Abstract-The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O 2 Ϫ ) was examined. O 2 Ϫ generation, measured by lucigenin chemiluminescence, was studied in 12-to 16-week male and female Wistar-Kyoto rats (WKY) Key Words: superoxide Ⅲ endothelium Ⅲ nitric oxide Ⅲ rats, inbred SHR Ⅲ nitric oxide synthase E ndothelial dysfunction and a relative deficiency in nitric oxide (NO) may be associated with hypertension in humans 1,2 and in some models of experimental hypertension. 3,4 In the spontaneously hypertensive stroke-prone rat (SHRSP), a model of genetic hypertension, we have shown an attenuation of functional basal NO despite increased eNOS enzymatic activity. 5 Although endothelial NO synthase (eNOS) enzymatic activity was greater in SHRSP than in Wistar-Kyoto rats (WKY) when examined in vitro the possibility that the actual amount of eNOS was reduced in SHRSP in vivo could not be excluded from these results. Alternatively, eNOS levels could be similar or elevated but NO availability decreased because of more rapid removal after synthesis. Superoxide anion (O 2 Ϫ ) is produced in the vasculature and can scavenge NO forming peroxynitrite. Increased scavenging of NO by O 2 Ϫ could lead to a decrease in NO availability despite increased synthesis. Raised O 2 Ϫ levels have been reported recently in a number of models of endothelial dysfunction including hypertension, induced by either angiotensin infusion 6 or aortic banding. 7 In the majority of cases the source of excess O 2 Ϫ is uncertain, although involvement of NADH/NADPH oxidases 8 and xanthine oxidase 9 have been suggested.The aim of this study was to examine the hypothesis that the decreased NO availability observed in SHRSP is due to excess O 2 Ϫ , to identify the source of this O 2 Ϫ , and to examine other molecular mechanisms involved such as the expression of the gene-encoding enzyme involved in NO generation in the endothelium (eNOS). Methods AnimalsThree-to 4-month-old male and female WKY and SHRSP were obtained from the colonies established in Glasgow by brother and sister mating as previously described. 9 Blood pressure was measured 1 week before study by tail plethysmography according to our published protocol. 10

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

Much attention has been focused on the role of nitric oxide in hypertension and cardiovascular disease. More recently, the role of superoxide anion and its interaction with nitric oxide has been investigated in this context. This review will concentrate on the role of superoxide in human and experimental hypertension, paying particular attention to the potential sources of superoxide within the vasculature and discussing some of the molecular mechanisms surrounding its production and dismutation. We discuss what is known about the human superoxide dismutase enzymes. We conclude that the balance between nitric oxide and superoxide is more important than the absolute levels of either alone.

Abstract-There is evidence in humans that hypertension and aging similarly impair endothelial function, although the mechanism remains unclear. Superoxide anion (O 2 Ϫ ) is a major determinant of nitric oxide (NO) bioavailability and thus endothelial function. We sought to determine the relationship between endothelial function, O 2 Ϫ , and age in normotensive Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Aortic rings were removed from female WKY and SHRSP at 3 to 4 months (young) and 9 to 12 months (old). O 2 Ϫ generation by aortic rings was measured before and after removal of the endothelium or incubation with N G nitro-L-arginine methyl ester, diphenyleneiodonium, or apocynin. Levels of p22phox were studied with immunohistochemistry and used as a marker of NAD (P) Key Words: endothelium Ⅲ nitric oxide Ⅲ hypertension, experimental Ⅲ aging T here is evidence that in animal models and in humans, impaired endothelial function and a decrease in nitric oxide (NO) bioavailability may occur in hypercholesterolemia, 1,2 , diabetes, 3 and hypertension 4 -6 despite normal or increased NO production by the endothelium. 6 A decrease in NO bioavailability may also occur with aging. [7][8][9][10] In a number of animal models of disease, including hypertension 11,12 and hypercholesterolemia, 13 an increase in superoxide (O 2 Ϫ ) occurs concurrent to the decrease in NO bioavailability. O 2 Ϫ rapidly reacts with NO, forming peroxynitrite and decreasing NO bioavailability. 14 Thus, it has been proposed that elevations in O 2 Ϫ levels contribute to the impaired endothelial function associated with atherosclerotic disease. 13,15 Taddei et al 9 proposed that the endothelial dysfunction that occurs in hypertension represents an accelerated form of the dysfunction that occurs with aging. However, the effects of aging on O 2 Ϫ production are less well defined. Huraux and colleagues 16 observed a negative correlation between O 2 Ϫ levels and age in human internal mammary arteries. In contrast, Berry et al 17 found basal O 2 Ϫ production in human internal mammary arteries to be weakly but positively associated with age. Potential vascular sources of O 2 Ϫ are endothelial NO synthase (eNOS), 18 xanthine oxidase, 19 and NAD(P)H oxidase. 20,21 eNOS 18 and NAD(P)H oxidase 22,23 have been proposed to be involved in O 2 Ϫ production in different models of hypertension, whereas xanthine oxidase may be involved in O 2 Ϫ production in hypercholesterolemia. 13 eNOS can be inhibited by arginine analogues such as N G nitro-L-arginine methyl ester (L-NAME). NAD(P)H oxidase is composed of at least 5 subunits, and apocynin can inhibit enzymatic activity by preventing association of the subunits. Diphenyleneiodonium (DPI) is a less specific inhibitor of flavincontaining oxidases, including NAD(P)H oxidase.In this study, the hypothesis that both hypertension and aging result in increased levels of O 2 Ϫ and decreased NO bioavailability in blood vessels from Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertens...

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.

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A deficiency of nitric oxide may be responsible for the increased vascular resistance associated with human essential hypertension and that seen in animal models of hypertension. Premenopausal females are relatively protected from hypertension and cardiovascular complications. Levels of superoxide can influence the availability of nitric oxide. We hypothesize that there are differences in nitric oxide availability between stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) and that superoxide may be responsible for at least some of these differences. We studied vascular reactivity in endothelium-intact aortic rings from WKY and SHRSP. We measured nitric oxide synthase activity in endothelial cells removed from aortas and also measured circulating nitrite/nitrate levels. We found the response to N(G)-nitro-L-arginine methyl ester to be significantly greater in WKY compared with SHRSP (95% CI: 20 to 174; P=.015) and in females compared with males in WKY (95% CI: 143 to 333; P=.00004) and SHRSP (95% CI: 70 to 224; P=.0006). Endothelial nitric oxide synthase activity was significantly greater in SHRSP compared with WKY (95% CI: 2.3 to 17.6; P=.016). The EC50 for relaxation to carbachol was significantly greater in male rats compared with female rats (95% CI: -1.1 to -0.2; P=.003) within the SHRSP strain. The maximum relaxation to carbachol was significantly attenuated in stroke prone spontaneously hypertensive compared with Wistar-Kyoto rats (95% CI: 1.7 to 14.4; P=.015). Diethyldithiocarbamate had a significantly greater effect on the stroke prone spontaneously hypertensive rats' carbachol response than that of Wistar-Kyoto rats (95% CI: 14.3 to 47.0; P=.0008). We conclude that superoxide may be responsible for strain differences in vascular reactivity, whereas nitric oxide availability may be responsible for sex differences independently of endothelial nitric oxide synthase activity and superoxide.

While aetiology and TTI were the two independent significant predictive factors for energy requirement, duration of atrial fibrillation was the only independent predictor of cardioversion success in a multivariate analysis. Conclusions-Electrode pad position is not a determinant of cardioversion success rate or energy requirement.