Increased AT 1 receptor expression and mRNA in kidney glomeruli of AT 2 receptor gene-disrupted mice

The proposed feedback between angiotensin II AT2 and AT1 receptors prompted us to study AT1 receptor expression in kidneys of male AT2 receptor-gene disrupted mice (agtr2 −/y). In wild-type (agtr2 +/y) mice, AT1 receptor binding and mRNA is abundant in glomeruli, and AT1 receptor binding is also high in the inner stripe of the outer medulla. AT2 receptors are scarce, primarily associated to cortical vascular structures. In agtr2 −/y mice, AT1 receptor binding and mRNA were increased in the kidney glomeruli, and AT1 receptor binding was higher in the rest of the cortex and outer stripe of the outer medulla, but not in its inner stripe, indicating different cellular regulation. Although AT2 receptor expression is very low in male agtr 2 +/y mice, their gene disruption alters AT1 receptor expression. AT1 upregulation alone may explain the AT2 gene-disrupted mice phenotype such as increased blood pressure, higher sensitivity to angiotensin II, and altered renal function. The indirect AT1/AT2 receptor feedback could have clinical significance because AT1antagonists are widely used in medical practice.Fil: Saavedra, Juan M.. National Institute of Mental Health; Estados UnidosFil: Häuser, Walter. National Institute of Mental Health; Estados UnidosFil: Ciuffo, Gladys Maria. National Institute of Mental Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Egidy, Giorgia. National Institute of Mental Health; Estados UnidosFil: Hoe, Kwang Lae. National Institute of Mental Health; Estados UnidosFil: Jöhren, Olaf. National Institute of Mental Health; Estados UnidosFil: Sembonmatsu, Takaaki. Vanderbilt University; Estados UnidosFil: Inagami, Tadashi. Vanderbilt University; Estados UnidosFil: Armando, Inés. National Institute of Mental Health; Estados Unido

Systematic review with meta-analysis: the impact of a depressive state on disease course in adult inflammatory bowel disease

Background Despite a higher prevalence of psychosocial morbidity in Inflammatory Bowel Disease (IBD), the association between depressive state and disease course in IBD is poorly understood. Aim To investigate the impact of depressive state on disease course in IBD. Methods We conducted a systematic review in MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and PsychINFO for prospective studies evaluating the impact of baseline depressive state on subsequent disease course in adult IBD. Results Eleven studies matched our entry criteria, representing 3194 patients with IBD. Three reported on patients with ulcerative colitis (UC), four included patients with Crohn's disease (CD) exclusively, and four studies included both UC and CD. Five studies reported an association between depressive state and disease course. None of the UC‐specific studies found any association. In three of four CD‐specific studies, a relationship between depressive state and worsening disease course was found. In four of five studies including patients in remission at baseline, no association between depressive state and disease course was found. Pooled analysis of IBD studies with patients in clinical remission at baseline identified no association between depressive state and disease course (HR 1.04, 95%CI: 0.97‐1.12). Conclusion There is limited evidence to support an association between depressive state and subsequent deterioration in disease course in IBD, but what data that exist are more supportive of an association with CD than UC. Baseline disease activity may be an important factor in this relationship. Further studies are needed to understand the relationship between mental health and outcomes in IBD

Modification of Noradrenaline Release in Pithed Spontaneously Hypertensive Rats by I 1 -Binding Sites in Addition to ␣ 2 -Adrenoceptors

ABSTRACT It is known that moxonidine acts as an agonist at presynaptic ␣ 2 -adrenoceptors of the postganglionic sympathetic nerve terminals and leads to a reduction in noradrenaline release. In addition, it is conceivable that I 1 -binding sites located in other regions of the pre-and postganglionic sympathetic neurons are involved in this effect. Our aim was to investigate whether and to what extent activation of the I 1 -binding sites contributes to the moxonidine-induced inhibition of noradrenaline release. Noradrenaline release was induced in pithed spontaneously hypertensive rats (pretreated with phenoxybenzamine/desipramine at 10/0.5 mg/kg) by stimulation of sympathetic overflow from the spinal cord. Noradrenaline overflow was reduced using moxonidine (0.18, 0.6, and 1.8 mg/kg) by 39.4, 70.4, or 78.7%, respectively, even when all ␣ 1 -/␣ 2 -adrenoceptors were blocked effectively by phenoxybenzamine. In contrast, the I 1 -antagonist efaroxan (0.1, 1, and 3 mg/kg) increased noradrenaline overflow from 453 (control) to 1710, 1999, or 2754 pg/ml, suggesting an autoreceptor-like function of I 1 -binding sites. In consequence, moxonidine (0.18, 0.6, and 1.8 mg/kg) reduced the increase in noradrenaline overflow in efaroxan-treated animals (1 mg/kg) by 22.7, 41.7, and 50.5%, respectively. Agmatine (6 and 60 mg/kg), an endogenous agonist at I 1 -binding sites, reduced noradrenaline overflow (Ϫ36 or 53%), even under ␣ 2 -adrenoceptor blockade. When 2-endo-amino-3-exoisopropylbicyclo[2.2.1]heptane (AGN192403) (10 mg/kg) was injected, a selective blocker of I 1 -binding sites, noradrenaline overflow was not influenced by agmatine. It is concluded that moxonidine reduces noradrenaline overflow by acting at I 1 -binding sites in addition to its agonistic property at ␣ 2 -adrenoceptors. The exact location of the I 1 -binding sites on the pre-or postsynaptic sympathetic neurons is unknown, but the location in the pre-or postsynaptic membrane of the sympathetic ganglion is the most plausible explanation. Clonidine and the related compounds moxonidine and rilmenidine that induce inhibition of noradrenaline release from sympathetic neurons are second line antihypertensives. Recently, the presynaptic ␣ 2 -adrenoceptor mediating an inhibition of noradrenaline release from sympathetic nerves at which these compounds act was subclassified as the ␣ 2A -and ␣ 2

