Eddie Weitzberg - Academia.edu (original) (raw)

Papers by Eddie Weitzberg

Free Radical Biology and Medicine, 2012

Endogenous nitric oxide (NO) generated from L-arginine by NO synthase regulates mitochondrial fun... more Endogenous nitric oxide (NO) generated from L-arginine by NO synthase regulates mitochondrial function by binding to cytochrome c oxidase in competition with oxygen. This interaction can elicit a variety of intracellular signaling events of both physiological and pathophysiological significance. Recent lines of research demonstrate that inorganic nitrate and nitrite, derived from oxidized NO or from the diet, are metabolized in vivo to form NO and other bioactive nitrogen oxides with intriguing effects on cellular energetics and cytoprotection. Here we discuss the latest advances in our understanding of the roles of nitrate, nitrite, and NO in the modulation of mitochondrial function, with a particular focus on dietary nitrate and exercise.

NO generated from L-arginine by NO synthases (NOSs) in the endothelium and in other cells plays a... more NO generated from L-arginine by NO synthases (NOSs) in the endothelium and in other cells plays a central role in several aspects of vascular biology. The biological activity of NO is acutely terminated by oxidation to nitrite and nitrate, and these compounds have long been considered only as inert end-products of NO. However, this dogma is now being challenged because

Acta Physiologica Scandinavica, 1995

Biochemical and Biophysical Research Communications, 1991

Six healthy subjects were given endothelin-l, intravenously in a dose of 4 pmol " kg "I " min -I ... more Six healthy subjects were given endothelin-l, intravenously in a dose of 4 pmol " kg "I " min -I for 20 min. Blood samples were drawn from arterial, hepatic and renal vein catheters for determinations of splanchnic and renal blood flows and the extraction of endothelin-i in these vascular beds. Intravenous infusion of endothelin-i increased the mean arterial blood pressure by 6.8 ± 2.0 mm Hg (p<0.05) and reduced splanchnic and renal blood flows by 34% (p<0.005) and 26% (p<0.001) respectively. Return to basal flow values occurred after about 1 hr for the splanchnic and 3 hrs for the renal blood flow. The fractional extractions of endothelin-l-like immunoreactivity corresponded to 75 ± 2% and 60 ± 2% in the splanchnic and renal vascular beds, respectively.

Thorax, 1999

The past decade has witnessed an explosion in the interest of biologists in the gas nitric oxide ... more The past decade has witnessed an explosion in the interest of biologists in the gas nitric oxide (NO). This highly reactive free radical, first considered only a noxious air pollutant, is produced in mammalian cells by specific enzymes and is believed to play a vital role in many biological events including regulation of blood flow, platelet function, immunity, and

Acta Physiologica Scandinavica, 1997

A continuous production of nitric oxide (NO) takes place in human nasal airways. NO in the nasal ... more A continuous production of nitric oxide (NO) takes place in human nasal airways. NO in the nasal airways is mainly derived from the paranasal sinuses. The factors that regulate NO synthesis in the upper airways are presently not known. We have investigated the effects of physical exercise on NO levels in the nasal airways. Nasal cavity NO levels were measured by chemiluminescence technique in five healthy non-smoking male subjects before, during and after 5 min of maximal exercise (245 W) on an ergometer cycle. In addition, in one subject NO levels were measured directly in the maxillary sinus during exercise. Nasal cavity NO levels were decreased by 47 % after only 1 min of exercise compared with the control situation. A maximal 76 % reduction was found at the end of the exercise period and thereafter NO levels slowly increased, reaching basal levels again in about 15-20 min. NO levels in the sinus decreased in a similar manner during exercise. The decrease in nasal cavity NO levels cannot be explained merely by dilution of nasal air due to changes in nasal cavity volume or increased ventilation. We conclude that the excretion of NO in the nasal airways is decreased acutely during heavy short term physical exercise.

Acta Physiologica Scandinavica, 1996

The vasodilator gas nitric oxide (NO) is produced in the paranasal sinuses and is excreted contin... more The vasodilator gas nitric oxide (NO) is produced in the paranasal sinuses and is excreted continuously into the nasal airways of humans. This NO will normally reach the lungs with inspiration, especially during nasal breathing. We wanted to investigate the possible effects of low-dose inhalation of NO from the nasal airways on pulmonary function. The effects of nasal and oral breathing on transcutaneous oxygen tension (tcPO2) were studied in healthy subjects. Furthermore, we also investigated whether restoring low-dose NO inhalation would influence pulmonary vascular resistance index (PVRI) and arterial oxygenation (PaO2) in intubated patients who are deprived of NO produced in the nasal airways. Thus, air derived from the patient's own nose was aspirated and led into the inhalation limb of the ventilator. In six out of eight healthy subjects tcPO2 was 10% higher during periods of nasal breathing when compared with periods of oral breathing. In six out of six long-term intubated patients PaO2 increased by 18% in response to the addition of nasal air samples. PVRI was reduced by 11% in four of 12 short-term intubated patients when nasal air was added to the inhaled air. The present study demonstrates that tcPO2 increases during nasal breathing compared with oral breathing in healthy subjects. Furthermore, in intubated patients, who are deprived of self-inhalation of endogenous NO. PaO2 increases and pulmonary vascular resistance may decrease by adding NO-containing air, derived from the patient's own nose, to the inspired air. The involvement of self-inhaled NO in the regulation of pulmonary function may represent a novel physiological principle, namely that of an enzymatically produced airborne messenger. Furthermore, our findings may help to explain one biological role of the human paranasal sinuses.

