Angiotensin II AT2 Receptors Contribute to Regulate the Sympathoadrenal and Hormonal Reaction to Stress Stimuli.

Angiotensin II, through AT1 receptor stimulation, mediates multiple cardiovascular, metabolic, and behavioral functions including the response to stressors. Conversely, the function of Angiotensin II AT2 receptors has not been totally clarified. In adult rodents, AT2 receptor distribution is very limited but it is particularly high in the adrenal medulla. Recent results strongly indicate that AT2 receptors contribute to the regulation of the response to stress stimuli. This occurs in association with AT1 receptors, both receptor types reciprocally influencing their expression and therefore their function. AT2 receptors appear to influence the response to many types of stressors and in all components of the hypothalamic-pituitary-adrenal axis. The molecular mechanisms involved in AT2 receptor activation, the complex interactions with AT1 receptors, and additional factors participating in the control of AT2 receptor regulation and activity in response to stressors are only partially understood. Further research is necessary to close this knowledge gap and to clarify whether AT2 receptor activation may carry the potential of a major translational advance.

Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade.

Non-synonymous GRK4 variants, R65L, A142V and A486V, are associated with essential hypertension in diverse populations. This study replicated the association of GRK4 variants, including GRK4(142V), with human essential hypertension in a Japanese population (n=588; hypertensive, n=486 normotensive controls) and determined whether the presence of GRK4 variants predicted the blood pressure (BP) response to angiotensin receptor blockers (ARBs) in patients with essential hypertension. We analyzed 829 patients and compared the response to ARBs between individuals with no GRK4 variants (n=136) and those with variants at one or any of the three loci (n=693). Carriers of hGRK4(142V) had a greater decrease in systolic BP in response to ARBs than non-carrier hypertensive patients. By contrast, those with variants only at GRK4(486V) were less likely to achieve the BP goal in response to an ARB than those with no variants. These studies showed for the first time the association between GRK4(142V) and a larger decrease in BP with ARBs in hypertensive patients.

Synthesis of photochromic oligophenylenimines: optical and computational studies.

Phenyleneimine oligomers 4,4'-(((1E,1'E)-(((1E,1'E)-(1,4-phenylenebis-(azanylylidene))bis(methanylylidene))bis(2,5-bis(octyloxy)-4,1-phenylene))bis(methanylyl-idene))-bis(azanylylidene))dianiline (OIC1MS) and 7,7'-(((1E,1'E)-(((1E,1'E)-((9H-fluorene-2,7-diyl)bis(azanylylidene))bis(methanylylidene))bis(2,5-bis(octyloxy)-4,1phenylene))bis- (methanylylidene))bis(azanylylidene))bis(9H-fluoren-2-amine) (OIC2MS) were prepared by means of conventional and mechanochemical synthesis and characterized by FT-IR, 1H- and 13C-NMR techniques. The optical properties of the compounds were studied in solution by using UV-visible spectroscopy, and the optical effects were analyzed as a function of solvent. The results show that OIC2MS exhibits interesting photochromic properties. Furthermore, the structural and electronic properties of the compounds were analyzed by TD-DFT. It was found that the mechanosynthesis is an efficient method for the synthesis of both tetraimines.

Clostridioides difficile colonization is not mediated by bile salts and requires Stickland fermentation of proline in an in vitro model of infection.

Treatment with antibiotics is a major risk factor for Clostridioides difficile infection, likely due to depletion of the gastrointestinal microbiota. Two microbiota-mediated mechanisms thought to limit C. difficile colonization include conversion of conjugated primary bile salts into secondary bile salts toxic to C. difficile growth, and competition between the microbiota and C. difficile for limiting nutrients. Using a continuous flow model of the distal colon, we investigated how treatment with six clinically-used antibiotics influenced susceptibility to C. difficile infection in 12 different microbial communities cultivated from healthy individuals. Antibiotic treatment reduced microbial richness; disruption varied by antibiotic class and microbiota composition, but did not correlate with C. difficile susceptibility. Antibiotic treatment also disrupted microbial bile salt metabolism, increasing levels of the primary bile salt, cholate, and decreasing levels of the secondary bile salt, deoxycholate. However, decreased levels of deoxycholate did not correlate with increased C. difficile susceptibility. Further, bile salts were not required to inhibit C. difficile colonization. We tested whether amino acid fermentation contributed to persistence of C. difficile in antibiotic-treated communities. C. difficile mutants unable to use proline as an electron acceptor in Stickland fermentation due to disruption of proline reductase (ΔprdB) had significantly lower levels of colonization than wild-type strains in four of six antibiotic-treated communities tested. This data provides further support for the importance of bile salt-independent mechanisms in regulating colonization of C. difficile.