Increased angiotensin II AT\u3csub\u3e1\u3c/sub\u3e receptor expression in paraventricular nucleus and hypothalamic-pituitary-adrenal axis stimulation in AT\u3csub\u3e2\u3c/sub\u3e receptor gene disrupted mice

Angiotensin II AT2 receptor gene-disrupted mice have increased blood pressure and response to angiotensin II, behavioral alterations, greater response to stress, and increased adrenal AT1 receptors. We studied hypothalamic AT1 receptor binding and mRNA by receptor autoradiography and in situ hybridization, adrenal catecholamines by HPLC, adrenal tyrosine hydroxylase mRNA by in situ hybridization and pituitary and adrenal hormones by RIA in AT2 receptor-gene disrupted mice and wild-type controls. To confirm the role of adrenal AT1 receptors, we treated wild-type C57 BL/6J mice with the AT1 antagonist candesartan for 2 weeks, and measured adrenal hormones, catecholamines and tyrosine hydroxylase mRNA. In the absence of AT2 receptor transcription, we found increased AT1 receptor binding in brain areas involved in the regulation of the hypothalamic-pituitary-adrenal axis, the hypothalamic paraventricular nucleus and the median eminence, and increased adrenal catecholamine synthesis as shown by higher adrenomedullary tyrosine hydroxylase mRNA and higher adrenal dopamine, norepinephrine and epinephrine levels when compared to wild-type mice. In addition, in AT2 receptor gene-disrupted mice there were higher plasma adrenocorticotropin (ACTH) and corticosterone levels and lower adrenal aldosterone content when compared to wild-type controls. Conversely, AT1 receptor inhibition in CB57 BL/6J mice reduced adrenal tyrosine hydroxylase mRNA and catecholamine content and increased adrenal aldosterone content. These results can help to explain the enhanced response of AT2 receptor gene-disrupted mice to exogenous angiotensin II, support the hypothesis of cross-talk between AT1 and AT2 receptors, indicate that the activity of the hypothalamic-pituitary-adrenal axis parallels the AT1 receptor expression, and suggest that expression of AT1 receptors can be dependent on AT2 receptor expression. Our results provide an explanation for the increased sensitivity to stress in this model. Copyright © 2002 S. Karger AG, Basel

Increased AT\u3csub\u3e1\u3c/sub\u3e receptors in adrenal gland of AT\u3csub\u3e2\u3c/sub\u3e receptor gene-disrupted mice

Angiotensin II (Ang II) AT2 receptor-gene disrupted mice have increased systemic blood pressure and response to exogenous Angiotensin II. To clarify the mechanism of these changes, we studied adrenal AT1 receptor expression and mRNA by receptor autoradiography and in situ hybridization in female AT2 receptor-gene disrupted mice (agtr 2-/-) and wild-type controls (agtr 2+/+). We found high expression of AT1 receptor binding and mRNA in adrenal zona glomerulosa of female wild-type mice. AT2 receptors and mRNA were highly expressed in adrenal medulla of wild-type mice, but were not detected in zona glomerulosa. There was no AT2 receptor binding or mRNA in adrenal glands of AT2 receptor-gene disrupted mice. In these animals, AT1 receptor binding and mRNA were increased in adrenal zona glomerulosa and AT1 receptor mRNA was increased in the adrenal medulla when compared with wild-type animals. The present data support the hypothesis of an interaction or cross talk between AT2 and AT1 receptors in adrenal gland. The significant increase in AT1 receptor expression in the absence of AT2 receptor transcription may be partially responsible for the increased blood pressure and for the enhanced response to exogenously administered Angiotensin II in this model. Published by Elsevier Science B.V