European Journal of Pharmacology, 1993

Nitric oxade (10 ppm) inhaled by pigs before or during endotoxln shock induced by an infusion of ... more Nitric oxade (10 ppm) inhaled by pigs before or during endotoxln shock induced by an infusion of E coh lipopolysacchande Nitric oxade inhalation selectively attenuated pulmonary hypertension during endotoxln infusion without influencing mean arterml blood pressure and cardtac output Upon cessation of nitric oxade inhalation, pulmonary artery pressure rapidly increased to levels seen m endotoxm-treated controls The oxygenation and pH of arterial blood were significantly higher m the ammals receiving mtnc oxide A marked increase m arterial plasma noradrenahne and neuropept~de Y was seen m endotorantreated control pigs whde m the mtnc oxide-treated pigs this increase was markedly reduced The increase In arterial plasma endothehn-1 was not influenced by mtric orade inhalation Infusion of L-arglnme (substrate for mtnc oxide synthesis) also attenuated the pulmonary hypertension but was not selectwe for the pulmonary vasculature L-Nltro-arglnme (a nitric oxide synthesis inhibitor) lnltmted a rapid but brief elevahon of arterial blood pressure and of pulmonary artery pressure as well as a reduction m cardiac output Nitric oxade inhalation selectively reduces pulmonary hypertension in porcine endotoxln shock and improves arterial oxygenation and pH with a marked attenuation of sympathetic actwatlon Nitric oxide (NO), Endotoxan shock, Pulmonary hypertension, Adult respiratory distress syndrome (ARDS), Endothehn, Noradrenahne, Neuropeptlde Y

Critical Care Medicine, 2001

Levosimendan is a novel inodilator that improves cardiac contractility by sensitizing troponin C ... more Levosimendan is a novel inodilator that improves cardiac contractility by sensitizing troponin C to calcium. This drug has proved to be effective in treating advanced congestive heart failure but has not been evaluated in septic settings. The purpose of the present study was to study the effects of this drug in a porcine model of endotoxemia. Prospective experimental study. Fourteen landrace pigs. All animals were anesthetized and catheterized for measurement of central and pulmonary hemodynamics. Ultrasonic flow probes were placed around the renal artery and portal vein to measure blood flow. A tonometer was placed in the ileum to measure mucosal pH. Levosimendan was given to six animals as a bolus (200 microg x kg(-1)) followed by a continuous infusion (200 microg x kg(-1) x hr(-1)). Thirty minutes after onset of levosimendan treatment, all animals received endotoxin (20 microg x kg(-1) x hr(-1) for 3 hrs). At baseline, levosimendan induced a systemic vasodilation with a reduction in blood pressure and an increase in heart rate. A tendency to an increase in cardiac index did not reach statistical significance (p =.055). Cardiac index and systemic oxygen delivery were markedly improved in the levosimendan group during endotoxemia. Systemic vascular resistance and blood pressure were reduced in the levosimendan group. The latter parameter, however, was only different from the control group during the initial phase of endotoxin shock but not at the late, most pronounced phase of shock. Levosimendan also efficiently attenuated endotoxin-induced pulmonary hypertension. Portal venous blood flow and gut oxygen delivery were improved, but no concomitant reduction in endotoxin-induced intestinal mucosal acidosis was observed. Renal blood flow was unaffected, as was the endotoxin-induced increase in plasma endothelin-1-like immunoreactivity. These findings support previous reports of calcium desensitization as a potential component in septic myocardial depression. Furthermore, the vasodilatory properties of this drug were well tolerated in the current model of hypodynamic endotoxin shock, and they may have contributed to improved regional blood flow as seen in the gut as well as improved systemic perfusion by means of reduced biventricular afterload. Pretreatment with levosimendan in pigs subjected to endotoxin shock improved cardiac output and systemic and gut oxygen delivery. In addition, pulmonary hypertension largely was attenuated without any adverse effects on gas exchange. These results are promising in several aspects, but the role of levosimendan in the treating circulatory failure in sepsis remains to be established.

