Protamine sulfate causes pulmonary hypertension and edema in isolated rat lungs

1987 ◽  
Vol 62 (4) ◽  
pp. 1363-1367 ◽  
Author(s):  
R. P. Fairman ◽  
C. N. Sessler ◽  
M. Bierman ◽  
F. L. Glauser
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Weight Ratio ◽  
Dry Weight ◽  
Protamine Sulfate ◽  
Pulmonary Vasculature ◽  
Lung Weight ◽  
Control Value ◽  
Pulmonary Arterial ◽  
Vascular Beds

The polycation protamine sulfate increases microvascular permeability in the kidney by reducing glomerular charge. We have exposed the pulmonary vasculature to protamine sulfate to determine whether electrical charges play a role in protein permeability in lung vascular beds. In anephric rats, protamine sulfate increased hematocrit approximately 25%. With protamine sulfate doses of 0.08 and 0.04 mg/g body wt, lung blood-free wet-to-dry weight ratios were increased (5.24 +/- 0.8 and 4.89 +/- 0.7) compared with control (3.85 +/- 0.3) (P less than 0.05). In isolated, ventilated, and perfused lungs 0.04 mg/g body wt protamine sulfate increased pulmonary arterial pressure from 5.2 +/- 1.4 to 16.3 +/- 3.9 mmHg (P less than 0.01). These lungs gained weight and lung wet-to-dry weight ratios were significantly increased (15.33 +/- 4.26 compared with 6.04 +/- 0.24 for control lungs). Poly-L-lysine, another polycation, also caused significant increases in pulmonary arterial pressure, lung weight, and lung wet-to-dry weight ratios. The addition of diphenhydramine to the perfusate 10 min before the addition of protamine sulfate did not prevent these changes. Heparin (90 U/mg protamine sulfate) reversed the abnormalities. Pulmonary arterial pressure (7.0 +/- 1.1 mmHg) was not significantly different from the control value, lung weight did not increase, and the lung wet-to-dry weight ratio was 6.24 +/- 0.23 (P greater than 0.05). We conclude that polycations have a significant effect on pulmonary vascular resistance and perhaps on permeability.

Cyclooxygenase and lipoxygenase inhibition by BW-755C reduces acrolein smoke-induced acute lung injury

1994 ◽  
Vol 77 (2) ◽  
pp. 888-895 ◽  
Author(s):  
S. P. Janssens ◽  
S. W. Musto ◽  
W. G. Hutchison ◽  
C. Spence ◽  
M. Witten ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Arterial Pressure ◽  
Pulmonary Edema ◽  
Pulmonary Arterial Pressure ◽  
Weight Ratio ◽  
Peak Inspiratory Pressure ◽  
Dry Weight ◽  
Lymph Flow ◽  
Pulmonary Arterial ◽  
Arterial Po2

Inhalation of smoke containing acrolein, the most common toxin in urban fires after carbon monoxide, causes vascular injury with non-cardiogenic pulmonary edema containing potentially edematogenic eicosanoids such as thromboxane (Tx) B2, leukotriene (LT) B4, and the sulfidopeptide LTs (LTC4, LTD4, and LTE4). To determine which eicosanoids are important in the acute lung injury, we pretreated sheep with BW-755C (a combined cyclooxygenase and lipoxygenase inhibitor), U-63557A (a specific Tx synthetase inhibitor), or indomethacin (a cyclooxygenase inhibitor) before a 10-min exposure to a synthetic smoke containing carbon particles (4 microns) with acrolein and compared the results with those from control sheep that received only carbon smoke. Acrolein smoke induced a fall in arterial PO2 and rises in peak inspiratory pressure, main pulmonary arterial pressure, pulmonary vascular resistance, lung lymph flow, and the blood-free wet-to-dry weight ratio. BW-755C delayed the rise in peak inspiratory pressure and prevented the fall in arterial PO2, the rise in lymph flow, and the rise in wet-to-dry weight ratio. Neither indomethacin nor U-63557A prevented the increase in lymph flow or wet-to-dry weight ratio, although they did blunt and delay the rise in airway pressure and did prevent the rises in pulmonary arterial pressure and pulmonary vascular resistance. Thus, cyclooxygenase products, probably Tx, are responsible for the pulmonary hypertension after acrolein smoke and to some extent for the increased airway resistance but not the pulmonary edema. Prevention of high-permeability pulmonary edema after smoke with BW-755C suggests that LTB4, may be etiologic, as previous work has eliminated LTC4, LTD4, and LTE4.

