Previous experiments have suggested that the vascular smooth muscle of Dahl salt-sensitive (DS) rats may possess a difference in the alpha1-adrenoceptor population or its transduction processes compared to Dahl salt-resistant (DR) rats. The purpose of the current research is to study the role of alpha1-adrenoceptors in the specific supersensitivity to norepinephrine (NE) seen prior to and early in the development of hypertension in the DS rat. Experiments in isolated perfused superior mesenteric arterial vasculature from DS rats chronically fed a high (7%) salt diet for 5 days or 3 weeks, in the absence or presence of an elevation in systolic blood pressure, respectively, demonstrated a specific supersensitivity to NE relative to DR rats. The enhanced responsiveness was specific to NE after 5 days of high salt since no differences in sensitivity of these preparations was observed to either KCl or 5-HT. A small but significant elevation in sensitivity to KCl following 3 weeks of treatment suggests that multiple factors may contribute to tissue responsiveness at this time. Radioligand binding experiments were performed using [125I]-HEAT to study the alpha1-adrenoceptor population and its subtypes. Saturation experiments using membranes prepared from the superior mesenteric arterial vasculature or mesenteric arterial branches showed no significant differences in overall alpha1-adrenoceptor population between DS and DR rats fed a high-salt diet for 5 days or 3 weeks. Competition experiments using membranes prepared from the superior mesenteric arterial branches in the presence of the alpha1A-subtype selective antagonist 5-methylurapidil showed two binding sites (high and low affinity) in these resistance vessels but no significant differences in nature or ratio of these sites between the DS and DR groups. These results suggest that changes in the alpha1-adrenoceptor population are not responsible for the specific supersensitivity to NE, which may be an early event in the induction and development of hypertension.

Introduction Concerns have been raised about the practical use and clinical benefits of medications and inhalers in older patients with chronic obstructive pulmonary disease (COPD). Here, we report analyses according to age from five clinical trials evaluating medications administered using the ELLIPTA dry-powder inhaler (DPI). Methods Efficacy and safety according to age groups (<65 and ≥65 years) were assessed using data from five clinical trials in patients ≥40 years of age with symptomatic COPD. There was a mix of pre-specified and post hoc analyses of two 24-week trials with fluticasone furoate (FF)/vilanterol (VI) 100/25 µg; one 24-week trial with umeclidinium (UMEC) 62.5 µg; and two 12-week trials with UMEC 62.5 µg + FF/VI 100/25 µg. The primary endpoint was trough forced expiratory volume in 1 second (FEV 1 ) obtained 23 and 24 hours after dosing on the last day of the study. Results A total of 2876 patients <65 years of age and 2148 patients ≥65 years of age were enrolled across all studies of whom 1333 and 1111 patients, respectively, received treatment at the doses presented. Statistically significant and clinically meaningful treatment differences in improvement from baseline in mean trough FEV 1 were reported for active comparators versus placebo at study end for both <65 and ≥65 years subgroups (FF/VI vs placebo: 143 mL and 111 mL; UMEC vs placebo: 110 mL and 123 mL; UMEC + FF/VI vs placebo + FF/VI: 136 mL and 105 mL; p<0.001 for all comparisons). The incidence of adverse events reported for active treatments was similar between age groups. Conclusion These data provide evidence to support the use of FF/VI, UMEC, or UMEC + FF/VI, all delivered via the ELLIPTA DPI, to treat older (≥65 years) and younger (<65 years) patients with COPD.

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Our laboratory developed an isolated perfused superior mesenteric arterial vascular bed preparation to study and correlate vascular smooth-muscle mechanics with associated biochemical events. This preparation provides consistent dose-dependent contractile responses, contains most of the superior mesenteric artery as well as first-, second-, and third-generation arterioles, and has been used for concurrent functional and biochemical analysis of vascular smooth muscle. Preparations isolated from Sprague-Dawley rats produced rapid, dose-related vasoconstrictor responses to norepinephrine (NE) and KCl, while appearing to be unresponsive to periarterial nerve stimulation. Endothelial relaxations to bolus doses of acetylcholine (ACh) in the presence of a constant infusion of NE (10 microM) were limited, producing reductions of perfusion pressures of <25%. Receptor-binding studies conducted to evaluate alpha1-adrenoceptor subtypes revealed high- and low-affinity binding sites composing 91 and 9% of the overall population, respectively. A 60-s time course for contractile response and inositol 1,4,5-triphosphate (IP3) production revealed a significant but transient increase of IP3 that paralleled the contractile response generated by using bolus injections of NE (30 microg). This preparation offers the capacity to conduct perfusion studies investigating vasoconstrictor responses, as well as biochemical studies including receptor-binding and second-messenger assays in the same tissue.

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