Nitrate: "the source makes the poison".

Interest in the role of dietary nitrate in human health and disease has grown exponentially in recent years. However, consensus is yet to be reached as to whether consuming nitrate from various food sources is beneficial or harmful to health. Global authorities continue to recommend an acceptable daily intake (ADI) of nitrate of 3.7 mg/kg-bw/day due to concerns over its carcinogenicity. This is despite evidence showing that nitrate consumption from vegetable sources, exceeding the ADI, is associated with decreased cancer prevalence and improvements in cardiovascular, oral, metabolic and neurocognitive health. This review examines the paradox between dietary nitrate and health and disease and highlights the key role of the dietary source and food matrix in moderating this interaction. We present mechanistic and epidemiological evidence to support the notion that consuming vegetable-derived nitrate promotes a beneficial increase in nitric oxide generation and limits toxic N-nitroso compound formation seen with high intakes of nitrate added during food processing or present in contaminated water. We demonstrate the need for a more pragmatic approach to nitrate-related nutritional research and guidelines. Ultimately, we provide an overview of our knowledge in this field to facilitate the various therapeutic applications of dietary nitrate, whilst maintaining population safety.

Dietary nitrate attenuates high-fat diet-induced obesity via mechanisms involving higher adipocyte respiration and alterations in inflammatory status.

Emerging evidence indicates that dietary nitrate can reverse several features of the metabolic syndrome, but the underlying molecular mechanisms still remain elusive. The aim of the present study was to explore mechanisms involved in the effects of dietary nitrate on the metabolic dysfunctions induced by high-fat diet (HFD) in mice. Four weeks old C57BL/6 male mice, exposed to HFD for ten weeks, were characterised by increased body weight, fat content, increased fasting glucose and impaired glucose clearance. All these metabolic abnormalities were significantly attenuated by dietary nitrate. Mechanistically, subcutaneous primary mouse adipocytes exposed to palmitate (PA) and treated with nitrite exhibited higher mitochondrial respiration, increased protein expression of total mitochondrial complexes and elevated gene expression of the thermogenesis gene UCP-1, as well as of the creatine transporter SLC6A8. Finally, dietary nitrate increased the expression of anti-inflammatory markers in visceral fat, plasma and bone marrow-derived macrophages (Arginase-1, Egr-2, IL-10), which was associated with reduction of NADPH oxidase-derived superoxide production in macrophages. In conclusion, dietary nitrate may have therapeutic utility against obesity and associated metabolic complications possibly by increasing adipocyte mitochondrial respiration and by dampening inflammation and oxidative stress.

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate.

Nitric oxide (NO) importantly contributes to cardiovascular homeostasis by regulating blood flow and maintaining endothelial integrity. Conversely, reduced NO bioavailability is a central feature during natural ageing and in many cardiovascular disorders, including hypertension. The inorganic anions nitrate and nitrite are endogenously formed after oxidation of NO synthase (NOS)-derived NO and are also present in our daily diet. Knowledge accumulated over the past two decades has demonstrated that these anions can be recycled back to NO and other bioactive nitrogen oxides via serial reductions that involve oral commensal bacteria and various enzymatic systems. Intake of inorganic nitrate, which is predominantly found in green leafy vegetables and beets, has a variety of favourable cardiovascular effects. As hypertension is a major risk factor of morbidity and mortality worldwide, much attention has been paid to the blood pressure reducing effect of inorganic nitrate. Here, we describe how dietary nitrate, via stimulation of the nitrate-nitrite-NO pathway, affects various organ systems and discuss underlying mechanisms that may contribute to the observed blood pressure-lowering effect.

Heparin-binding protein as a biomarker of post-injury sepsis in trauma patients.

