. Ann Allergy Asthma Immunol 2012;109:237–42 outcomes Gustafson D, Wise M, Bhatacharya A, Pulvermacher A, Shanovich K, Philips B, et al. No eligible economic The effects of combining web-based eHealth with telephone nurse case management for outcomes pediatric asthma control: a randomized controlled trial. J Med Internet Res 2012;14:41–59 Halterman JS, Fagnano M, Tremblay PJ, Fisher SG, Wang H, Rand C, et al. Prompting Ineligible intervention Asthma Intervention in Rochester-Uniting Parents and Providers (PAIR-UP): a randomized trial. JAMA Pediatrics 2014;168:e141983 Harish Z, Bregante AC, Morgan C, Fann CS, Callaghan CM, Witt MA, et al. A comprehensive No eligible health outcomes inner-city asthma program reduces hospital and emergency room utilization. Ann Allergy Asthma Immunol 2001;86:185–9 106 NIHR Journals Library www. Randomised comparison Absent/ineligible comparator of the effectiveness and costs of community and hospital based mental health services for children with behavioural disorders. BMJ 2000;321:1047–50 Honeycutt AA, Khavjou OA, Jones DJ, Cuellar J, Forehand RL. Helping the noncompliant No eligible economic child: an assessment of program costs and cost-effectiveness. J Child Fam Stud outcomes 2015;24:499–504 Hudson A, Cameron C, Matthews J. The wide-scale implementation of a support program Ineligible population for parents of children with an intellectual disability and difficult behaviour. J Intellect Dev Disabil 2008;33:117–26 Hui SHL, Leung TF, Ha G, Wong E, Li AM, Fok TF. Evaluation of an asthma management Wrong study design program for Chinese children with mild-to-moderate asthma in Hong Kong. Pediatr Pulmonol 2002;33:22–9 Izquierdo R, Morin PC, Bratt K, Moreau Z, Meyer S, Ploutz-Snyder R, et al. School-centered Ineligible intervention telemedicine for children with type 1 diabetes mellitus. J Pediatr 2009;155:374–9 Kamps AWA, Brand PLP, Kimpen JLL, Maille AR, Overgoor-Van De Groes AW, Ineligible intervention Van Helsdingen-Peek LCJAM, et al. Outpatient management of childhood asthma by paediatrician or asthma nurse: randomised controlled study with one year follow up. Thorax 2003;58:968–73 Karnick P, Margellos-Anast H, Seals G, Whitman S, Aljadeff G, Johnson D. The pediatric No eligible health outcomes asthma intervention: a comprehensive cost-effective approach to asthma management in a disadvantaged inner-city community. J Asthma 2007;44:39–44 Kelly CS, Morrow AL, Shults J, Nakas N, Strope GL, Adelman RD. Outcomes evaluation of a No eligible health outcomes comprehensive intervention program for asthmatic children enrolled in Medicaid. Pediatrics 2000;105:1029–35 King CA, Klaus N, Kramer A, Venkataraman S, Quinlan P, Gillespie B. The youth-nominated No eligible economic support team-version ii for suicidal adolescents: a randomized controlled intervention trial. Sick day management using Ineligible intervention blood 3-hydroxybutyrate (3-OHB) compared with urine ketone monitoring reduces hospital visits in young people with T1DM: a randomized clinical trial.
Similarly in the brain and putative N-linked glycosylation site was found at amino spleen generic cefuroxime 500mg free shipping,the pharmacologic rank order profile of CRF-related acid 203 buy cefuroxime,which agrees with the previous observation of the peptides for stimulation of adenylate cyclase is analogous presence of asparagine-linked sugar moieties on the native to the profile seen in pituitary and in keeping with the protein (49) generic cefuroxime 250mg with visa. Subsequent screening of a rat cerebral cortical affinities of these compounds for receptor binding buy cefuroxime 250mg low price. In addi- cDNA library,revealed the presence of a single clone con- tion,the putative CRF receptor antagonist -hel ovine taining a 1. The transduction mechanisms may be involved in the actions of pharmacology of these proteins appears to be similar with CRF. For example,CRF has been shown to increase protein both the rat and human binding proteins having high affin- carboxyl methylation,and phospholipid methylation in ity for the rat/human CRF (Kd 0. Preliminary evidence suggests that CRF affinity for the ovine form of CRF (Kd 250 nM). Al- may regulate cellular responses through products of arachi- though there may be some similarities in the binding do- donic acid metabolism (42). Furthermore,although the evi- mains of the binding protein and the CRF receptor (as dence in anterior pituitary cells suggests that CRF does not evidenced by the equal affinity of r/hCRF),these are distinct directly regulate phosphatidylinositol turnover or protein proteins,each with unique characteristics and distributions. Thus, the effects of CRF on anterior pituitary cells and possibly Although the human and rat forms of the CRF-BP are ho- in neurons and other cell types expressing CRF receptors mologous (as indicated),there is a somewhat different ana- are likely to involve complex interactions among several in- tomic distribution pattern in the two species. Peripheral expres- sion of the binding protein may have its greatest utility in CRF and Its Binding Protein in Human the modulation and control of the elevated levels of CRF Plasma in circulating plasma induced by various normal physiologic Under normal conditions,the plasma levels of CRF