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Topical administration of a novel nitric oxide donor, linear polyethylenimine-nitric oxide/nucleophile adduct (DS1), selectively increases vaginal blood flow in anesthetized rats

Pacher, P; Mabley, J G; Liaudet, L; Evgenov, O V; Southan, G J; Abdelkarim, G E; Szabó, C; Salzman, A L
The aim of the present study was to test the effects of a topical administration of a novel nitric oxide donor, linear polyethylenimine-nitric oxide/nucleophile adduct (DS1), on vaginal blood flow and hemodynamics in rats. Laser Doppler flowmetry was used to measure blood flow changes following topical application of DS1 (0.3 or 1.5 mg in 0.15 ml saline) into the vagina of anesthetized Wistar rats. In vivo hemodynamic parameters were measured with Millar-tip-catheter placed in the left ventricle. DS1 (1.5 mg) increased vaginal blood flow by 191+/-24, 226+/-22 and 166+/-23% of the baseline value (at 5, 15 and 30 min, respectively, after application) without affecting systemic blood pressure, heart rate and cardiac function. The increased vaginal blood flow following DS1 application returned to baseline between 45 and 60 min. Thus, topical application of nitric oxide donors such as DS1 may be useful for the treatment of female sexual dysfunction that develops due to an impairment of local blood flow supply to the vaginal tissue.
PMID: 14671668
ISSN: 0955-9930
CID: 3572592

Parenteral administration of glipizide sodium salt, an inhibitor of adenosine triphosphate-sensitive potassium channels, prolongs short-term survival after severe controlled hemorrhage in rats

Evgenov, Oleg V; Pacher, Pál; Williams, William; Evgenov, Natalia V; Mabley, Jon G; Cicila, James; Sikó, Zsombor B; Salzman, Andrew L; Szabó, Csaba
OBJECTIVE:Recent experimental evidence suggests that activation of adenosine triphosphate (ATP)-sensitive potassium channels contributes to vascular failure and early mortality after hemorrhagic shock. The present investigation evaluated the effects of the water-soluble sodium salt of glipizide, an inhibitor of ATP-sensitive potassium channels, in anesthetized and awake rats subjected to severe controlled hemorrhage. DESIGN/METHODS:Prospective, randomized, controlled study. SETTING/METHODS:Animal research laboratory. SUBJECTS/METHODS:Male Wistar rats. INTERVENTIONS/METHODS:Anesthetized rats were subjected to bleeding to reduce mean arterial pressure to either 40 or 35 mm Hg, which was maintained constant for 60 mins. In addition, awake rats underwent blood withdrawal of 4.25 mL/100 g over 20 mins. At the end of the hemorrhage period and 30 mins later, the animals received intravenous (5 and 20 mg/kg) or intramuscular (10 and 40 mg/kg) injections of glipizide sodium salt or vehicle. MEASUREMENTS AND MAIN RESULTS/RESULTS:In anesthetized rats subjected to pressure-controlled hemorrhage, glipizide sodium salt improved mean arterial pressure in a dose-dependent manner. Compared with the vehicle-treated animals, mean arterial pressure increased from 41.6 +/- 4.6 to 63.1 +/- 3.1 mm Hg in the 20 mg/kg intravenous group and from 33.2 +/- 4.9 to 54.0 +/- 4.7 mm Hg in the 40 mg/kg intramuscular group 60 mins after a 40-mm Hg shock. Furthermore, the drug did not affect the hemorrhage-induced changes in blood glucose concentrations. However, the higher doses of glipizide sodium salt attenuated the increments in plasma concentrations of lactate, alanine aminotransferase, creatinine, and amylase. Moreover, the higher doses markedly improved short-term survival after pressure- and volume-controlled bleeding. Overall, the intramuscular injections of the drug exerted salutary effects that were comparable to the intravenous administration. CONCLUSIONS:In rats, parenteral administration of the water-soluble glipizide sodium salt attenuates vascular and end-organ dysfunction associated with severe hemorrhagic shock and prolongs short-term survival. The intramuscular administration provides comparable benefits as obtained by the intravenous injection.
PMID: 14530747
ISSN: 0090-3493
CID: 3567362

Administration of methylene blue in human septic shock: renaissance of an old drug? [Letter]