BACKGROUND: Heparin-binding protein (HBP) is a neutrophil-derived protein advocated as a biomarker in sepsis. We evaluated plasma HBP as a predictor of post-injury sepsis in trauma patients. METHODS: Ninety-seven trauma patients were studied during the first week of intensive care. Injury-related data were collected and clinical parameters registered daily. Plasma HBP was sampled on day 1, 3 and 5 after trauma and evaluated for associations with injury-related parameters and sepsis. The predictive properties of HBP were compared to C-reactive protein (CRP) and white blood cell count (WBC). RESULTS: Median Injury Severity Score was 33, one-third of the trauma patients received massive transfusion and a quarter was in shock on arrival. Overall 30-day mortality was 8%. Plasma HBP was significantly higher in severely injured patients and associated with shock on arrival, massive transfusions and organ failure. Septic patients had higher levels of HBP only on day 5. When evaluated for prediction of onset of sepsis during the two following days after plasma sampling by receiver operating characteristic (ROC) analyses, areas under the curves were non-significant for all time points. Similar patterns were seen for CRP and WBC. CONCLUSION: In trauma patients, HBP levels are related to severity of injury and organ dysfunction. Heparin-binding protein was weakly associated with sepsis and only at the later stage of the observation period of 1 week. Moreover, HBP showed poor discriminatory properties as an early biomarker of post-injury sepsis. Trauma-induced inflammation during the post-injury phase may blunt the sepsis-predictive performance of HBP.

Effects of nitrate supplementation in trained and untrained muscle are modest with initial high plasma nitrite levels.

Nitrate (NO3-) supplementation resulting in higher plasma nitrite (NO2-) is reported to lower resting mean arterial blood pressure (MAP) and oxygen uptake (VO2 ) during submaximal exercise in non-athletic populations, whereas effects in general are absent in endurance-trained individuals. To test whether physiologic effects of NO3- supplementation depend on local muscular training status or cardiovascular fitness, male endurance-trained cyclists (CYC, n=9, VO2 -max: 64±3 mL/min/kg; mean±SD) and recreational active subjects serving as a control group (CON, n=8, 46±3 mL/min/kg), acutely consumed nitrate-rich beetroot juice ([NO3-] ~9 mmol) (NIT) or placebo (PLA) with assessment of resting MAP and energy expenditure during moderate intensity (~50% VO2 -max) and incremental leg cycling (LEG-ex) and arm-cranking exercise (ARM-ex). NIT increased (P<.001) resting plasma NO3- by ~1200% relative to PLA. Plasma NO2- increased ~25% (P<.01) with a significant change only in CYC. LEG-ex VO2 (~2.60 L/min), ARM-ex VO2 (~1.14 L/min), and resting MAP (~87 mm Hg) remained unchanged for CYC, and similarly for CON, no changes were observed for LEG-ex VO2 (~2.03 L/min), ARM-ex VO2 (~1.06 L/min), or resting MAP (~85 mm Hg). VO2 -max was not affected by supplementation, but incremental test peak power was higher (P<.05) in LEG-ex for CYC in NIT relative to PLA (418±47 vs 407±46 W). In both CYC and CON, high initial baseline values and small increases in plasma NO2- after NIT may have lowered the effect of the intervention implying that muscular and cardiovascular training status is likely not the only factors that influence the physiologic effects of NO3- supplementation.

Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases.

Nitric oxide (NO) is generated endogenously by NO synthases to regulate a number of physiological processes including cardiovascular and metabolic functions. A decrease in the production and bioavailability of NO is a hallmark of many major chronic diseases including hypertension, ischaemia-reperfusion injury, atherosclerosis and diabetes. This NO deficiency is mainly caused by dysfunctional NO synthases and increased scavenging of NO by the formation of reactive oxygen species. Inorganic nitrate and nitrite are emerging as substrates for in vivo NO synthase-independent formation of NO bioactivity. These anions are oxidation products of endogenous NO generation and are also present in the diet, with green leafy vegetables having a high nitrate content. The effects of nitrate and nitrite are diverse and include vasodilatation, improved endothelial function, enhanced mitochondrial efficiency and reduced generation of reactive oxygen species. Administration of nitrate or nitrite in animal models of cardiovascular disease shows promising results, and clinical trials are currently ongoing to investigate the therapeutic potential of nitrate and nitrite in hypertension, pulmonary hypertension, peripheral artery disease and myocardial infarction. In addition, the nutritional aspects of the nitrate-nitrite-NO pathway are interesting as diets suggested to protect against cardiovascular disease, such as the Mediterranean diet, are especially high in nitrate. Here, we discuss the potential therapeutic opportunities for nitrate and nitrite in prevention and treatment of cardiovascular and metabolic diseases.

