Thrombin Does Not Alter Vascular Hyporeactivity in Models of Endotoxin-Induced Septic Shock in Rats

1995 ◽  
Vol 88 (2) ◽  
pp. 149-157 ◽  
Author(s):  
Viviane Martin ◽  
Marie-Louise Wiesel ◽  
Anne Albert ◽  
Alain Beretz
Keyword(s):  
Nitric Oxide ◽  
Disseminated Intravascular Coagulation ◽  
Vascular Tone ◽  
Endotoxic Shock ◽  
Vascular Wall ◽  
Anticoagulant Treatment ◽  
Intravascular Coagulation ◽  
Vascular Hyporeactivity

1. Hypotension and vascular hyporesponsiveness to vasoconstrictors are observed during endotoxic shock, and are associated with increased production of nitric oxide in the vascular wall. Disseminated intravascular coagulation is another feature of septicaemia. We hypothesized that thrombin generated during disseminated intravascular coagulation might modulate the changes in vascular tone induced by endotoxin. 2. Incubation of rat aortic rings for 4 h with α-thrombin (0.003–3.0 NIH units/ml) did not change their reactivity to noradrenaline. Incubation for 4 h with lipopolysaccharide increased the EC50 for noradrenaline, whereas co-incubation of thrombin (0.5 NIH units/ml) with lipopolysaccharide did not alter this hyporeactivity to noradrenaline. 3. In vivo in rats, lipopolysaccharide caused early (1 h) and late (4–6 h) hyporeactivity to noradrenaline. In rats infused with lipopolysaccharide and heparin (1 U min−1 kg−1, 0.4 ml/h) or hirudin (2.2 mg ml−1 kg−1, 0.8 ml/h), vasopressor responses to noradrenaline were not different from those after infusion of lipopolysaccharide alone. Aortic rings taken from rats receiving both anticoagulant treatment and lipopolysaccharide had the same sensitivity to noradrenaline as those obtained from rats receiving lipopolysaccharide alone. 4. Our results suggest that, in vivo, disseminated intravascular coagulation does not modify the early and late effects of lipopolysaccharide on arterial pressure and that, in vitro, thrombin neither induces hyporeactivity to noradrenaline nor modifies lipopolysaccharide-induced hyporeactivity. We propose that thrombin generated during disseminated intravascular coagulation in rats does not play a major role in the alterations of vascular tone observed during endotoxic shock.

scholarly journals Heme proteins mediate the conversion of nitrite to nitric oxide in the vascular wall

2008 ◽  
Vol 295 (2) ◽  
pp. H499-H508 ◽  
Author(s):  
Wael F. Alzawahra ◽  
M. A. Hassan Talukder ◽  
Xiaoping Liu ◽  
Alexandre Samouilov ◽  
Jay L. Zweier
Keyword(s):  
Nitric Oxide ◽  
Heme Proteins ◽  
Soluble Guanylyl Cyclase ◽  
Vascular Wall ◽  
Rat Aorta ◽  
No Production ◽  
Paramagnetic Resonance ◽  
Physiological Importance

Nitric oxide (NO) has been shown to be the endothelium-derived relaxing factor (EDRF), and its impairment contributes to a variety of cardiovascular disorders. Recently, it has been recognized that nitrite can be an important source of NO; however, questions remain regarding the activity and mechanisms of nitrite bioactivation in vessels and its physiological importance. Therefore, we investigated the effects of nitrite on in vivo hemodynamics in rats and in vitro vasorelaxation in isolated rat aorta under aerobic conditions. Studies were performed to determine the mechanisms by which nitrite is converted to NO. In anesthetized rats, nitrite dose dependently decreased both systolic and diastolic blood pressure with a threshold dose of 10 μM. Similarly, nitrite (10 μM-2 mM) caused vasorelaxation of aortic rings, and NO was shown to be the intermediate factor responsible for this activity. With the use of electrochemical as well as electron paramagnetic resonance (EPR) spectroscopy techniques NO generation was measured from isolated aortic vessels following nitrite treatment. Reduction of nitrite to NO was blocked by heating the vessel, suggesting that an enzymatic process is involved. Organ chamber experiments demonstrated that aortic relaxation induced by nitrite could be blocked by both hemoglobin and soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). In addition, both electrochemical and EPR spin-trapping measurements showed that ODQ inhibits nitrite-mediated NO production. These findings thus suggest that nitrite can be a precursor of EDRF and that sGC or other heme proteins inhibited by ODQ catalyze the reduction of nitrite to NO.