Identification of Simplified Microbial Communities That Inhibit Clostridioides difficile Infection through Dilution/Extinction.

The gastrointestinal microbiome plays an important role in limiting susceptibility to infection with Clostridioides difficile To better understand the ecology of bacteria important for C. difficile colonization resistance, we developed an experimental platform to simplify complex communities of fecal bacteria through dilution and rapidly screen for their ability to resist C. difficile colonization after challenge, as measured by >100-fold reduction in levels of C. difficile in challenged communities. We screened 76 simplified communities diluted from cultures of six fecal donors and identified 24 simplified communities that inhibited C. difficile colonization in vitro Sequencing revealed that simplified communities were composed of 19 to 67 operational taxonomic units (OTUs) and could be partitioned into four distinct community types. One simplified community could be further simplified from 56 to 28 OTUs through dilution and retain the ability to inhibit C. difficile We tested the efficacy of seven simplified communities in a humanized microbiota mouse model. We found that four communities were able to significantly reduce the severity of the initial C. difficile infection and limit susceptibility to disease relapse. Analysis of fecal microbiomes from treated mice demonstrated that simplified communities accelerated recovery of indigenous bacteria and led to stable engraftment of 19 to 22 OTUs from simplified communities. Overall, the insights gained through the identification and characterization of these simplified communities increase our understanding of the microbial dynamics of C. difficile infection and recovery.IMPORTANCEClostridioides difficile is the leading cause of antibiotic-associated diarrhea and a significant health care burden. Fecal microbiota transplantation is highly effective at treating recurrent C. difficile disease; however, uncertainties about the undefined composition of fecal material and potential long-term unintended health consequences remain. These concerns have motivated studies to identify new communities of microbes with a simpler composition that will be effective at treating disease. This work describes a platform for rapidly identifying and screening new simplified communities for efficacy in treating C. difficile infection. Four new simplified communities of microbes with potential for development of new therapies to treat C. difficile disease are identified. While this platform was developed and validated to model infection with C. difficile, the underlying principles described in the paper could be easily modified to develop therapeutics to treat other gastrointestinal diseases.

Cardiac imaging studies in the COVID-19 pandemic.

COVID-19 is an acute respiratory syndrome caused by coronavirus-2 (SARS COV2). The different cardiac imaging methods have issued specific recommendations for the different imaging methods in this pandemic, so it is essential to emphasize the recommendations for carrying out these studies.

El COVID-19 es un síndrome respiratorio agudo ocasionado por el coronavirus-2 (SARS COV2). Los diferentes métodos de imagen cardiaca han dictado recomendaciones específicas de los diferentes métodos de imagen en esta pandemia, por lo que es indispensable recalcar las recomendaciones para la realización de estos estudios.

Excerpts from the documents of Mexican positions and recommendations in cardiovascular diseases and COVID-19.

The recommendations in which the Mexican Society of Cardiology (SMC) in conjunction with the National Association of Cardiologists of Mexico (ANCAM) as well as different Mexican medical associations linked to cardiology are presented, after a comprehensive and consensual review and analysis of the topics related to cardiovascular diseases in the COVID-19 pandemic. Scientific positions are analyzed and responsible recommendations on general measures are given to patients, with personal care, healthy eating, regular physical activity, actions in case of cardio-respiratory arrest, protection of the patient and health personnel as well as precise indications in the use of non-invasive cardiovascular imaging, prescription of medications, care in specific topics such as systemic arterial hypertension, heart failure, arrhythmias and acute coronary syndromes, in addition to emphasizing electrophysiology, interventionism, cardiac surgery and in cardiac rehabilitation. The main interest is to provide the medical community with a general orientation on what to do in daily practice and patients with cardiovascular diseases in the setting of this unprecedented epidemiological crisis of COVID-19.