The oral microbiome and nitric oxide homoeostasis.

The tiny radical nitric oxide (NO) participates in a vast number of physiological functions including vasodilation, nerve transmission, host defence and cellular energetics. Classically produced by a family of specific enzymes, NO synthases (NOSs), NO signals via reactions with other radicals or transition metals. An alternative pathway for the generation of NO is the nitrate-nitrite-NO pathway in which the inorganic anions nitrate (NO(3)(-)) and nitrite (NO(2)(-)) are reduced to NO and other reactive nitrogen intermediates. Nitrate and nitrite are oxidation products from NOS-dependent NO generation but also constituents in our diet, mainly in leafy green vegetables. Irrespective of origin, active uptake of circulating nitrate in the salivary glands, excretion in saliva and subsequent reduction to nitrite by oral commensal bacteria are all necessary steps for further NO generation. This central role of the oral cavity in regulating NO generation from nitrate presents a new and intriguing aspect of the human microbiome in health and disease. In this review, we present recent advances in our understanding of the nitrate-nitrite-NO pathway and specifically highlight the importance of the oral cavity as a hub for its function.

Clinical evidence demonstrating the utility of inorganic nitrate in cardiovascular health.

The discovery of nitric oxide and its role in almost every facet of human biology opened a new avenue for treatment through manipulation of its canonical signaling and by attempts to augment endogenous nitric oxide generation through provision of substrate and co-factors to the endothelial nitric oxide synthase complex. This has been particularly so in the cardiovascular system and it is well recognized that there is reduced bioavailable nitric oxide in patients with both cardiovascular risk factors and manifest vascular disease. However, these attempts have failed to deliver the expected benefits of such an approach. Recently, an alternative pathway for nitric oxide synthesis has been elucidated that can produce authentic nitric oxide from the 1 electron reduction of inorganic nitrite. Furthermore, it has long been known that symbiotic, facultative, oral microflora can facilitate the reduction of inorganic nitrate, that is ingested in the average diet in millimolar amounts, to inorganic nitrite itself. Thus, there exists an alternative reductive pathway from nitrate, via nitrite as an intermediate, to nitric oxide that provides a novel pathway that may be amenable to therapeutic manipulation. As such, various research groups have explored the utility of manipulation of this nitrate-nitrite-nitric oxide pathway in situations in which nitric oxide is known to have a prominent role. Animal and early-phase human studies of both inorganic nitrite and nitrate supplementation have shown beneficial effects in blood pressure control, platelet function, vascular health and exercise capacity. This review considers in detail the pathways of inorganic nitrate bioactivation and the evidence of clinical utility to date on the cardiovascular system.

Heparin-binding protein (HBP/CAP37) - a link to endothelin-1 in endotoxemia-induced pulmonary oedema?

BACKGROUND: Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions. METHODS: Sixteen anesthetized pigs were subjected to 5 h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2 h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c. RESULTS: Endotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP. CONCLUSIONS: ET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.

Heparin-binding protein (HBP): an early marker of respiratory failure after trauma?

BACKGROUND: Trauma and its complications contribute to morbidity and mortality in the general population. Trauma victims are susceptible to acute respiratory distress syndrome (ARDS) and sepsis. Polymorphonuclear leucocytes (PMNs) are activated after trauma and there is substantial evidence of their involvement in the development of ARDS. Activated PMNs release heparin-binding protein (HBP), a granule protein previously shown to be involved in acute inflammatory reactions. We hypothesised that there is an increase in plasma HBP content after trauma and that the increased levels are related to the severity of the trauma or later development of severe sepsis and organ failure (ARDS). METHODS AND MATERIAL: We investigated HBP in plasma samples within 36 h from trauma in 47 patients admitted to a level one trauma centre with a mean injury severity score (ISS) of 26 (21-34). ISS, admission sequential organ failure assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were recorded at admission. ARDS and presence of severe sepsis were determined daily during intensive care. RESULTS: We found no correlation between individual maximal plasma HBP levels at admission and ISS, admission SOFA or APACHE II. We found, however, a correlation between HBP levels and development of ARDS (P = 0.026, n = 47), but not to severe sepsis. CONCLUSION: HBP is a potential biomarker candidate for early detection of ARDS development after trauma. Further research is required to confirm a casual relationship between plasma HBP and the development of ARDS.