Estimating oxygen transport resistance of the microvascular wall

2000 ◽  
Vol 279 (2) ◽  
pp. H657-H671 ◽  
Author(s):  
Arjun Vadapalli ◽  
Roland N. Pittman ◽  
Aleksander S. Popel
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Diffusion Model ◽  
Oxygen Transport ◽  
Vascular Wall ◽  
Nitric Oxide Production ◽  
Endothelial Surface

The problem of diffusion of O2 across the endothelial surface in precapillary vessels and its utilization in the vascular wall remains unresolved. To establish a relationship between precapillary release of O2 and vascular wall consumption, we estimated the intravascular flux of O2 on the basis of published in vivo measurements. To interpret the data, we utilized a diffusion model of the vascular wall and computed possible physiological ranges for O2 consumption. We found that many flux values were not consistent with the diffusion model. We estimated the mitochondrial-based maximum O2 consumption of the vascular wall (Mmt) and a possible contribution to O2 consumption of nitric oxide production by endothelial cells (MNO). Many values of O2 consumption predicted from the diffusion model exceeded Mmt + MNO. In contrast, reported values of O2consumption for endothelial and smooth muscle cell suspensions and vascular strips in vitro do not exceed Mmt. We conjecture that most of the reported values of intravascular O2 flux are overestimated, and the likely source is in the experimental estimates of convective O2 transport at upstream and downstream points of unbranched vascular segments.

scholarly journals Endothelium-derived relaxing factor, nitric oxide: effects on and production by mesangial cells and the glomerulus.

1993 ◽  
Vol 3 (8) ◽  
pp. 1435-1441
Author(s):  
L Raij ◽  
P J Shultz
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor

The endothelium-derived relaxing factor nitric oxide (EDRF/NO) is a labile, endogenous vasodilator that is important in the control of systemic vascular tone. This review focuses on the effects of EDRF/NO on glomerular mesangial cells in vitro and on the role of EDRF/NO in mesangial and glomerular physiology and pathophysiology in vivo. It was concluded that EDRF/NO can stimulate increases in cGMP, inhibit mesangial cell contraction, and inhibit growth factor-induced proliferation of mesangial cells in culture. Furthermore, incubation with endotoxin or cytokines stimulates mesangial cells to produce EDRF/NO, via an inducible NO synthase enzyme. Therefore, it is likely that NO could play a role in the inflammatory response within the glomerulus. Finally, recent studies providing evidence that EDRF/NO is functional within the glomerulus in vivo, especially during endotoxemia and inflammation are also reviewed.

A Novel Platelet Activating Factor Antagonist, SM-12502, Attenuates Endotoxin-induced Disseminated Intravascular Coagulation and Acute Pulmonary Vascular Injury by Inhibiting TNF Production in Rats

1996 ◽  
Vol 75 (06) ◽  
pp. 965-970 ◽  
Author(s):  
Kazunori Murakami ◽  
Kenji Okajima ◽  
Mitsuhiro Uchiba ◽  
Masayoshi Johno ◽  
Hiroaki Okabe ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Degradation Products ◽  
Platelet Activating Factor ◽  
Pulmonary Vascular Permeability ◽  
Intravascular Coagulation ◽  
Tnf Α ◽  
Histologic Changes ◽  
Factor Antagonist