scholarly journals Exposure of Stored Packed Erythrocytes to Nitric Oxide Prevents Transfusion-associated Pulmonary Hypertension

2016 ◽  
Vol 125 (5) ◽  
pp. 952-963 ◽  
Author(s):  
Stefan Muenster ◽  
Arkadi Beloiartsev ◽  
Binglan Yu ◽  
E Du ◽  
Sabia Abidi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Erythrocyte Deformability ◽  
Pulmonary Vasculature ◽  
Prolonged Storage ◽  
Systemic Hemodynamic ◽  
Promising Therapeutic Approach ◽  
Erythrocyte Survival ◽  
Pulmonary Arterial

Abstract Background Transfusion of packed erythrocytes stored for a long duration is associated with increased pulmonary arterial pressure and vascular resistance. Prolonged storage decreases erythrocyte deformability, and older erythrocytes are rapidly removed from the circulation after transfusion. The authors studied whether treating stored packed ovine erythrocytes with NO before transfusion could prevent pulmonary vasoconstriction, enhance erythrocyte deformability, and prolong erythrocyte survival after transfusion. Methods Ovine leukoreduced packed erythrocytes were treated before transfusion with either NO gas or a short-lived NO donor. Sheep were transfused with autologous packed erythrocytes, which were stored at 4°C for either 2 (“fresh blood”) or 40 days (“stored blood”). Pulmonary and systemic hemodynamic parameters were monitored before, during, and after transfusion. Transfused erythrocytes were labeled with biotin to measure their circulating lifespan. Erythrocyte deformability was assessed before and after NO treatment using a microfluidic device. Results NO treatment improved the deformability of stored erythrocytes and increased the number of stored erythrocytes circulating at 1 and 24 h after transfusion. NO treatment prevented transfusion-associated pulmonary hypertension (mean pulmonary arterial pressure at 30 min of 21 ± 1 vs. 15 ± 1 mmHg in control and NO–treated packed erythrocytes, P < 0.0001). Washing stored packed erythrocytes before transfusion did not prevent pulmonary hypertension. Conclusions NO treatment of stored packed erythrocytes before transfusion oxidizes cell-free oxyhemoglobin to methemoglobin, prevents subsequent NO scavenging in the pulmonary vasculature, and limits pulmonary hypertension. NO treatment increases erythrocyte deformability and erythrocyte survival after transfusion. NO treatment might provide a promising therapeutic approach to prevent pulmonary hypertension and extend erythrocyte survival.

Chronic activation of neurokinin-1 receptor induces pulmonary hypertension in rats

1999 ◽  
Vol 276 (5) ◽  
pp. H1543-H1551 ◽  
Author(s):  
Li-Wen Chen ◽  
Chau-Fong Chen ◽  
Yih-Loong Lai
Keyword(s):  
Pulmonary Hypertension ◽  
Substance P ◽  
Arterial Pressure ◽  
Sea Level ◽  
Pulmonary Arterial Pressure ◽  
Weight Ratio ◽  
Pulmonary Arterial ◽  
Chronic Activation ◽  
Neurokinin 1 ◽  
Hypoxic Group

In this study we explored the hypothesis that chronic activation of neurokinin-1 (NK-1) receptor induces pulmonary hypertension in Wistar rats. First, the activation of NK-1 receptor on the pulmonary circulation was investigated by use of a chronic injection of NK-1 agonist [Ser9,Met(O2)11]-substance P (1 × 10−9mol/kg) for 2 wk at sea level (rats breathed room air) and during hypoxia (rats were placed in a hypobaric 380-Torr chamber). Second, we studied the effect of NK-1 antagonist (CP-96345) on developing and developed (after 4 wk of chronic hypoxia) pulmonary hypertension. Pulmonary arterial pressure, the weight ratio of right ventricle to left ventricle + septum, hematocrit, and substance P (SP) were measured. We found that NK-1 agonist significantly increased pulmonary arterial pressure in the sea-level but not in the hypoxic group. However, NK-1 agonist induced neither right heart hypertrophy nor polycythemia. CP-96345 significantly decreased pulmonary arterial pressure in the hypoxic group but had no effect in the sea-level group. Furthermore, CP-96345 significantly attenuated the acute SP-induced increase in pulmonary arterial pressure in the sea-level and hypoxic groups, with a larger increase in the hypoxic group. These results suggest that chronic activation of NK-1 receptor induces pulmonary hypertension and that there is an increase in the sensitivity of pulmonary vessels in response to SP in chronically hypoxic rats.