Se presentan las recomendaciones en las cuales la Sociedad Mexicana de Cardiología (SMC) en conjunto con la Asociación Nacional de Cardiólogos de México (ANCAM), así como diferentes asociaciones médicas mexicanas vinculadas con la cardiología, después de una revisión y análisis exhaustivo y consensuado sobre los tópicos relacionados con las enfermedades cardiovasculares en la pandemia de COVID-19, se analizan posturas científicas y se dan recomendaciones responsables sobre medidas generales a los pacientes, con cuidados personales, alimentación saludable, actividad física regular, acciones en caso de paro cardiorrespiratorio, la protección del paciente y del personal de salud así como las indicaciones precisas en el uso de la imagen cardiovascular no invasiva, la prescripción de medicamentos, cuidados en tópicos específicos como en la hipertensión arterial sistémica, insuficiencia cardiaca, arritmias y síndromes coronarios agudos, además de hacer énfasis en los procedimientos de electrofisiología, intervencionismo, cirugía cardiaca y en la rehabilitación cardiaca. El interés principal es brindar a la comunidad médica una orientación general sobre el quehacer en la práctica cotidiana y pacientes con enfermedades cardiovasculares en el escenario esta crisis epidemiológica sin precedentes de COVID-19.

Angiotensin II AT(1) receptor blockade selectively enhances brain AT(2) receptor expression, and abolishes the cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the locus coeruleus of spontaneously hypertensive rats.

Spontaneously hypertensive rats, a stress-sensitive strain, were pretreated orally for 14 days with the AT(1) receptor antagonist candesartan before submission to 2 h of cold-restraint stress. In non-treated rats, stress decreased AT(1) receptor binding in the median eminence and basolateral amygdala, increased AT(2) receptor binding in the medial subnucleus of the inferior olive, decreased AT(2) binding in the ventrolateral thalamic nucleus and increased tyrosine hydroxylase mRNA level in the locus coeruleus. In non-stressed rats, AT(1) receptor blockade reduced AT(1) receptor binding in all areas studied and enhanced AT(2) receptor binding in the medial subnucleus of the inferior olive. Candesartan pretreatment produced a similar decrease in brain AT(1) binding after stress, and prevented the stress-induced AT(2) receptor binding decrease in the ventrolateral thalamic nucleus. In the locus coeruleus and adrenal medulla, AT(1) blockade abolished the stress-induced increase in tyrosine hydroxylase mRNA level. Our results demonstrate that oral administration of candesartan effectively blocked brain AT(1) receptors, selectively increased central AT(2) receptor expression and prevented the stress-induced central stimulation of tyrosine hydroxylase transcription. The present results support a role of brain AT(1) and AT(2) receptors in the regulation of the stress response, and the hypothesis that AT(1) receptor antagonists may be considered as potential therapeutic compounds in stress related disorders in addition to their anti-hypertensive properties.

Positron emission tomographic imaging of cardiac sympathetic innervation using 6-[18F]fluorodopamine: initial findings in humans.

OBJECTIVES: This study evaluated the safety, efficacy and validity of 6-[18F]fluorodopamine positron emission tomographic scanning of cardiac sympathetic innervation and function in humans. METHODS: Positron emission tomography (PET) scans, arterial blood and urine were obtained after a 3-min intravenous infusion of 6-[18F]fluorodopamine (1 to 4 mCi, 188 to 809 mCi/mmol) in healthy volunteers, with or without pretreatment with oral desipramine to inhibit neuronal uptake of catecholamines. RESULTS: 6-[18F]Fluorodopamine PET scanning visualized the left ventricular myocardium. Blood pressure increased slightly and transiently. The estimated absorbed radiation dose to the main target organ, the wall of the urinary bladder, was 0.8 to 1.0 rad/mCi of injected 6-[18F]fluorodopamine. By 24 h after the injection, the main 6F-compound in urine was 6F-vanillymandelic acid, a metabolite of 6F-norepinephrine. Desipramine attenuated accumulation of myocardial 6-[18F]fluorodopamine-derived radioactivity and plasma 6F-dihydroxyphenylacetic acid. CONCLUSIONS: 6-[18F]Fluorodopamine produces negligible hemodynamic effects and acceptable radiation exposure at doses that visualize the left ventricular myocardium. Sympathetic nerves take up 6-[18F]fluorodopamine, which is translocated from the axoplasm into storage vesicles, where is it beta-hydroxylated to the fluorinated analogue of the sympathetic neurotransmitter norepinephrine. Therefore, the basis for visualization of myocardium after 6-[18F]fluorodopamine injection in humans is radiolabeling by 6-[18F]fluorodopamine and 6-[18F]fluoronorepinephrine of vesicles in sympathetic terminals. 6-[18F]Fluorodopamine PET scanning provides a novel means for assessing sympathetic innervation and function noninvasively in the human heart.

