Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism

Jacob Schultz, Asger Andersen, Inger Lise Gade, Benedict Kjaergaard, Jens Erik Nielsen-Kudsk

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

BACKGROUND: Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism.

METHODS: Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat ( n=6), sildenafil ( n=6), inhaled NO ( n=6) or vehicle ( n=6). Sham animals ( n=4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis.

RESULTS: Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352±29 vs. baseline: 107±6 dynes, p<0.0001). All treatments lowered pulmonary vascular resistance compared with vehicle (riociguat: -158±35, sildenafil: -224±35, inhaled NO: -156±35 dynes, p<0.0001). Sildenafil, but neither inhaled NO nor riociguat, caused a decrease in systemic vascular resistance (sildenafil 678±41 vs. vehicle 1081±93 dynes, p=0.02) and increased cardiac output (sildenafil 8.8±0.8 vs. vehicle: 5.9±0.2 L/min, p<0.001). Systemic blood pressure was unaltered in all treatment groups.

CONCLUSION: Stimulation of the NO-sGC-cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.

OriginalsprogEngelsk
TidsskriftEuropean Heart Journal: Acute Cardiovascular Care
Antal sider9
ISSN2048-8726
DOI
StatusE-pub ahead of print - apr. 2019

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Right Ventricular Function
Pulmonary Embolism
Vascular Resistance
Nitric Oxide
Swine
Cyclic GMP
Blood Pressure
Lung
Pulmonary Circulation
Transesophageal Echocardiography
Therapeutics
Sildenafil Citrate
riociguat
Vasodilator Agents
Vasodilation
Cardiac Output
Thrombosis
Hemodynamics
Pressure

Citer dette

@article{11a4acb45b6a49f7b04a4a24855c5a35,
title = "Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism",
abstract = "BACKGROUND: Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism.METHODS: Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat ( n=6), sildenafil ( n=6), inhaled NO ( n=6) or vehicle ( n=6). Sham animals ( n=4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis.RESULTS: Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352±29 vs. baseline: 107±6 dynes, p<0.0001). All treatments lowered pulmonary vascular resistance compared with vehicle (riociguat: -158±35, sildenafil: -224±35, inhaled NO: -156±35 dynes, p<0.0001). Sildenafil, but neither inhaled NO nor riociguat, caused a decrease in systemic vascular resistance (sildenafil 678±41 vs. vehicle 1081±93 dynes, p=0.02) and increased cardiac output (sildenafil 8.8±0.8 vs. vehicle: 5.9±0.2 L/min, p<0.001). Systemic blood pressure was unaltered in all treatment groups.CONCLUSION: Stimulation of the NO-sGC-cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.",
author = "Jacob Schultz and Asger Andersen and Gade, {Inger Lise} and Benedict Kjaergaard and Nielsen-Kudsk, {Jens Erik}",
year = "2019",
month = "4",
doi = "10.1177/2048872619840772",
language = "English",
journal = "European Heart Journal: Acute Cardiovascular Care",
issn = "2048-8726",
publisher = "SAGE Publications",

}

TY - JOUR

T1 - Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism

AU - Schultz, Jacob

AU - Andersen, Asger

AU - Gade, Inger Lise

AU - Kjaergaard, Benedict

AU - Nielsen-Kudsk, Jens Erik

PY - 2019/4

Y1 - 2019/4

N2 - BACKGROUND: Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism.METHODS: Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat ( n=6), sildenafil ( n=6), inhaled NO ( n=6) or vehicle ( n=6). Sham animals ( n=4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis.RESULTS: Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352±29 vs. baseline: 107±6 dynes, p<0.0001). All treatments lowered pulmonary vascular resistance compared with vehicle (riociguat: -158±35, sildenafil: -224±35, inhaled NO: -156±35 dynes, p<0.0001). Sildenafil, but neither inhaled NO nor riociguat, caused a decrease in systemic vascular resistance (sildenafil 678±41 vs. vehicle 1081±93 dynes, p=0.02) and increased cardiac output (sildenafil 8.8±0.8 vs. vehicle: 5.9±0.2 L/min, p<0.001). Systemic blood pressure was unaltered in all treatment groups.CONCLUSION: Stimulation of the NO-sGC-cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.

AB - BACKGROUND: Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism.METHODS: Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat ( n=6), sildenafil ( n=6), inhaled NO ( n=6) or vehicle ( n=6). Sham animals ( n=4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis.RESULTS: Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352±29 vs. baseline: 107±6 dynes, p<0.0001). All treatments lowered pulmonary vascular resistance compared with vehicle (riociguat: -158±35, sildenafil: -224±35, inhaled NO: -156±35 dynes, p<0.0001). Sildenafil, but neither inhaled NO nor riociguat, caused a decrease in systemic vascular resistance (sildenafil 678±41 vs. vehicle 1081±93 dynes, p=0.02) and increased cardiac output (sildenafil 8.8±0.8 vs. vehicle: 5.9±0.2 L/min, p<0.001). Systemic blood pressure was unaltered in all treatment groups.CONCLUSION: Stimulation of the NO-sGC-cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.

U2 - 10.1177/2048872619840772

DO - 10.1177/2048872619840772

M3 - Journal article

JO - European Heart Journal: Acute Cardiovascular Care

JF - European Heart Journal: Acute Cardiovascular Care

SN - 2048-8726

ER -