Clinical Physiology, 1993

To investigate the effects and elimination of endothelin-1 in humans, an intravenous infusion of ... more To investigate the effects and elimination of endothelin-1 in humans, an intravenous infusion of endothelin-1 (ET-1) (4 pmol kg-1 min-1 for 20 min) was given to 10 healthy volunteers. Arterial plasma endothelin-1 like immunoreactivity (ET-1-LI) increased eleven-fold. The fractional extraction of ET-1-LI was 41% and 30% across the pulmonary and skeletal muscle vascular beds, respectively. The lung eliminated almost half of the administered ET-1. No fractional extraction was found in the cerebral circulation. The pulmonary oxygen uptake (VO2) was increased slightly by endothelin-1. Across both the cerebral and skeletal muscle vascular beds the arterio-venous oxygen difference decreased (P < 0.05), suggesting vasodilation, the effect lasting up to 1 h after the end of endothelin-1 infusion in the cerebral circulation. Arterial-pulmonary artery oxygen difference increased by 20%. ET-1 infusion led to a decrease in heart rate (10%), cardiac output (14%) and stroke volume (8%) (all with P < 0.05) as well as a 7% increase in mean arterial blood pressure. Pulmonary and systemic vascular resistance increased by 67% and 25%, respectively (P < 0.05). These results demonstrate the regional differences in the removal of circulating endothelin-1, the lung being mainly responsible for the plasma elimination. Endothelin-1 seems to exert both vasoconstrictive and vasodilatory actions in humans, probably depending on differences in receptor populations and endothelium configuration in various vascular beds.

European Journal of Pharmacology, 2000

The view of the endothelium as a passive barrier has gradually changed as a number of endothelium... more The view of the endothelium as a passive barrier has gradually changed as a number of endothelium-derived substances have been discovered. Substances like nitric oxide, prostaglandins and endothelins have potent and important properties, involving not only the circulation as such but also the response to stimuli like inflammation and trauma. The endothelin system, discovered in 1988, has not only strong

Nature Reviews Microbiology, 2004

Nitrate is generally considered a water pollutant and an undesirable fertilizer residue in the fo... more Nitrate is generally considered a water pollutant and an undesirable fertilizer residue in the food chain. Research in the 1970s indicated that, by reducing nitrate to nitrite, commensal bacteria might be involved in the pathogenesis of gastric cancers and other malignancies, as nitrite can enhance the generation of carcinogenic N-nitrosamines. More recent studies indicate that the bacterial metabolism of nitrate

Redox Biology, 2015

Background: Inorganic nitrate (NO 3 − ) is a precursor of nitric oxide (NO) in the body and a lar... more Background: Inorganic nitrate (NO 3 − ) is a precursor of nitric oxide (NO) in the body and a large number of short-term studies with dietary nitrate supplementation in animals and humans show beneficial effects on cardiovascular health, exercise efficiency, host defense and ischemia reperfusion injury. In contrast, there is a long withstanding concern regarding the putative adverse effects of chronic nitrate exposure related to cancer and adverse hormonal effects. To address these concerns we performed in mice, a physiological and biochemical multi-analysis on the effects of long-term dietary nitrate supplementation. Design: 7 week-old C57BL/6 mice were put on a low-nitrate chow and at 20 weeks-old were treated with NaNO 3 (1 mmol/L) or NaCl (1 mmol/L, control) in the drinking water. The groups were monitored for weight gain, food and water consumption, blood pressure, glucose metabolism, body composition and oxygen consumption until one group was reduced to eight animals due to death or illness. At that point remaining animals were sacrificed and blood and tissues were analyzed with respect to metabolism, cardiovascular function, inflammation, and oxidative stress. Results: Animals were supplemented for 17 months before final sacrifice. Body composition, oxygen consumption, blood pressure, glucose tolerance were measured during the experiment, and vascular reactivity and muscle mitochondrial efficiency measured at the end of the experiment with no differences identified between groups. Nitrate supplementation was associated with improved insulin response, decreased plasma IL-10 and a trend towards improved survival. Conclusions: Long term dietary nitrate in mice, at levels similar to the upper intake range in the western society, is not detrimental.

Antioxidants & Redox Signaling, 2014

Abstract Aims: Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as ... more Abstract Aims: Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as alternative substrates for nitric oxide (NO) formation in addition to the classic L-arginine NO synthase (NOS)-dependent pathway. Here we investigated a potential crosstalk between these two pathways in regulation of vascular function.