Lowered pulmonary arterial pressure prevents edema after endotoxin in sheep

1987 ◽  
Vol 63 (3) ◽  
pp. 1008-1011 ◽  
Author(s):  
S. J. Allen ◽  
R. E. Drake ◽  
J. Katz ◽  
J. C. Gabel ◽  
G. A. Laine
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Venous Pressure ◽  
Dry Weight ◽  
Base Line ◽  
Capillary Membrane ◽  
Significant Difference ◽  
Pulmonary Arterial ◽  
The Difference

Escherichia coli endotoxin causes increased capillary membrane permeability and increased pulmonary arterial pressure (PAP) in sheep. If the pulmonary hypertension extends to the level of the microvasculature, then the increased microvascular pressure may contribute to the pulmonary edema caused by endotoxin. We tested the hypothesis that reducing the pulmonary hypertension would reduce the amount of edema caused by endotoxin. Twelve sheep were chronically instrumented with catheters to measure PAP, left atrial pressure, and central venous pressure. The sheep were divided into two groups. One group (E) of six sheep received an intravenous infusion of 4 micrograms/kg of E. coli endotoxin. The second group (E + SNP) received the same dose of endotoxin as well as a continuous infusion of sodium nitroprusside (SNP) to reduce PAP. Three hours after the endotoxin infusions, the sheep were terminated and the extravascular fluid-to-blood-free dry weight ratios of the lungs were determined (EVF). The base-line PAP was 17.5 +/- 2.7 mmHg. A two-way analysis of variance demonstrated a significant difference (P less than 0.01) in PAP between the E and E + SNP groups. Although PAP in each group varied as a function of time, the difference between the two groups did not. The mean PAP for the E + SNP group (20.9 +/- 1.5 mmHg) was lower than the E group PAP of 27.3 +/- 2.1 mmHg after the endotoxin spike. Furthermore, the E + SNP group EVF (3.9 +/- 0.2) was significantly less than the EVF of the E group (4.7 +/- 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Endothelial pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure in mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Zdravka Daneva ◽  
Matteo Ottolini ◽  
Yen Lin Chen ◽  
Eliska Klimentova ◽  
Maniselvan Kuppusamy ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Transient Receptor Potential ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Vasculature ◽  
Transient Receptor Potential Vanilloid ◽  
Caveolin 1 ◽  
Pannexin 1 ◽  
Pulmonary Arterial ◽  
Atp Efflux ◽  
Trpv4 Channel

Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates endothelial TRPV4 channels. We hypothesized that endothelial Panx1–ATP–TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.

scholarly journals Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide

2010 ◽  
Vol 299 (4) ◽  
pp. H1153-H1159 ◽  
Author(s):  
Adeleke M. Badejo ◽  
Vaughn E. Nossaman ◽  
Edward A. Pankey ◽  
Manish Bhartiya ◽  
Chandrika B. Kannadka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Guanylyl Cyclase ◽  
Pulmonary Arterial Pressure ◽  
Soluble Guanylyl Cyclase ◽  
Systemic Arterial Pressure ◽  
Intravenous Injections ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Vascular Beds

BAY 41-8543 is a nitric oxide (NO)-independent stimulator of soluble guanylyl cyclase (sGC). Responses to intravenous injections of BAY 41-8543 were investigated under baseline and elevated tone conditions and when NO synthase (NOS) was inhibited with Nω-nitro-l-arginine methyl ester (l-NAME). Under baseline conditions, intravenous injections of BAY 41-8543 caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and increases in cardiac output. When pulmonary arterial pressure was increased to ∼30 mmHg with an intravenous infusion of U-46619, intravenous injections of BAY 41-8543 produced larger dose-dependent decreases in pulmonary arterial pressure, and the relative decreases in pulmonary and systemic arterial pressure in response to the sGC stimulator were similar. Treatment with l-NAME markedly decreased responses to BAY 41-8543 when pulmonary arterial pressure was increased to similar values (∼30 mmHg) in U-46619-infused and in U-46619-infused plus l-NAME-treated animals. The intravenous injection of a small dose of sodium nitroprusside (SNP) when combined with BAY 41-8543 enhanced pulmonary and systemic vasodilator responses to the sGC stimulator in l-NAME-treated animals. The present results indicate that BAY 41-8543 has similar vasodilator activity in the systemic and pulmonary vascular beds when pulmonary vasoconstrictor tone is increased with U-46619. These results demonstrate that pulmonary and systemic vasodilator responses to BAY 41-8543 are significantly attenuated when NOS is inhibited by l-NAME and show that vasodilator responses to BAY 41-8543 are enhanced when combined with a small dose of SNP in l-NAME-treated animals. The present results are consistent with the concept that pulmonary and systemic vasodilator responses to the sGC stimulator are NO-independent; however, the vasodilator activity of the compound is greatly diminished when endogenous NO production is inhibited with l-NAME. These data show that BAY 41-8543 has similar vasodilator activity in the pulmonary and systemic vascular beds in the rat.