remain conditions (see the preceding). In addition,expression of low; however,CRF levels are markedly elevated in plasma this binding protein in the brain and pituitary offers addi- during the late gestational stages of pregnancy (43–45). The tional mechanisms by which CRF-related neuronal or neu- source of the pregnancy-associated CRF is most likely the roendocrine actions may be modulated. The CRF in brain regions including neocortex,hippocampus (primarily the maternal plasma is bioactive in releasing ACTH from in the dentate gyrus),and olfactory bulb. In spite of the high levels of brain,mRNA is localized to the amygdaloid complex with CRF in the maternal plasma,there is no evidence of mark- a distinct lack of immunostained cells in the medial nucleus. A plausible explanation for this paradoxic the brainstem particularly in the auditory,vestibular,and situation could be the presence of a binding protein in the trigeminal systems,raphe nuclei of the midbrain and pons, plasma of pregnant women that could specifically inhibit and reticular formation (50). In addition,high expression the biological actions of CRF (44,45). This hypothesis was levels of binding protein mRNA are seen in the anterior validated by the isolation of a CRF-binding protein (CRF- pituitary,predominantly restricted to the corticotrope cells. BP) from human plasma and its subsequent cloning and Expression of this protein in the corticotropes strongly sug- expression (see the following). Norepinephrine has been the interactions of CRF with its receptor,which is also reported to have both stimulatory and inhibitory effects on known to reside on corticotropes; however,the detailed role CRF release that may be a consequence of the dose adminis- of the binding protein in regulating pituitary–adrenal func- tered as well as the receptor subtype involved. Similarly,opioids have been re- ported to either inhibit or stimulate CRF release depending Regulation of Pituitary Hormone on the nature of the opioid tested,dose utilized,and recep- Secretion tor specificity ( versus ) involved. Drugs acting at CRF is the major physiologic regulator of the basal and GABA–benzodiazepine–chloride ionophore complex are stress-induced release of ACTH, -endorphin,and other potent inhibitors of CRF secretion. The extent and time course of changes POMC-derived peptides in anterior pituitary cells in culture in CRF in the paraventricular nucleus and median eminence and in vivo; these actions of CRF can be antagonized by of the hypothalamus following application of stress are the CRF receptor antagonist -helical ovine CRF(9-41) or highly dependent on the nature of the stressor as well as by immunoneutralization with an anti-CRF antibody. The effects of stress to increase eral other lines of evidence support a critical role for endoge- the release and synthesis of CRF are mediated by many of nous CRF in regulating ACTH secretion. For example,in- neurotransmitter systems described in the preceding. Administration of CRF anti- back regulation the hypothalamic–pituitary–adrenocortical sera or the CRF receptor antagonist results in attenuation of axis,are potent inhibitors of CRF release. Conversely,the stress- or adrenalectomy-induced ACTH secretion further absence of glucocorticoids following adrenalectomy results substantiating a role for CRF in regulating ACTH secretion in marked elevations in the synthesis and release of CRF. In addition to effects in the The actions of glucocorticoids to inhibit CRF release are anterior pituitary,CRF also has been reported to stimulate mediated directly at the level of the paraventricular nucleus POMC-derived peptide secretion from the intermediate of the hypothalamus as well as indirectly through actions lobe of the pituitary gland. Central administration of CRF inhibits the secretion of luteinizing hormone (LH) and growth hormone without Modulation of Pituitary CRF Receptors any major effects on follicle-stimulating hormone,thyroid Stress (29,32,33,53) or adrenalectomy (29,32,33) result in stimulating hormone,or prolactin secretion (3,4). The ef- hypersecretion of CRF and a consequent down-regulation fects of CRF to inhibit LH secretion appear to be mediated of receptors in the anterior pituitary. The adrenalectomy- at the hypothalamic level through effects of CRF to inhibit induced decreases in anterior pituitary receptors can be pre- gonadotropin releasing hormone secretion. CRF-induced vented by glucocorticoid replacement with corticosterone inhibition of LH secretion may also involve endogenous or dexamethasone (29,32,33). In addition, chronic adminis- opioids since the effects are attenuated by administration tration of corticosterone has been reported to cause dose- of naloxone or antiserum to -endorphin (3,4). An age-related decline in anterior pitui- Regulation of Hypothalamic CRF Release tary CRF receptors has also been reported (54). In contrast, lesions of the paraventricular nucleus that result in dramatic Plotsky and associates (52) and Owens and Nemeroff (4) reductions in hypothalamic CRF secretion have been re- provide a comprehensive review of the neurotransmitter reg- ported to increase the density of pituitary CRF receptors ulation of hypothalamic CRF release. Thus,CRF receptors in the anterior pituitary appear