Evgenov, Oleg V; Bjertnaes, Lars J
PMID: 12771654
ISSN: 0090-3493
CID: 3567352

Flagellin from gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis

Liaudet, Lucas; Szabó, Csaba; Evgenov, Oleg V; Murthy, Kanneganti G; Pacher, Pál; Virág, László; Mabley, Jon G; Marton, Anita; Soriano, Francisco G; Kirov, Mikhail Y; Bjertnaes, Lars J; Salzman, Andrew L
Flagellin is a recently identified bacterial product that elicits immune response via toll-like receptor 5. Here, we demonstrate that flagellin is an extraordinarily potent proinflammatory stimulus in the lung during sepsis. In vitro, flagellin triggers the production of interleukin (IL)-8 by human lung epithelial (A549) cells, with 50% of the maximal response obtained at a concentration of 2 x 10(-14) M. Flagellin also induces the expression of ICAM-1 in vitro. Intravenous administration of flagellin to mice elicited a severe acute lung inflammation that was significantly more pronounced than following lipopolysaccharide (LPS) administration. Flagellin induced a local release of proinflammatory cytokines, the accumulation of inflammatory cells, and the development of pulmonary hyperpermeability. These effects were associated with the nuclear translocation of the transcription NF-kappaB in the lung. Flagellin remained active in inducing pulmonary inflammation at doses as low as 10 ng/mouse. In the plasma of patients with sepsis, flagellin levels amounted to 7.1 +/- 0.1 ng/mL. Plasma flagellin levels showed a significant positive correlation with the lung injury score, with the alveolar-arterial oxygen difference as well as with the duration of the sepsis. Flagellin emerges as a potent trigger of acute respiratory complications in gram-negative bacterial sepsis.
PMID: 12578121
ISSN: 1073-2322
CID: 3567342

Combination of intravenously infused methylene blue and inhaled nitric oxide ameliorates endotoxin-induced lung injury in awake sheep

Kirov, Mikhail Y; Evgenov, Oleg V; Bjertnaes, Lars J
OBJECTIVE:To evaluate the effects of a combination of methylene blue, an inhibitor of the nitric oxide pathway, and inhaled nitric oxide on endotoxin-induced acute lung injury in awake sheep. DESIGN/METHODS:Prospective, randomized, controlled experimental study. SETTING/METHODS:University animal laboratory. SUBJECTS/METHODS:Twenty-four yearling, awake sheep. INTERVENTIONS/METHODS:The sheep were anesthetized and instrumented with vascular catheters. After 1 wk of recovery, the animals underwent tracheotomy and were subjected to intravenous infusions of endotoxin 10 ng x kg-1 x min-1 and isotonic saline 3 mL x kg-1 x hr-1 for 8 hrs. The sheep were randomly assigned to three groups of eight animals each: a) the control group received endotoxin and saline; b) the INO group received endotoxin, saline, and inhaled nitric oxide 40 ppm for 5 hrs; and c) the MB/INO group received endotoxin, saline, and methylene blue 3 mg/kg as an intravenous bolus injection followed by a continuous infusion of 3 mg x kg-1 x min-1 for 6 hrs in combination with inhaled nitric oxide 40 ppm for 5 hrs. MEASUREMENTS AND MAIN RESULTS/RESULTS:Hemodynamic variables and blood gases were determined hourly. In the early phase of endotoxemia (0-2 hrs), methylene blue/inhaled nitric oxide reduced the increments in pulmonary arterial pressure, pulmonary microvascular pressure, and pulmonary vascular resistance index by 60% compared with the controls and to a greater extent than did inhaled nitric oxide alone. During the late phase, all the preceding variables returned closely to baseline following inhaled nitric oxide or methylene blue/inhaled nitric oxide but remained remarkably elevated in the control group. Inhaled nitric oxide and methylene blue/inhaled nitric oxide reduced the increase in extravascular lung water by 40% and 80%, respectively. Inhaled nitric oxide transiently attenuated the increase in venous admixture and did not prevent a decrease in arterial oxygenation. In the methylene blue/inhaled nitric oxide group, blood gases remained unchanged from baseline. CONCLUSIONS:In sheep, methylene blue/inhaled nitric oxide protects more efficiently against acute lung injury than inhaled nitric oxide alone, as indicated by a milder pulmonary hypertension, less extravascular lung water accumulation, and maintained gas exchange.
PMID: 12545013
ISSN: 0090-3493
CID: 3567332

Aerosolized linear polyethylenimine-nitric oxide/nucleophile adduct attenuates endotoxin-induced lung injury in sheep