Proceedings of the National Academy of Sciences, 2010

The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk... more The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes. A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Recently, an alternative pathway for NO formation in mammals was described where inorganic nitrate, a supposedly inert NO oxidation product and unwanted dietary constituent, is serially reduced to nitrite and then NO and other bioactive nitrogen oxides. Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions. In humans, this dose corresponds to a rich intake of vegetables, the dominant dietary nitrate source. Nitrate administration increased tissue and plasma levels of bioactive nitrogen oxides. Moreover, chronic nitrate treatment reduced visceral fat accumulation and circulating levels of triglycerides and reversed the prediabetic phenotype in these animals. In rats, chronic nitrate treatment reduced blood pressure and this effect was also present during NOS inhibition. Our results show that dietary nitrate fuels a nitratenitrite-NO pathway that can partly compensate for disturbances in endogenous NO generation from eNOS. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against cardiovascular disease and type 2 diabetes. glucose | insulin | s-nitrosothiol | obesity | bacteria

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014

The maximum power principle dictates that open biological systems tend to self-organize to a leve... more The maximum power principle dictates that open biological systems tend to self-organize to a level of efficiency that allows maximal power production. Applying this principle to cellular energetics and whole-body physiology would suggest that for every metabolic challenge, an optimal efficiency exists that maximizes power production. On exposure to hypoxia, it would be favorable if metabolic efficiency would rapidly adjust so as to better preserve work performance. We tested this idea in humans by measuring metabolic efficiency and exercise tolerance under normoxic (Fio2=20.9%) and hypoxic (Fio2=16%) conditions, where Fio2 is fraction of inhaled oxygen. The results were compared with respirometric analyses of skeletal muscle mitochondria from the same individuals. We found that among healthy trained subjects (n=14) with a wide range of metabolic efficiency (ME), those with a high ME during normoxic exercise were able to better maintain exercise capacity (Wmax) in hypoxia. On hypoxic...

Drug design, development and therapy, 2015

The current study describes novel multifunctional polymer-shelled microbubbles (MBs) loaded with ... more The current study describes novel multifunctional polymer-shelled microbubbles (MBs) loaded with nitric oxide (NO) for integrated therapeutic and diagnostic applications (ie, theranostics) of myocardial ischemia. We used gas-filled MBs with an average diameter of 4 μm stabilized by a biocompatible shell of polyvinyl alcohol. In vitro acoustic tests showed sufficient enhancement of the backscattered power (20 dB) acquired from the MBs' suspension. The values of attenuation coefficient (0.8 dB/cm MHz) and phase velocities (1,517 m/s) were comparable with those reported for the soft tissue. Moreover, polymer MBs demonstrate increased stability compared with clinically approved contrast agents with a fracture threshold of about 900 kPa. In vitro chemiluminescence measurements demonstrated that dry powder of NO-loaded MBs releases its gas content in about 2 hours following an exponential decay profile with an exponential time constant equal to 36 minutes. The application of high-powe...

Urology, 1997

The bacteriostatic gas nitric oxide (NO) is formed when nitrite is acidified. Infected urine may ... more The bacteriostatic gas nitric oxide (NO) is formed when nitrite is acidified. Infected urine may contain considerable amounts of nitrite as a result of bacterial nitrate reductase activity, and detection of nitrite in urine is routinely used in the diagnosis of bacterial cystitis. We sought to determine whether NO was generated from acidified nitrite-containing urine. Furthermore, we also studied the growth of the urinary pathogen Escherichia coll in acidified nitrite-containing urine. Urine, collected from healthy control subjects or from patients with infected nitrite-containing urine, was acidified and incubated in a closed syringe with varying amounts of nitrite added. After 30 minutes, the headspace gas was removed and immediately injected into a chemiluminescence NO analyzer. In addition, NO was measured in urine collected from healthy control subjects after ingestion of vitamin C. Bacterial growth was measured continuously in control urine for 10 hours after incubation for 2 ...

Free radical biology & medicine, 2015

The kidney is vulnerable to hypoxia, and substantial efforts have been made to ameliorate renal i... more The kidney is vulnerable to hypoxia, and substantial efforts have been made to ameliorate renal ischemic injury secondary to pathological conditions. Stimulation of the nitrate-nitrite-nitric oxide pathway is associated with renal and cardiovascular protection in disease models, but less is known about the vascular effects during renal ischemia. This study aimed at investigating the vascular effects of nitrite in the kidney during normoxia and ischemic condition. Using a multi wire myograph system, nitrite-mediated relaxation (10(-9)-10(-4)mol/L) was assessed in preconstricted isolated renal interlobar arteries (ILA) from C57BL6 mice during normal conditions (pO213kPa; pH 7.4) and with low oxygen tension and low pH to mimic ischemia (pO2 3kPa; pH 6.6). Xanthine oxidoreductase expression was analyzed by quantitative PCR, and production of reactive nitrogen species was measured by DAF-FM DA fluorescence. During normoxia significant vasodilatation (15±3%) was observed only at the highe...