DOCA/salt hypertension alters Period1 and orexin-related gene expression in the medulla and hypothalamus of male rats: Diurnal influences.

In peripheral tissues, aldosterone alters expression of multiple genes, including the clock gene Period 1 (Per1), 11 beta-hydroxysteroid dehydrogenase-2 (11-HSD2), and α-ENAC, the epithelial sodium channel subunit. We evaluated the impact of chronic aldosterone exposure (DOCA) and salt intake on nocturnal changes in gene expression in the male Sprague Dawley rat brain. Additionally, genes associated with the orexin (ORX) system were also evaluated based on the role of this neuropeptide in arousal, feeding and hypertension and an interconnection with Per1 expression. DOCA/salt treatment increased saline intake primarily at night, elevated arterial pressure and lowered heart rate. In the medulla oblongata, DOCA/salt upregulated Per1, 11-HSD2, and α-ENAC expression independent of time of day, but did not change ORX receptor type 1 (ORX-R1) or type 2 (ORX-R2) expression. ORX-R1, and ORX-R2 expression in the medulla did however correlate with Per1 expression following DOCA/salt treatment but not in controls. In the hypothalamus, DOCA/salt treatment upregulated Per1, ORX-A, and ORX-R2 expression, in general, and Per1 and ORX-A expression at night. ORX-A, ORX-R1 and ORX-R2 expression in the hypothalamus correlated with Per1 expression following DOCA/salt but not in controls. These findings demonstrate for the first time that DOCA/salt hypertension modulates ORX gene expression in the brain and suggest that changes in expression in the ORX system may occur directly or indirectly via aldosterone-induced changes in Per1 expression. Our findings also build on emerging evidence that monitoring gene expression during both the day and night is critical to understanding the role of specific genes in hypertension.

The impact of psychiatric and extraintestinal comorbidity on quality of life and bowel symptom burden in functional GI disorders.

BACKGROUND: Functional gastrointestinal disorders (FGID) patients report poor health-related quality of life (HRQOL) and experience high rates of psychiatric and extraintestinal functional disorder (EIFD) comorbidity. The independent influence of these comorbidities on HRQOL and symptom burden remains unknown. We sought to determine whether FGID with mood or EIFD comorbidity have poorer HRQOL and greater GI symptom burdens; to determine the influence of comorbidities on HRQOL in FGID independent of bowel symptoms. METHODS: Subjects reported on comorbidities (anxiety, depression, somatization, EIFD), FGID criteria (irritable bowel syndrome, IBS; functional dyspepsia, FD) using ROME III Research questionnaire, GI symptom burden, and HRQOL. Differences in measures were assessed between subjects with and without ROME III criteria. Multiple regression determined the relative contribution of comorbidities to HRQOL, and mediation analysis explored whether comorbidity influences HRQOL. KEY RESULTS: In a cohort of 912 GI outpatients (47.2 ± 1.5 years, 75.8% female), 606 (66.4%) met Rome III IBS and/or FD criteria. Comorbidities were common in FGID (≥1 in 77.4%), leading to lower HRQOL and greater GI symptom burden (each p < 0.05). Poorer HRQOL was predicted by both psychiatric and EIFD comorbidity (each p < 0.05) independent of GI symptoms (p < 0.001). Comorbidities together exerted a greater effect on predicted variation in HRQOL (70.9%) relative to GI symptoms (26.5%). CONCLUSIONS & INFERENCES: Psychiatric and EIFD comorbidities are common in FGID, decrease HRQOL and are associated with greater GI symptom burdens; these factors were stronger predictors of HRQOL than GI symptoms in FGID patients.