strate stimulatory effects of cholinergic and serotonergic to be reciprocally regulated by hypothalamic CRF release. The muscarinic and/or nicotinic cholinergic receptor subtypes involved in the stimulatory effects of acetylcholine on CRF secretion remain to be pre- CRF REGULATION OF CNS ACTIVITY cisely elucidated. The effects of serotonin to stimulate CRF Electrophysiologic Effects of CRF release appear to be mediated by a variety of receptor sub- types,including 5-HT2,5-HT1A,and 5-HT1C receptors. CRF stimulates the electrical activity of neurons in various The effects of catecholamines and opioids on hypothalamic brain regions that contain CRF and CRF receptors,includ- Chapter 7: Corticotropin-Releasing Factor 101 ing locus ceruleus (55),hippocampus (56),cerebral cortex, Gastrointestinal Effects of CRF and hypothalamus as well as in lumbar spinal cord motor Studies examining the gastrointestinal effects of CRF have neurons (3,4). In contrast, CRF has inhibitory actions in determined that CRF modulates gastrointestinal activity by the lateral septum,thalamus,and hypothalamic PVN (3, acting at central and possibly peripheral sites,and that these 4). The electrophysiologic effects of CRF on spontaneous effects are qualitatively similar to those observed following and sensory-evoked activity of locus ceruleus neurons are exposure to various stressors. Furthermore,dysfunc- and fecal excretion in a dose-dependent manner when ad- tion of this nucleus has been implicated in the pathophysiol- ministered centrally or systemically to dogs or rats. Centrally administered CRF equipotent in inhibiting gastric emptying in both species increases the spontaneous discharge rate of the locus ceru- following both central and peripheral routes of administra- leus in both anesthetized and unanesthetized rats,while de- tion. The central effects of CRF on gastric acid secretion creasing evoked activity in the nucleus (55). Thus,the over- do not appear to result from leakage of the peptide into all effect of CRF in the locus ceruleus is to decrease the peripheral blood because measurable quantities of CRF are signal to noise ratio between evoked and spontaneous dis- not present in the circulation following injection of CRF charge rates. Furthermore,an intrave- The effects of CRF on EEG activity have been reviewed nous injection of anti-CRF serum completely abolishes the in detail (3,4,57). CRF causes a generalized increase in EEG peripheral but not the central effect of CRF on gastric acid activity associated with increased vigilance and decreased secretion. These data strongly implicate CRF in the mecha- sleep time. Higher doses of the peptide, on the other hand,cause seizure activity that is indistin- guishable from seizures produced by electrical kindling of Behavioral Effects of CRF the amygdala,further confirming the role of CRF in brain activation. The behavioral effects of CRF in the CNS have been re- viewed extensively (3,4,61). The effects of CRF on behavior are dependent on both the dose of peptide administered Autonomic Effects of CRF and the specific conditions under which the tests are per- A great deal of anatomic,pharmacologic,and physiologic formed. Although very low doses of CRF produce example,central administration of CRF results in activation locomotor activation when tested in an open field test, of the sympathetic nervous system resulting in stimulation higher doses produce a dramatic decrease in locomotor ac- of epinephrine secretion from the adrenal medulla and nora- tivity. CRF administered intracerebrally also produces addi- drenergic outflow to the heart,kidney,and vascular beds. The behavioral effects of pathetic actions of the peptide. In contrast,CRF acts in CRF are not an indirect consequence of actions of the pep- brain to inhibit cardiac parasympathetic nervous activity. The physiologic role of CRF methasone that adequately block pituitary–adrenal activa- in regulating the autonomic nervous system is supported tion. Of critical importance is the observation that these by data demonstrating central effects of the CRF receptor effects of CRF can all be blocked by administration of the antagonist, -helical ovine CRF(9-41) to attenuate adrenal peptide antagonist -helical ovine CRF(9-41),strongly sup- epinephrine secretion resulting from stressors such as insu- porting a specific CRF receptor-mediated event in these lin-induced hypoglycemia,hemorrhage,and exposure to behaviors. Furthermore,the CRF receptor antagonist by ether vapor (59). Overall,these data substantiate a major itself attenuates many of the behavioral consequences of role for CRF in coordinating the autonomic responses to stress underscoring the role of endogenous peptide in me- stress. Furthermore,the inci- DISORDERS AND NEURODEGENERATIVE dence of depression in anorexia nervosa patients is high. DISEASES Like depressed patients,anorexics show a markedly attenu- ated ACTH response to intravenously administered CRF Major Depression and Anxiety Disorders (4,64,65). When the underweight anorexic subjects are Many patients with major depression are hypercortisolemic studied after their body weight had been restored to normal, and exhibit an abnormal dexamethasone suppression test.
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