Inhalation of the ETAreceptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction

2008 ◽  
Vol 294 (2) ◽  
pp. R601-R605 ◽  
Author(s):  
Bodil Petersen ◽  
Maria Deja ◽  
Roland Bartholdy ◽  
Bernd Donaubauer ◽  
Sven Laudi ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Experimental Model ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasculature ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
To Receive

Endogenous endothelin (ET)-1 modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ETAreceptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ETAreceptor antagonist might act selectively on the pulmonary vasculature and investigated the effects of aerosolized LU-135252 in an experimental model of HPV. Sixteen piglets (weight: 25 ± 1 kg) were anesthetized and mechanically ventilated at an inspiratory oxygen fraction (FiO2) of 0.3. After 1 h of hypoxia at FiO20.15, animals were randomly assigned either to receive aerosolized LU-135252 as bolus (0.3 mg/kg for 20 min; n = 8, LU group), or to receive aerosolized saline ( n = 8, controls). In all animals, hypoxia significantly increased mean pulmonary arterial pressure (32 ± 1 vs. 23 ± 1 mmHg; P < 0.01; means ± SE) and increased arterial plasma ET-1 (0.52 ± 0.04 vs. 0.37 ± 0.05 fmol/ml; P < 0.01) compared with mild hyperoxia at FiO20.3. Inhalation of LU-135252 induced a significant and sustained decrease in mean pulmonary arterial pressure compared with controls (LU group: 27 ± 1 mmHg; controls: 32 ± 1 mmHg; values at 4 h of hypoxia; P < 0.01). In parallel, mean systemic arterial pressure and cardiac output remained stable and were not significantly different from control values. Consequently, in our experimental model of HPV, the inhaled ETAreceptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects.

Air embolism-induced lung injury in isolated rat lungs

1992 ◽  
Vol 72 (4) ◽  
pp. 1235-1242 ◽  
Author(s):  
D. Wang ◽  
M. H. Li ◽  
K. Hsu ◽  
C. Y. Shen ◽  
H. I. Chen ◽  
...  
Keyword(s):  
Weight Gain ◽  
Lung Injury ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Air Embolism ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Lung Model ◽  
Lung Weight ◽  
Pulmonary Arterial

Pulmonary air embolism causes physical obstruction of microvasculature and leads to permeability changes, release of mediators, and injury to lung tissue. In this study we employed an isolated perfused rat lung model to investigate the primary and secondary effects produced by infusion of air into the pulmonary artery. Infusion of various doses of air (0.10–0.25 ml) over a 1-min period produced a dose-dependent increase in pulmonary arterial pressure and lung weight gain. In contrast, when a constant air dose was administered over various periods of time (0.25 ml over 0.5–8.0 min), the pulmonary arterial pressure rose to the same extent regardless of the infusion rate, whereas the lung weight gain increased proportionately with the rate of infusion. Total vascular resistance rose from 1.41 +/- 0.04 to 5.04 +/- 0.09 mmHg.ml-1.min in rats given 0.25 ml air over 1 min (n = 14, P less than 0.001), with greater than or equal to 90% of this increase occurring in the arterial segments. Both thromboxane B2 and endothelin concentrations also increased in the perfusate, suggesting their involvement in this increased resistance. Furthermore the pulmonary filtration coefficient increased from 0.21 +/- 0.05 to 1.28 +/- 0.26 g.min-1.cmH2O–1.100 g (n = 8, P less than 0.001), and the protein concentration in lung lavage fluid also rose, indicating lung injury. Leukocyte counts in the perfusate were unaffected by embolization, but chemiluminescent activity was increased, indicating a possible role for activated leukocytes in lung injury induced by air emboli.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous injury in isolated sheep lungs: role of perfusate leukocytes and platelets