SummaryAdult respiratory distress syndrome and disseminated intravascular coagulation are important pathologic conditions affecting the outcome of patients with sepsis. To elucidate the possible therapeutic efficacy of SM-12502, a novel platelet activating factor antagonist, on acute lung injury and disseminated intravascular coagulation in sepsis, we investigated the effect of SM-12502 on an endotoxin (ET)-induced septic model in rats. SM-12502 prevented ET-induced increases in pulmonary vascular permeability and ET-induced histologic changes, such as leukocyte infiltration and pulmonary interstitial edema, 6 h following the administration of ET (5 mg/kg). SM-12502 also inhibited the decrease in fibrinogen and the increase in fibrin and fibrinogen degradation products observed following ET administration. SM-12502 prevented increases in the serum concentration of tumor necrosis factor (TNF) 90 min following ET administration in vivo, and significantly inhibited the production of TNF-α by ET-stimulated monocytes in vitro.These findings suggest that SM-12502 attenuates the actions of endotoxin by the inhibition of TNF production

scholarly journals Endothelium-Derived Hyperpolarizing Factor and Myoendothelial Coupling: The in vivo Perspective

2020 ◽  
Vol 11 ◽  
Author(s):  
Kjestine Schmidt ◽  
Cor de Wit
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Membrane Potential ◽  
Vascular Tone ◽  
Radial Spread ◽  
Distinct Features ◽  
Type Response ◽  
Chemical Mediators

The endothelium controls vascular tone adopting blood flow to tissue needs. It releases chemical mediators [e.g., nitric oxide (NO), prostaglandins (PG)] and exerts appreciable dilation through smooth muscle hyperpolarization, thus termed endothelium-dependent hyperpolarization (EDH). Initially, EDH was attributed to release of a factor, but later it was suggested that smooth muscle hyperpolarization might be derived from radial spread of an initial endothelial hyperpolarization through heterocellular channels coupling these vascular cells. The channels are indeed present and formed by connexins that enrich in gap junctions (GJ). In vitro data suggest that myoendothelial coupling underlies EDH-type dilations as evidenced by blocking experiments as well as simultaneous, merely identical membrane potential changes in endothelial and smooth muscle cells (SMCs), which is indicative of coupling through ohmic resistors. However, connexin-deficient animals do not display any attenuation of EDH-type dilations in vivo, and endothelial and SMCs exhibit distinct and barely superimposable membrane potential changes exerted by different means in vivo. Even if studied in the exact same artery EDH-type dilation exhibits distinct features in vitro and in vivo: in isometrically mounted vessels, it is rather weak and depends on myoendothelial coupling through connexin40 (Cx40), whereas in vivo as well as in vitro under isobaric conditions it is powerful and independent of myoendothelial coupling through Cx40. It is concluded that EDH-type dilations are distinct and a significant dependence on myoendothelial coupling in vitro does not reflect the situation under physiologic conditions in vivo. Myoendothelial coupling may act as a backup mechanism that is uncovered in the absence of the powerful EDH-type response and possibly reflects a situation in a pathophysiologic environment.

scholarly journals Podoplanin-Fc reduces lymphatic vessel formation in vitro and in vivo and causes disseminated intravascular coagulation when transgenically expressed in the skin

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4376-4384 ◽  
Author(s):  
Leah N. Cueni ◽  
Lu Chen ◽  
Hui Zhang ◽  
Daniela Marino ◽  
Reto Huggenberger ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Lymphatic Vessel ◽  
Embryoid Bodies ◽  
Intravascular Coagulation ◽  
Vessel Formation ◽  
Fatal Hemorrhage ◽  
Keratin 14 ◽  
Vessel Growth

Abstract Podoplanin is a small transmembrane protein required for development and function of the lymphatic vascular system. To investigate the effects of interfering with its function, we produced an Fc fusion protein of its ectodomain. We found that podoplanin-Fc inhibited several functions of cultured lymphatic endothelial cells and also specifically suppressed lymphatic vessel growth, but not blood vessel growth, in mouse embryoid bodies in vitro and in mouse corneas in vivo. Using a keratin 14 expression cassette, we created transgenic mice that overexpressed podoplanin-Fc in the skin. No obvious outward phenotype was identified in these mice, but surprisingly, podoplanin-Fc—although produced specifically in the skin—entered the blood circulation and induced disseminated intravascular coagulation, characterized by microthrombi in most organs and by thrombocytopenia, occasionally leading to fatal hemorrhage. These findings reveal an important role of podoplanin in lymphatic vessel formation and indicate the potential of podoplanin-Fc as an inhibitor of lymphangiogenesis. These results also demonstrate the ability of podoplanin to induce platelet aggregation in vivo, which likely represents a major function of lymphatic endothelium. Finally, keratin 14 podoplanin-Fc mice represent a novel genetic animal model of disseminated intravascular coagulation.