Estudios de imagen cardiaca en la pandemia COVID-19 / Cardiac imaging studies in the COVID-19 pandemic

Resumen El COVID-19 es un síndrome respiratorio agudo ocasionado por el coronavirus-2 (SARS COV2). Los diferentes métodos de imagen cardiaca han dictado recomendaciones específicas de los diferentes métodos de imagen en esta pandemia, por lo que es indispensable recalcar las recomendaciones para la realización de estos estudios.

Abstract COVID-19 is an acute respiratory syndrome caused by coronavirus-2 (SARS COV2). The different cardiac imaging methods have issued specific recommendations for the different imaging methods in this pandemic, so it is essential to emphasize the recommendations for carrying out these studies.

Extractos de los documentos de posicionamientos y recomendaciones mexicanas en enfermedades cardiovasculares y COVID-19 / Excerpts from the documents of Mexican positions and recommendations in cardiovascular diseases and COVID-19

Resumen Se presentan las recomendaciones en las cuales la Sociedad Mexicana de Cardiología (SMC) en conjunto con la Asociación Nacional de Cardiólogos de México (ANCAM), así como diferentes asociaciones médicas mexicanas vinculadas con la cardiología, después de una revisión y análisis exhaustivo y consensuado sobre los tópicos relacionados con las enfermedades cardiovasculares en la pandemia de COVID-19, se analizan posturas científicas y se dan recomendaciones responsables sobre medidas generales a los pacientes, con cuidados personales, alimentación saludable, actividad física regular, acciones en caso de paro cardiorrespiratorio, la protección del paciente y del personal de salud así como las indicaciones precisas en el uso de la imagen cardiovascular no invasiva, la prescripción de medicamentos, cuidados en tópicos específicos como en la hipertensión arterial sistémica, insuficiencia cardiaca, arritmias y síndromes coronarios agudos, además de hacer énfasis en los procedimientos de electrofisiología, intervencionismo, cirugía cardiaca y en la rehabilitación cardiaca. El interés principal es brindar a la comunidad médica una orientación general sobre el quehacer en la práctica cotidiana y pacientes con enfermedades cardiovasculares en el escenario esta crisis epidemiológica sin precedentes de COVID-19.

Abstract The recommendations in which the Mexican Society of Cardiology (SMC) in conjunction with the National Association of Cardiologists of Mexico (ANCAM) as well as different Mexican medical associations linked to cardiology are presented, after a comprehensive and consensual review and analysis of the topics related to cardiovascular diseases in the COVID-19 pandemic. Scientific positions are analyzed and responsible recommendations on general measures are given to patients, with personal care, healthy eating, regular physical activity, actions in case of cardio-respiratory arrest, protection of the patient and health personnel as well as precise indications in the use of non-invasive cardiovascular imaging, prescription of medications, care in specific topics such as systemic arterial hypertension, heart failure, arrhythmias and acute coronary syndromes, in addition to emphasizing electrophysiology, interventionism, cardiac surgery and in cardiac rehabilitation. The main interest is to provide the medical community with a general orientation on what to do in daily practice and patients with cardiovascular diseases in the setting of this unprecedented epidemiological crisis of COVID-19.

Catecholamines levels and parotid secretion in children with chronic atopic dermatitis.