Endothelin-mediated gut microcirculatory dysfunction during porcine endotoxaemia.

BACKGROUND: The potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of the microcirculatory dysfunction seen in sepsis. The mixed endothelin receptor antagonist tezosentan and the selective endothelin A-receptor antagonist TBC3711 were used to investigate the importance of the different endothelin receptors in modulating splanchnic regional blood flow and microvascular blood flow in endotoxaemia. METHODS: Eighteen anaesthetized pigs were i.v. infused with endotoxin (Escherichia coli lipopolysaccharide, serotype 0111:b4) for 300 min. After 120 min, six animals received tezosentan and six animals received TBC3711. Six animals served as endotoxin-treated controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and ileum. Superior mesenteric artery flow (SMA(FI)) and portal vein flow (PV(FI)) were measured with ultrasonic flow probes, and air tonometry was used to measure Pco2 in the ileal mucosa. RESULTS: TBC3711 did not improve splanchnic regional blood flow or splanchnic microvascular blood flow compared with endotoxin-treated controls. Tezosentan increased PV(FI) (P<0.05), but SMA(FI) was not improved compared with the other groups. In the tezosentan group, microvascular blood flow in the ileal mucosa (MCQ(muc)) improved and mucosal-arterial Pco2 gap decreased (P<0.05 for both) compared with endotoxin-treated controls and the TBC3711 group. CONCLUSIONS: Tezosentan improved MCQ(muc) without any concomitant increase in SMA(FI), implying a direct positive effect on the microcirculation. TBC3711 was not effective in improving regional splanchnic blood flow or splanchnic microvascular blood flow. Dual endothelin receptor antagonism was necessary to improve MCQ(muc), indicating a role for the endothelin B-receptor in mediating the microcirculatory failure in the ileal mucosa.

Left ventricular mechanical dyssynchrony is load independent at rest and during endotoxaemia in a porcine model.

AIM: In diseased or injured states, the left ventricle displays higher degrees of mechanical dyssynchrony. We aimed at assessing mechanical dyssynchrony ranges in health related to variation in load as well as during acute endotoxin-induced ventricular injury. METHODS: In 16 juvenile anaesthetized pigs, a five-segment conductance catheter was placed in the left ventricle as well as a balloon-tipped catheter in the inferior vena cava. Mechanical dyssynchrony during systole, including dyssynchrony time in per cent during systole and internal flow fraction during systole, were measured at rest and during controlled pre-load reduction sequences, as well as during 3 h of endotoxin infusion (0.25 microg kg(-)1 h(-1)). RESULTS: Systolic dyssynchrony and internal flow fraction did not change during the course of acute beat-to-beat pre-load alteration. Endotoxin-produced acute pulmonary hypertension by left ventricular dyssynchrony measures was not changed during the early peak of pulmonary hypertension. Endotoxin ventricular injury led to progressive increases in systolic mechanical segmental dyssynchrony (7.9 +/- 1.2-13.0 +/- 1.3%) and ventricular systolic internal flow fraction (7.1 +/- 2.4-16.6 +/- 2.8%), respectively for baseline and then at hour 3. There was no localization of dyssynchrony changes to segment or region in the ventricular long axis during endotoxin infusion. CONCLUSION: These results suggest that systolic mechanical dyssynchrony measures may be load independent in health and during acute global ventricular injury by endotoxin. More study is needed to validate ranges in health and disease for parameters of mechanical dyssynchrony.