Kirov, Mikhail Y; Evgenov, Oleg V; Kuklin, Vladimir N; Virag, Laszlo; Pacher, Pal; Southan, Garry J; Salzman, Andrew L; Szabo, Csaba; Bjertnaes, Lars J
Pulmonary hypertension and edema are mainstays of acute lung injury (ALI). We synthesized linear polyethylenimine-nitric oxide/nucleophile adduct (DS-1), a water-soluble nitric oxide donor, and demonstrated that it is a potent relaxant of precontracted rat aortic rings without inducing desensitization. Moreover, DS-1 does not suppress the viability of human pulmonary epithelial cells in vitro. We also tested whether DS-1 counteracts ALI in endotoxemic sheep. Animals were instrumented for a chronic study. In 16 awake, spontaneously breathing sheep, Escherichia coli endotoxin (10 ng/kg/minute) was infused for 8 hours. From 2 hours of endotoxemia, sheep received either nebulized DS-1 (1 mg/kg/hour) or isotonic saline. DS-1 reduced endotoxin-induced rises in pulmonary arterial and microwedge pressures and vascular resistance index by 40-70%. In parallel, DS-1 decreased the accumulation of extravascular lung water by 60-70% and reduced the increment in right ventricle stroke work index and the falls in right ventricle ejection fraction, stroke volume, and left ventricle stroke work indices. Furthermore, DS-1 reduced venous admixture and improved arterial oxygen saturation. In four healthy animals, DS-1 alone slightly increased arterial oxygenation but had no other effects. Thus, aerosolized DS-1 attenuates endotoxin-induced ALI in sheep by reducing pulmonary hypertension and edema and improving myocardial function and gas exchange.
PMID: 12450933
ISSN: 1073-449x
CID: 3567322

Methylene blue reduces pulmonary oedema and cyclo-oxygenase products in endotoxaemic sheep

Evgenov, O V; Evgenov, N V; Mollnes, T E; Bjertnaes, L J
The authors recently demonstrated that methylene blue (MB), an inhibitor of the nitric oxide (NO) pathway, reduces the increments in pulmonary capillary pressure, lung lymph flow and protein clearance in endotoxaemic sheep. In the present study, the authors examined whether MB influences pulmonary haemodynamics and accumulation of extravascular lung water (EVLW) by mechanisms other than the NO pathway. Sixteen awake, chronically-instrumented sheep randomly received either an intravenous injection of MB 10 mg x kg(-1) or isotonic saline. Thirty minutes later, all sheep received an intravenous infusion of Escherichia coli endotoxin 1 microg x kg(-1) for 20 min and either an intravenous infusion of MB 2.5 mg x kg(-1) x h(-1) or isotonic saline for 6 h. MB markedly attenuated the endotoxin-induced pulmonary hypertension and right ventricular failure, and reduced the accumulation of EVLW. Moreover, MB reduced the increments in plasma thromboxane B2 and 6-keto-prostaglandin F1alpha, and abolished the febrile response. However, MB had no effect on the changes in circulating neutrophils, serum hyaluronan, and total haemolytic activity of the alternative complement pathway. The authors conclude that in sheep, methylene blue attenuates the endotoxin-induced pulmonary hypertension and oedema, at least in part, by inhibiting the cyclo-oxygenase products of arachidonic acid. This is a novel effect of methylene blue in vivo.
PMID: 12412689
ISSN: 0903-1936
CID: 3572582

Continuously infused methylene blue modulates the early cardiopulmonary response to endotoxin in awake sheep

Evgenov, O V; Sveinbjørnsson, B; Bjertnaes, L J
BACKGROUND:In endotoxemia and septic shock, enhanced generation of endogenous nitric oxide (NO) contributes to myocardial depression, hypotension, and derangement of gas exchange. We hypothesized that continuous infusion of methylene blue (MB), an inhibitor of the NO pathway, would counteract these effects in endotoxemic sheep. METHODS:Twenty-one sheep were anesthetized and instrumented for a chronic study with vascular catheters. On the day of the experiment, 18 conscious animals randomly received either an intravenous injection of MB 10 mg x kg(-1) or isotonic saline. Thirty minutes later, sheep received a 20-min intravenous infusion of Escherichia coli endotoxin 1 microg x kg(-1) and either an intravenous infusion of MB 2.5 mg x kg(-1) x h(-1) or isotonic saline, respectively, for 5 h. In addition, 3 animals were exposed to the same dose of MB alone. RESULTS:MB reduced the early endotoxin-induced declines in stroke volume, left ventricular stroke work and cardiac indices, and prevented mean arterial pressure from falling. Moreover, MB ameliorated the increases in pulmonary arterial pressure and pulmonary vascular resistance index. In addition, MB reduced the increments in venous admixture and AaPO2, decreased the falls in PaO2, SaO2, and oxygen delivery, and maintained oxygen consumption. MB also prevented the rises in body temperature and plasma nitrites and nitrates, and delayed the elevation of plasma lactate. When given alone to healthy sheep, MB transiently reduced plasma lactate and PaO2, and increased AaPO2. CONCLUSION/CONCLUSIONS:In ovine endotoxemia, continuously infused MB counteracts the early myocardial dysfunction and derangement of hemodynamics and gas exchange.
PMID: 11736678
ISSN: 0001-5172
CID: 3572572

Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study

Kirov, M Y; Evgenov, O V; Evgenov, N V; Egorina, E M; Sovershaev, M A; Sveinbjørnsson, B; Nedashkovsky, E V; Bjertnaes, L J
OBJECTIVE:To evaluate the effects of continuous infusion of methylene blue (MB), an inhibitor of the nitric oxide pathway, on hemodynamics and organ functions in human septic shock. DESIGN/METHODS:Prospective, randomized, controlled, open-label, pilot study. SETTING/METHODS:Multidisciplinary intensive care unit of a university hospital. PATIENTS/METHODS:Twenty patients with septic shock diagnosed <24 hrs before randomization. INTERVENTIONS/METHODS:Patients were randomized 1:1 to receive either MB (MB group, n = 10) or isotonic saline (control group, n = 10), adjunctive to conventional treatment. MB was administered as an intravenous bolus injection (2 mg/kg), followed 2 hrs later by infusion at stepwise increasing rates of 0.25, 0.5, 1, and 2 mg/kg/hr that were maintained for 1 hr each. During infusion, mean arterial pressure was maintained between 70 and 90 mm Hg, while attempting to reduce concurrent adrenergic support. MEASUREMENTS AND MAIN RESULTS/RESULTS:Hemodynamics and organ function variables were assessed over a 24-hr period, and the survival rate at day 28 was noted. Infusion of MB prevented the stroke volume and the left-ventricular stroke work indexes from falling and increased mean arterial pressure. Compared with the control group, MB reduced the requirement for norepinephrine, epinephrine, and dopamine by as much as 87%, 81%, and 40%, respectively. Oxygen delivery remained unchanged in the MB group and decreased in the control group. MB also reduced the body temperature and the plasma concentration of nitrates/nitrites. Leukocytes and organ function variables such as bilirubin, alanine aminotransferase, urea, and creatinine were not significantly affected. Platelet count decreased in both groups. Five patients treated with MB survived vs. three patients receiving conventional treatment. CONCLUSIONS:In human septic shock, continuously infused MB counteracts myocardial depression, maintains oxygen transport, and reduces concurrent adrenergic support. Infusion of MB appears to have no significant adverse effects on the selected organ function variables.
PMID: 11588440
ISSN: 0090-3493
CID: 3572562

Methylene blue reduces lung fluid filtration during the early phase of endotoxemia in awake sheep

Evgenov, O V; Sager, G; Bjertnaes, L J
OBJECTIVE:To determine whether methylene blue (MB), an inhibitor of soluble guanylate cyclase and nitric oxide synthase, alters lung hemodynamics and fluid filtration after endotoxin in sheep. DESIGN/METHODS:Prospective, randomized, controlled experimental study with repeated measurements. SETTING/METHODS:University animal laboratory. SUBJECTS/METHODS:Eight yearling, awake sheep. INTERVENTIONS/METHODS:Sheep were instrumented for a chronic study with vascular and lung lymph catheters. In two experiments, separated by 1 wk of recovery, the animals received intravenously either an injection of MB 10 mg/kg or a corresponding volume of 0.9% sodium chloride as pretreatment. Thirty minutes later, sheep received a bolus injection of Escherichia coli endotoxin 1 microg/kg, followed by either an infusion of MB 2.5 mg/kg/hr or a corresponding volume of 0.9% sodium chloride for 5 hrs. MEASUREMENTS AND MAIN RESULTS/RESULTS:MB decreased the early phase endotoxin-induced rises in pulmonary capillary pressure and pulmonary vascular resistance. MB also reduced the increments in lung lymph flow (QL) and protein clearance (CL) as well as the rightward shift of the permeability-surface area product (PS). In addition, MB diminished the decrease in cardiac output, stabilized mean arterial pressure, and precluded the rise in plasma and lung lymph cyclic guanosine 3'-5' monophosphate. However, during the late phase, MB-treated sheep presented with a faster rise in QL with no difference in CL and PS from the endotoxemic controls. CONCLUSIONS:During the early phase of endotoxemia in sheep, MB attenuates lung injury by decreasing the enhanced lung fluid filtration as a result of reduced pulmonary capillary pressure and permeability. However, MB does not counteract the late phase increase in lung fluid filtration.
PMID: 11246319
ISSN: 0090-3493
CID: 3572552