The Glycosaminoglycan of Recombinant Human Soluble Thrombomodulin Affects Antithrombotic Activity in a Rat Model of Tissue Factor-Induced Disseminated Intravascular Coagulation

1992 ◽  
Vol 67 (03) ◽  
pp. 366-370 ◽  
Author(s):  
Katsuhiko Nawa ◽  
Teru Itani ◽  
Mayumi Ono ◽  
Katsu-ichi Sakano ◽  
Yasumasa Marumoto ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Disseminated Intravascular Coagulation ◽  
Rat Model ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Soluble Thrombomodulin ◽  
Intravascular Coagulation ◽  
Platelet Counts ◽  
Recombinant Human Soluble Thrombomodulin

SummaryPrevious studies on recombinant human soluble thrombomodulin (rsTM) from Chinese hamster ovary cells revealed that rsTM was expressed as two proteins that differed functionally in vitro due to the presence (rsTMp) or absence (rsTMa) of chondroitin-4-sulfate. The current study evaluates the in vivo behavior of rsTM in rats and in a rat model of tissue factor-induced disseminated intravascular coagulation (DIC). rsTMp was more potent than rsTMa for prolongation of the activated partial thromboplastin time (APTT) and their in vivo half-lives determined by ELISA were 20 min for rsTMp and 5.0 h for rsTMa. Injection of a tissue factor suspension (5 mg/kg) resulted in DIC as judged by decreased platelet counts and fibrinogen concentrations, prolonged APTT, and increased fibrin and fibrinogen degradation products (FDP) levels. A bolus injection of either rsTM (0.2 mg/kg) 1 min before induction of DIC essentially neutralized effects on platelets, fibrinogen, and FDP levels, and had only a moderate effect on APTT prolongation. The dose of anticoagulant to inhibit the drop in platelet counts by 50% (ED50) was 0.2 mg/kg rsTMa, 0.07 mg/kg rsTMp, and 7 U/ kg heparin. The effect of increasing concentrations of rsTM and heparin on bleeding times were compared in experiments involving incision of the rat tail. Doubling of the bleeding times occurred at 5 mg/kg rsTMa, 3 mg/kg rsTMp or 90 U/kg heparin. These values represent a 25-fold increase over the ED50 for rsTMa, 43-fold for rsTMp and 13-fold for heparin. These results suggest that rsTMp is a potent anticoagulant to inhibit the platelet reduction when injected prior to the induction of DIC in rats.

Disseminated intravascular coagulation syndrome

2020 ◽  
pp. 22-40
Author(s):  
A. Kulikov
Keyword(s):  
Clinical Practice ◽  
Disseminated Intravascular Coagulation ◽  
Blood Cells ◽  
Physical State ◽  
Clinical Manifestations ◽  
Vascular Wall ◽  
Stages Of Development ◽  
Intravascular Coagulation ◽  
Hemostatic Disorder

Presented material reveals main links in the pathogenesis of hemostatic disorder. In particular, attention is paid to the role of the lungs, liver and other organs in the development of this process. Role of vascular wall and blood cells in regulation of the physical state of blood is described in detail. The most frequent factors leading to hypercoagulation are indicated. Difference between hypercoagulation and thrombophilia is shown. The latter is found in clinical practice quite often, but at the same time, it is poorly diagnosed. Such a terrible complication of hemostatic disorder as disseminated intravascular coagulation is described. Its classification, stages of development, clinical manifestations are offered to the readers.

Sign in / Sign up

Export Citation Format

Share Document