The purpose of this study was to evaluate the in vivo state of both branches of the autonomic nervous system in children with chronic atopic dermatitis. In 15 patients, age 4 to 11, the following parameters were analyzed: (1) basal plasma levels of epinephrine, norepinephrine, and dopamine; (2) poststimulation (standing and i.v. furosemide administration); (3) basal urinary excretion of epinephrine, norepinephrine, and vainillin mandelic acid; (4) 30 min postfurosemide administration; (5) parotid secretory response to intraoral 0.1 m citric acid: flow rate, saliva pH, and concentrations of bicarbonate, chlorides, inorganic phosphates, total protein, and amylase activity. No differences in plasma and urinary basal levels of the catecholamines were observed. In response to standing, plasma norepinephrine from atopic children showed a greater increase than that seen in normal healthy children. From the salivary factors studied, no differences were found in parotid flow-rate, bicarbonates, chlorides, and inorganic phosphates. Protein concentration as well as amylase activity were significantly decreased in children with atopic dermatitis. These findings suggest that in atopic dermatitis, the beta-sympathetic mediated responses are impaired; on the other hand, parasympathetic mediated responses remain preserved.

Hypercortisolemia inhibits yohimbine-induced release of norepinephrine in the posterolateral hypothalamus of conscious rats.

Chronic hypercortisolemia attenuates yohimbine (YOH)-induced increments in plasma levels of the sympathetic neurotransmitter norepinephrine (NE). The present study used in vivo microdialysis to study the effects of hypercortisolemia on YOH-induced release of NE in the brain. Cortisol (25 mg/kg.day) or saline was infused sc into rats for 7 days via an osmotic minipump. Microdialysate and plasma concentrations of NE and its metabolites dihydroxyphenylglycol and methoxyhydroxyphenylglycol were measured before and after YOH (1 mg/kg, iv) administration in conscious animals, with microdialysate and plasma collections beginning 20-24 h after probe implantation. Chronic cortisol treatment resulted in attenuated NE, dihydroxyphenylglycol, and methoxyhydroxyphenylglycol responses in both microdialysate and plasma. The results indicate that YOH increases central neural as well as peripheral release, reuptake, turnover, and metabolism of NE and that hypercortisolemia suppresses these responses.

Peripheral administration of an angiotensin II AT(1) receptor antagonist decreases the hypothalamic-pituitary-adrenal response to isolation Stress.

Angiotensin II, which stimulates AT(1) receptors, is a brain and peripheral stress hormone. We pretreated rats with the AT(1) receptor antagonist candesartan for 13 d via sc-implanted osmotic minipumps, followed by 24-h isolation in individual metabolic cages. We measured angiotensin II receptor-type binding and mRNAs and tyrosine hydroxylase mRNA by quantitative autoradiography and in situ hybridization, catecholamines by HPLC, and hormones by RIA. Isolation increased AT(1) receptor binding in hypothalamic paraventricular nucleus as well as anterior pituitary ACTH, and decreased posterior pituitary AVP. Isolation stress also increased AT(1) receptor binding and AT(1B) mRNA in zona glomerulosa and AT(2) binding in adrenal medulla, adrenal catecholamines, tyrosine hydroxylase mRNA, aldosterone, and corticosterone. Candesartan blocked AT(1) binding in paraventricular nucleus and adrenal gland; prevented the isolation-induced alterations in pituitary ACTH and AVP and in adrenal corticosterone, aldosterone, and catecholamines; abolished the increase in AT(2) binding in adrenal medulla; and substantially decreased urinary AVP, corticosterone, aldosterone, and catecholamines during isolation. Peripheral pretreatment with an AT(1) receptor antagonist blocks brain and peripheral AT(1) receptors and inhibits the hypothalamic-pituitary-adrenal response to stress, suggesting a physiological role for peripheral and brain AT(1) receptors during stress and a possible beneficial effect of AT(1) antagonism in stress-related disorders.

Total plasma dopamine/norepinephrine ratio in catecholamine-secreting tumors. Its relation to hypertension.