The endothelin receptor antagonist tezosentan improves renal microcirculation in a porcine model of endotoxemic shock.

BACKGROUND: Impaired renal microcirculation has been suggested as a factor contributing to the development of renal dysfunction in sepsis. This study was conducted to elucidate the role of endothelin-1 (ET-1)in mediating reductions in renal microcirculatory blood flow during endotoxemic shock. METHODS: A prospective, randomized, and experimental study was performed with 16 anesthetized and mechanically ventilated pigs. After 2 h of lipopolysaccaride-induced endotoxemia, eight animals received a bolus dose of the dual endothelin receptor antagonist tezosentan (1 mg/kg), followed by a continuous infusion of 1 mg/kg/h throughout the experiment. Eight animals served as the control group. Renal microcirculation, total renal blood flow, plasma creatinine levels, cardiac index, and mean arterial pressure were measured. Plasma samples were collected for the measurement of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), ET-1, angiotensin II, and aldosterone. RESULTS: Endotoxin infusion resulted in a state of circulatory shock with impairment of renal microcirculation. An increase in the plasma levels of TNF-alpha, IL-6, IL-10, ET-1, angiotensin II, and aldosterone was also observed. Tezosentan attenuated the decrease in renal microcirculation and renal blood flow, and attenuated the increase in plasma creatinine. Treatment with tezosentan did not significantly affect the plasma cytokine, angiotensin II, or aldosterone response to endotoxemia. CONCLUSION: These results indicate that treatment with the dual endothelin receptor tezosentan in endotoxemic shock attenuates the reduction of renal microcirculation and total renal blood flow independently of plasma changes in the renin-angiotensin-aldosterone system or early plasma cytokine response.

Validation study of nasal nitric oxide measurements using a hand-held electrochemical analyser.

BACKGROUND: Exhaled nitric oxide (NO) measurement is a simple and non-invasive method for monitoring airway inflammation. Similarly, nasal NO has been proposed as a surrogate marker in inflammatory diseases of the upper airways, e.g. allergic rhinitis. A new portable analyser using an electrochemical sensor has been developed for measurements of exhaled NO, and its reproducibility and comparison with other analysers has been tested recently in healthy subjects and in patients with lower airways disease. The application of this hand-held analyser in nasal NO analysis was tested and compared to the gold standard represented by a chemiluminescence analyser. MATERIALS AND METHODS: Thirty subjects including 15 patients with allergic rhinitis (AR) and 15 healthy subjects (HS) were studied. The intraindividual variability, calculated as the difference in nasal NO levels between two measurements from a single nasally exhaled breath manoeuvre, and the comparison between the electrochemical analyser (NIOX MINO, Aerocrine) and a chemiluminescence analyser (NOA, Sievers) were performed. RESULTS: In AR patients mean nasal NO was 59.0 +/- 16.3 p.p.b. with the MINO and 58.3 +/- 15.6 p.p.b. with the NOA. In HS nasal NO was 49.1 +/- 10.8 p.p.b. with the MINO and 49.8 +/- 8.2 p.p.b. with the NOA. The Bland-Altman analysis showed bias values of 0.005 +/- 3.6 with the 95% limits of agreement from -6.97 to 6.98 p.p.b. CONCLUSION: Measurements of nasal NO levels with a hand-held electrochemical analyser are reproducible and the results are comparable to a stationary chemiluminescence analyser.

Effects of dietary nitrate on oxygen cost during exercise.