1989 ◽  
Vol 66 (3) ◽  
pp. 1287-1296 ◽  
Author(s):  
D. B. Pearse ◽  
R. G. Brower ◽  
N. F. Adkinson ◽  
J. T. Sylvester
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pressure Ratio ◽  
Pulmonary Sequestration ◽  
Dry Weight ◽  
Lymph Flow ◽  
Thromboxane B2 ◽  
Pulmonary Arterial ◽  
Lung Lymph ◽  
Lung Lymph Flow

Perfusion of isolated sheep lungs with blood causes spontaneous edema and hypertension preceded by decreases in perfusate concentrations of leukocytes (WBC) and platelets (PLT). To determine whether these decreases were caused by pulmonary sequestration, we continuously measured blood flow and collected pulmonary arterial and left atrial blood for cell concentration measurements in six lungs early in perfusion. Significant sequestration occurred in the lung, but not in the extracorporeal circuit. To determine the contribution of these cells to spontaneous injury in this model, lungs perfused in situ with a constant flow (100 ml.kg-1.min-1) of homologous leukopenic (WBC = 540 mm-3, n = 8) or thrombocytopenic blood (PLT = 10,000 mm-3, n = 6) were compared with control lungs perfused with untreated homologous blood (WBC = 5,320, PLT = 422,000, n = 8). Perfusion of control lungs caused a rapid fall in WBC and PLT followed by transient increases in pulmonary arterial pressure, lung lymph flow, and perfusate concentrations of 6-ketoprostaglandin F1 alpha and thromboxane B2. The negative value of reservoir weight (delta W) was measured as an index of fluid entry into the lung extravascular space during perfusion. delta W increased rapidly for 60 min and then more gradually to 242 g at 180 min. This was accompanied by a rise in the lymph-to-plasma oncotic pressure ratio (pi L/pi P). Relative to control, leukopenic perfusion decreased the ratio of wet weight to dry weight, the intra- plus extravascular blood weight, and the incidence of bloody lymph. Thrombocytopenic perfusion increased lung lymph flow and the rate of delta W, decreased pi L/pi P and perfusate thromboxane B2, and delayed the peak pulmonary arterial pressure. These results suggest that perfusate leukocytes sequestered in the lung and contributed to hemorrhage but were not necessary for hypertension and edema. Platelets were an important source of thromboxane but protected against edema by an unknown mechanism.

The Rho kinase inhibitor azaindole-1 has long-acting vasodilator activity in the pulmonary vascular bed of the intact chest rat

2012 ◽  
Vol 90 (7) ◽  
pp. 825-835 ◽  
Author(s):  
Edward A. Pankey ◽  
Ryuk J. Byun ◽  
William B. Smith ◽  
Manish Bhartiya ◽  
Franklin R. Bueno ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Kinase Inhibitor ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Vascular Beds

Responses to a selective azaindole-based Rho kinase (ROCK) inhibitor (azaindole-1) were investigated in the rat. Intravenous injections of azaindole-1 (10–300 µg/kg), produced small decreases in pulmonary arterial pressure and larger decreases in systemic arterial pressure without changing cardiac output. Responses to azaindole-1 were slow in onset and long in duration. When baseline pulmonary vascular tone was increased with U46619 or L-NAME, the decreases in pulmonary arterial pressure in response to the ROCK inhibitor were increased. The ROCK inhibitor attenuated the increase in pulmonary arterial pressure in response to ventilatory hypoxia. Azaindole-1 decreased pulmonary and systemic arterial pressures in rats with monocrotaline-induced pulmonary hypertension. These results show that azaindole-1 has significant vasodilator activity in the pulmonary and systemic vascular beds and that responses are larger, slower in onset, and longer in duration when compared with the prototypical agent fasudil. Azaindole-1 reversed hypoxic pulmonary vasoconstriction and decreased pulmonary and systemic arterial pressures in a similar manner in rats with monocrotaline-induced pulmonary hypertension. These data suggest that ROCK is involved in regulating baseline tone in the pulmonary and systemic vascular beds, and that ROCK inhibition will promote vasodilation when tone is increased by diverse stimuli including treatment with monocrotaline.

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