No abstract

Tetrahydrobiopterin (BH 4 ) is an essential cofactor for nitric oxide synthases (NOS). This study investigated the effect of increasing BH 4 levels on hypoxia-induced pulmonary vasoconstriction (HPV).Sprague Dawley rats and hph-1 (BH 4 deficient) mice were given BH 4 before and during HPV in an isolated perfused lung preparation. BH 4 inhibited HPV in a concentration-dependent manner and increased NO metabolites in the perfusate. Bradykinin-induced reductions in HPV were blunted in hph-1 mice and pre-administration of BH 4 restored the response. The effect of BH 4 was attenuated by L-NAME (NOS inhibitor), PTIO (NO scavenger), and catalase (H 2 O 2 catalyser) administered prior to HPV but enhanced by MnTMPyP (superoxide dismutase mimetic). The effect of BH 4 on HPV was partially recapitulated by NH 4 , a stereoisomer that shares antioxidant properties with BH 4 but is not a NOS cofactor.The bioavailability of BH 4 is an important determinant of the pulmonary vascular response to hypoxia. Its effects are mediated via nitric oxide, hydrogen peroxide and its antioxidant properties, and are attenuated by oxidant stress. Pharmacological administration of BH 4 may have therapeutic potential in pulmonary hypertension.

Background Comprehensive geriatric assessment (CGA) has been in use for the last three decades. However, some doubts remain regarding its clinical use. Therefore, we aimed to capture the breadth of outcomes reported and assess the strength of evidence of the use of comprehensive geriatric assessment (CGA) for health outcomes in older persons. Methods Umbrella review of systematic reviews of the use of CGA in older adults searching in Pubmed, Embase, Scopus, Cochrane library and CINHAL until 05 November 2021. All possible health outcomes were eligible. Two independent reviewers extracted key data. The grading of evidence was carried out using the GRADE for intervention studies, whilst data regarding systematic reviews were reported as narrative findings. Results Among 1,683 papers, 31 systematic reviews (19 with meta-analysis) were considered, including 279,744 subjects. Overall, 13/53 outcomes were statistically significant (P < 0.05). There was high certainty of evidence that CGA reduces nursing home admission (risk ratio [RR] = 0.86; 95% confidence interval [CI]: 0.75–0.89), risk of falls (RR = 0.51; 95%CI: 0.29–0.89), and pressure sores (RR = 0.46; 95%CI: 0.24–0.89) in hospital medical setting; decreases the risk of delirium (OR = 0.71; 95%CI: 0.54–0.92) in hip fracture; decreases the risk of physical frailty in community-dwelling older adults (RR = 0.77; 95%CI: 0.64–0.93). Systematic reviews without meta-analysis indicate that CGA improves clinical outcomes in oncology, haematology, and in emergency department. Conclusions CGA seems to be beneficial in the hospital medical setting for multiple health outcomes, with a high certainty of evidence. The evidence of benefits is less strong for the use of CGA in other settings.

Endothelin-1 (ET-1) exerts its biological actions through two receptor subtypes: endothelin-A (ETA) receptor and endothelin-B (ETB) receptor. We demonstrated previously that ET-1 induces systemic and renal cortical vasoconstriction via ETA whereas ETB mediates medullary vasodilation. Congestive heart failure (CHF) is characterized by increased vascular resistance and impaired renal hemodynamic and excretory function. While the pathophysiological effects of ET-1 in CHF are well established, the status of ETA and ETB in the kidney is poorly characterized. The present study examined the immunostaining and localization of ETA and ETB in the renal cortex and medulla of rats with experimental CHF induced by aorto-caval fistula. Rats with CHF were further subdivided, based on their daily urinary sodium excretion, into rats with compensated (urinary sodium excretion > 1200 microEq/day) and decompensated CHF (urinary sodium excretion < 200 microEq/day). ETA is predominantly localized to the cortex mainly in the peritubular capillaries, and is upregulated in rats with compensated and decompensated CHF compared with sham controls. In contrast, ETB is preferentially expressed in the outer and inner medulla, mainly in the vasa recta, the thick ascending limb of Henle's loop and the collecting duct. While compensated CHF is associated with upregulation of ETB in the collecting duct and vasa recta, decompensated CHF is accompanied with enhanced ETB abundance in the vasa recta and remarkable downregulation of this receptor subtype in the collecting duct. The findings suggest that upregulation of ETA may lead to a decrease in cortical blood flow while upregulation of ETB in the vasa recta probably contributes to the preservation of medullary blood flow. Furthermore, downregulation of ETB in the collecting duct, only in rats with decompensated CHF, could contribute to sodium retention in that subgroup.