AIM: Nitric oxide (NO), synthesized from l-arginine by NO synthases, plays a role in adaptation to physical exercise by modulating blood flow, muscular contraction and glucose uptake and in the control of cellular respiration. Recent studies show that NO can be formed in vivo also from the reduction of inorganic nitrate (NO(3) (-)) and nitrite (NO(2) (-)). The diet constitutes a major source of nitrate, and vegetables are particularly rich in this anion. The aim of this study was to investigate if dietary nitrate had any effect on metabolic and circulatory parameters during exercise. METHOD: In a randomized double-blind placebo-controlled crossover study, we tested the effect of dietary nitrate on physiological and metabolic parameters during exercise. Nine healthy young well-trained men performed submaximal and maximal work tests on a cycle ergometer after two separate 3-day periods of dietary supplementation with sodium nitrate (0.1 mmol kg(-1) day-1) or an equal amount of sodium chloride (placebo). RESULTS: The oxygen cost at submaximal exercise was reduced after nitrate supplementation compared with placebo. On an average Vo(2) decreased from 2.98 +/- 0.57 during CON to 2.82 +/- 0.58 L min(-1) during NIT (P < 0.02) over the four lowest submaximal work rates. Gross efficiency increased from 19.7 +/- 1.6 during CON to 21.1 +/- 1.3% during NIT (P < 0.01) over the four lowest work rates. There was no difference in heart rate, lactate [Hla], ventilation (VE), VE/Vo(2) or respiratory exchange ratio between nitrate and placebo during any of the submaximal work rates. CONCLUSION: We conclude that dietary nitrate supplementation, in an amount achievable through a diet rich in vegetables, results in a lower oxygen demand during submaximal work. This highly surprising effect occurred without an accompanying increase in lactate concentration, indicating that the energy production had become more efficient. The mechanism of action needs to be clarified but a likely first step is the in vivo reduction of dietary nitrate into bioactive nitrogen oxides including nitrite and NO.

Effects of the dual endothelin receptor antagonist tezosentan and hypertonic saline/dextran on porcine endotoxin shock.

AIM: To evaluate the haemodynamic effects of the dual endothelin receptor antagonist tezosentan, both alone and combined with hypertonic saline/dextran (HSD), on porcine endotoxin shock, with focus on cardiopulmonary circulation. The effects on gas exchange and short-term survival were also studied. METHODS: A prospective, randomized experimental study was carried out. Thirty-two anaesthetized pigs underwent pulmonary and carotid artery catheterization. Following haemodynamic stabilization and baseline measurements, endotoxaemia was induced by an Escherichia coli-endotoxin infusion over 180 min and the animals observed another 120 min. After 60 min of endotoxaemia, directly before intervention, animals were randomized into four groups: a tezosentan group, an HSD group, a combined tezosentan/HSD group and a control group. The consequent haemodynamic effects and blood gas results were recorded. RESULTS: The endotoxin infusion reduced mean arterial blood pressure from 111 +/- 14 (mean +/- standard deviation) to 77 +/- 27 mmHg and cardiac index from 126.9 +/- 27.2 to 109.3 +/- 22.6 mL min(-1) kg(-1) within 90 min in the control group. In addition, endotoxin simultaneously increased mean pulmonary artery pressure from 24 +/- 17 to 38 +/- 19 mmHg and reduced arterial oxygenation from 18.9 +/- 2.0 to 12.2 +/- 5.3 kPa. Tezosentan, alone and combined with HSD, reversed the pulmonary hypertension and prevented the reduction in cardiac index and arterial oxygenation, resulting in reduced metabolic acidosis. Additionally, in the tezosentan group, the mean arterial blood pressure was reduced to the same level as in controls, an effect not prevented by the addition of HSD. It was found that all three interventions improved survival rates. CONCLUSION: Tezosentan, alone and in combination with HSD, improved cardiac index and arterial oxygenation. The addition of HSD to tezosentan treatment did not improve the endotoxin-induced hypotension, but beneficial effects on microcirculation and systemic oxygenation were seen despite low perfusion pressure, as indicated by increased SvO(2) and reduced metabolic acidosis.

Cardiac effects of endothelin receptor antagonism in endotoxemic pigs.