We used a radioenzymatic method to determine plasma levels of free and total (free plus sulfoconjugated) norepinephrine and dopamine in 20 children with neuroblastoma (two were hypertensive), seven patients with pheochromocytoma, and 39 normotensive controls (24 children and 15 adults). No significant differences were noted between the two control groups. Patients with neuroblastoma and pheochromocytoma showed significantly higher levels of free and total norepinephrine than controls (p less than 0.01), and those with pheochromocytoma had higher levels than those with neuroblastoma (p less than 0.01). Although the differences were not statistically significant, free dopamine was higher in both groups of patients than in controls. Total dopamine was significantly higher in patients than in controls (p less than 0.01). A positive correlation was noted between levels of total norepinephrine and total dopamine in controls (r = 0.41, p less than 0.05) and in patients with neuroblastoma (r = 0.72, p less than 0.001). Such a correlation was not found in patients with pheochromocytoma. The total dopamine/total norepinephrine ratio was higher (p less than 0.005) in patients with neuroblastoma than in controls and patients with pheochromocytoma. Patients with pheochromocytoma had significantly lower ratios than the other groups (p less than 0.001). A negative correlation was found between the ratios in the different groups and either systolic (p less than 0.001) or diastolic (p less than 0.001) blood pressure. Our results not only support a role for plasma dopamine in the regulation of blood pressure but also suggest that, regardless of the actual levels of both catecholamines, a balance has to be achieved in order to maintain normal blood pressure levels.

Potential role of glycerol leading to rat fructose hypertension.

A fructose-enriched diet promotes hypertension in rats. We thought that an enhancement of the glycolytic and/or lipid disorder (s) that raise blood pressure could be the cause. Therefore, we studied 4 groups of Sprague-Dawley rats (+/-200 g): (1) control rats received a standard diet and tap water; (2) the glycerol group of rats received a standard diet and 0.54 mol/L glycerol in tap water; (3) the fructose group was given a fructose-enhanced diet (chow had 55% fructose instead of dextrin) and tap water; and (4) the fructose-glycerol group was given the fructose-enhanced diet and 0. 54 mol/L glycerol in drinking water. At the end of the second week, the findings were as follows. Blood pressure was 149+/-2 mm Hg in the fructose-glycerol group versus 129+/-2 (P<0.001), 131+/-2 (P<0. 001), and 140+/-3 (P<0.005) mm Hg in the control, glycerol, and fructose groups, respectively. Insulinemia was higher in the fructose-glycerol group than the control (P<0.001), glycerol (P<0. 001), and fructose groups (P<0.001); triglyceridemia was higher in the fructose-glycerol (P<0.02), fructose (P<0.05), and glycerol groups (P<0.02) than the control group. Thoracic aorta rings showed a lower ED(50) to 12,13-phorbol dibutyrate in the fructose-glycerol group than in the control (P<0.001), glycerol (P<0.002), and fructose groups (P<0.001). In conclusion, glycerol-fructose administration resulted in hypertriglyceridemia, hyperinsulinemia, and increased vascular sensitivity to 12,13-phorbol dibutyrate (with respect to the control group), and significantly greater expression of protein kinase C alpha and betaII (with respect to the glycerol group).

Endogenous dopa and dopamine responses to dietary salt loading in salt-sensitive rats.

We measured daily urinary excretion rates of dopamine and dopa during dietary salt loading and natriuretic responses to exogenous dopamine in Dahl salt-sensitive (DS), Dahl salt-resistant (DR) and Sprague-Dawley rats. Excretion rates of dopa increased approximately sixfold during salt loading in all rat strains. Maximal urinary dopa responses were attained within 1 day of salt loading. Daily excretion rates of dopamine also increased about five- to sixfold in DS and DR rats and about twofold in Sprague-Dawley rats, with maximal dopamine responses attained by day 5. Dopamine infusion (3 micrograms/kg per min) increased urinary sodium excretion by 406 +/- 132 % (mean +/- s.e.m.) in Sprague-Dawley rats but only 267 +/- 131% and 147 +/- 80% in DS and DR rats (P less than 0.05 for Sprague-Dawley versus Dahl rats). The results demonstrate that salt loading markedly and rapidly increases dopa excretion in rats. Considering values for dopamine excretion in other rat strains, the results suggest that Dahl rats have increased formation of dopamine for a given amount of dopa delivery to the kidney and that this abnormality is unrelated to salt-sensitive hypertension in DS rats. The results also provide in vivo support for the view that the responsiveness of renal dopamine receptors mediating natriuresis is related to production of endogenous dopamine in the kidney.

Angiotensin II AT1 and AT2 receptor types regulate basal and stress-induced adrenomedullary catecholamine production through transcriptional regulation of tyrosine hydroxylase.