Myocardial depression in sepsis is frequently encountered clinically and contributes to morbidity and mortality. Increased plasma levels of endothelin-1 (ET-1) have been described in septic shock, and previous reports have shown beneficial effects on cardiovascular performance and survival in septic models using ET receptor antagonists. The aim of the current study was to investigate specific cardiac effects of ET receptor antagonism in endotoxicosis. Sixteen domestic pigs were anesthetized and subjected to endotoxin for 5 h. Eight of these pigs were given tezosentan (dual ET receptor antagonist) after 3 h. Cardiac effects were evaluated using the left ventricular (LV) pressure-volume relationship. Endotoxin was not associated with any effects on parameters of LV contractile function [end-systolic elastance (Ees), preload recruitable stroke work (PRSW), power(max)/end-diastolic volume (PWR(max)/EDV) and dP/dt(max)/end-diastolic volume (dP/dt(max)/EDV)] but with impairments in isovolumic relaxation (time constant for pressure decay, tau) and mechanical efficiency. Tezosentan administration decreased Ees, PWR(max)/EDV, and dP/dt(max)/EDV, while improving tau and LV stiffness. Thus, dual ET receptor antagonism was associated with a decline in contractile function but, in contrast, improved diastolic function. Positive hemodynamic effects from ET receptor antagonism in acute endotoxemia may be due to changes in cardiac load and enhanced diastolic function rather than improved contractile function.

Sounding airflow enhances aerosol delivery into the paranasal sinuses.

BACKGROUND: The use of aerosol therapy is commonly suggested in the treatment of paranasal disorders but it is difficult to achieve an effective penetration of drugs into the sinuses. The authors have recently shown that an oscillating airflow produced by phonation (nasal humming) causes a large increase in the gas exchange between the nose and the paranasal sinuses. This is reflected by a high peak in nasally exhaled nitric oxide (NO) levels because NO accumulated in the sinuses is rapidly washed-out via the sinus ostia. OBJECTIVE: This study was designed to test whether the increase in sinus gas exchange caused by an oscillating airflow could be used to enhance penetration of a drug into the sinuses. MATERIALS AND METHODS: In six healthy subjects a nitric oxide-synthase inhibitor L-NAME was administrated into the nostrils by a jet nebulizer connected to a duck call, which could be modified to generate either a sounding airflow or a non-sounding airflow. The degree of L-NAME penetration into the sinuses was judged from the reduction in nasal NO during humming exhalations. Sinus drug deposition was also studied in a model of the nose and sinus. RESULTS: In humans the delivery of L-NAME with the non-sounding airflow had no effect on the NO levels achieved during humming, whereas L-NAME administration with sound caused a significant 22-35% reduction in nasal NO. In the model the aerosol delivery with the sounding airflow caused a fourfold increase in sinus drug deposition as compared with an aerosol without sound. CONCLUSION: A sounding airflow increases the delivery of an aerosolized drug into the paranasal sinuses.

Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo.

The endothelin (ET) system is involved in the regulation of myocardial function in health as well as in several diseases, such as congestive heart failure, myocardial infarction, and septic myocardial depression. Conflicting results have been reported regarding the acute contractile properties of ET-1. We therefore investigated the effects of intracoronary infusions of ET-1 and of the selective ET(B) receptor-selective agonist sarafotoxin 6c with increasing doses in anesthetized pigs. Myocardial effects were measured through analysis of the left ventricular pressure-volume relationship. ET-1 elicited increases in the myocardial contractile status (end-systolic elastance value of 0.94 +/- 0.11 to 1.48 +/- 0.23 and preload recruitable stroke work value of 68.7 +/- 4.7 to 83.4 +/- 7.2) that appear to be mediated through ET(A) receptors, whereas impairment in left ventricular isovolumic relaxation (tau = 41.5 +/- 1.4 to 58.1 +/- 5.0 and t(1/2) = 23.0 +/- 0.7 to 30.9 +/- 2.6, where tau is the time constant for pressure decay and t(1/2) is the half-time for pressure decay) was ET(B) receptor dependent. In addition, intravenous administration of ET-1 impaired ventricular relaxation but had no effect on contractility. Intracoronary sarafotoxin 6c administration caused impairments in left ventricular relaxation (tau from 43.3 +/- 1.8 to 54.4 +/- 3.4) as well as coronary vasoconstriction. In conclusion, ET-1 elicits positive inotropic and negative lusitropic myocardial effects in a pig model, possibly resulting from ET(A) and ET(B) receptor activation, respectively.