The sympathoadrenal response to stress includes a profound increase in adrenomedullary catecholamine synthesis driven by stimulation of tyrosine hydroxylase (TH) transcription. We studied the role of Angiotensin II type 1 and 2 (AT(1) and AT(2)) receptors during isolation stress, and under basal conditions. Pretreatment of rats with the AT(1) receptor antagonist candesartan for 14 days prior to isolation completely prevented the stress-induced stimulation of catecholamine synthesis, decreasing tyrosine hydroxylase transcription by preventing the expression of the transcriptional factor, Fos-related antigen 2 (Fra-2). In addition, AT(1) receptor antagonism prevented the stress-induced increase in adrenomedullary AT(2) receptor binding and protein. Treatment of non-stressed, grouped animals under basal conditions with the AT(1) receptor or with PD 123319, an AT(2) receptor antagonist, decreased the adrenomedullary norepinephrine (NE) content and TH transcription. While AT(1) receptor antagonism decreased the levels of Fra-2 and the phosphorylated forms of cAMP responsive element binding protein (pCREB) and EKR2 (p-ERK2, phosphor-p42 MAP kinase), the AT(2) antagonist decreased Fra-2 with no change in the phosphorylation of CREB or EKR2. Our results demonstrate that both adrenomedullary AT(1) and AT(2) receptor types maintain and promote the adrenomedullary catecholamine synthesis and the transcriptional regulation of TH. Instead of opposing effects, however, our results indicate a complex synergistic regulation between the AT(1) and AT(2) receptor types.

Brain angiotensin II, an important stress hormone: regulatory sites and therapeutic opportunities.

The presence of a brain Angiotensin II (Ang II) system, separated from and physiologically integrated with the peripheral, circulating renin-angiotensin system, is firmly established. Ang II is made in the brain and activates specific brain AT(1) receptors to regulate thirst and fluid metabolism. Some AT(1) receptors are located outside the blood-brain barrier and are sensitive to brain and circulating Ang II. Other AT(1) receptors, located inside the blood-brain barrier, respond to stimulation by Ang II of brain origin. AT(1) receptors in the subfornical organ, the hypothalamic paraventricular nucleus (PVN), and the median eminence are involved in the regulation of the stress response. In particular, AT(1) receptors in the PVN are under glucocorticoid control and regulate corticotrophin-releasing hormone (CRH) formation and release. In the PVN, restraint elicits a fast increase in AT(1) receptor mRNA expression. The expression of paraventricular AT(1) receptors is increased during repeated restraint and after 24 h of isolation stress, and their stimulation is essential for the hypothalamic-pituitary-adrenal axis activation, the hallmark of the stress response. Peripheral administration of an AT(1) receptor antagonist blocks peripheral and brain AT(1) receptors, prevents the sympathoadrenal and hormonal response to isolation stress, and prevents the gastric stress ulcers that are a characteristic consequence of cold-restraint stress. This evidence indicates that pharmacologic inhibition of the peripheral and brain Ang II system by AT(1) receptor blockade has a place in the prevention and treatment of stress-related disorders.

Angiotensin II AT1 receptor blockade prevents gastric ulcers during cold-restraint stress.

Cold-restraint stress reduces gastric blood flow and produces acute gastric ulcers. We studied the role of Angiotensin II (Ang II) on gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats, a stress-sensitive strain, were pretreated for 14 days with the AT(1) receptor antagonist candesartan before cold-restraint stress. AT(1) blockade increased gastric blood flow 40% to 50%; prevented gastric ulcer formation by 70% to 80%; reduced the increase in adrenomedullary epinephrine and TH mRNA without preventing the stress-induced increase in adrenal corticosterone; decreased the stress-induced expression of tumor necrosis factor alpha (TNF-alpha) and adhesion protein ICAM-1 in arterial endothelium, and neutrophil infiltration in the gastric mucosa; and decreased PGE(2) content. AT(1) receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, anti-inflammatory effects with reduction in TNF-alpha, and ICAM-1 expression, leading to reduced neutrophil infiltration while maintaining the protective glucocorticoid effects and PGE(2) release. Ang II has a crucial role, through stimulation of AT(1) receptors, in the production and progression of stress-induced gastric injury, and AT(1) receptor antagonists could be of therapeutic benefit.