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Topic: Basic or Translational Science
Jahandideh, Forough1; Macala, Kimberly1,2,3; Panahi, Sareh4; Khadaroo, Rachel2,3; Gragasin, Ferrante1; Bourque, Stephane1,4
1Dept Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Canada; 2Dept Critical Care Medicine, University of Alberta, Edmonton, Canada; 3Dept Surgery, University of Alberta, Edmonton, Canada; 4Dept Pharmacology, University of Alberta, Edmonton, Canada
Introduction: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. If unimpeded, sepsis can progress to septic shock, characterized by refractory hypotension and unresponsive vasculature (i.e. vasoplegia) resulting in tissue hypoperfusion and eventually organ failure1. The overall mortality rate of septic shock is more than 30%. The vascular dysfunction and refractory hypotension in septic shock are caused, at least in part, by excess reactive oxygen species (ROS) generation and dysregulated nitric oxide (NO) production (via inducible NO synthase upregulation and increased scavenging by excess ROS)2. Moreover, excess ROS oxidizes and hence damages soluble guanylate cyclase (sGC), the downstream mediator of NO, resulting in the impaired organ blood flow3. We believe the loss of sGC-mediated vasodilation is a critical determinant of reduced organ blood flow in sepsis.
Objectives: To assess the state of vascular dysfunction and altered blood flow patterns as sepsis progresses to septic shock. We hypothesized restoring defective sGC in sepsis using cinaciguat would improve survival in a murine model of sepsis.
Methods: Studies were in accordance with Canadian Council on Animal Care guidelines and the Animal Care and Use Committee at the University of Alberta. Male C57Bl/6 mice (10-12 weeks of age) were instrumented with fibre-optic pressure sensors for direct blood pressure monitoring under anesthesia. Flow probes were placed around the left common carotid, superior mesenteric, and right renal arteries to monitor blood flow to the brain, gut, and kidney, respectively. After baseline recordings, sepsis was induced by an intraperitoneal injection of fecal slurry (FS, 1.3mg/g) or equivalent volume of vehicle. In a separate series of experiments, mice were treated with cinaciguat (15μg/kg IV) 30 minutes after FS injection and survival time was monitored.
Results: Blood pressure decreased steadily over time after FS administration (44%±4% after 4h) compared to control mice (p<0.01), but no changes in heart rate were noted (p>0.05). Blood flow in the carotid, superior mesenteric, and renal arteries reduced at 47±4%, 71±8%, and 57±13% respectively, 4h after FS injection.
Vessel reactivity, assessed by monitoring constrictor and relaxation responses to bolus doses of phenylephrine (10µg/kg body weight) and sodium nitroprusside (5µg/kg body weight) was reduced by 36±9% and 53±7% respectively, in mice administered FS compared to controls, suggesting impaired regional vascular function. These data suggest certain organs are more susceptible to vascular dysfunction and hypoperfusion with the progression of sepsis. Administration of cinaciguat 30 minutes after FS injection improved survival (3.3h vs 4.8h; p<0.001). While sGC activity was impaired in septic mice, cinacigaut administration restored its activity by 87±2% (p<0.05).
Conclusion: Vascular dysfunction occurs as sepsis progresses to septic shock. Sepsis impairs sGC activity and regional blood flow while cinaciguat administration restores defective sGC, hence improving survival in septic mice.
1. Sharawy N. J Crit Care. 2014;29:83-87.
2. Levy B, Collin S, Sennoun N, Ducrocq N, Kimmoun A, Asfar P, Perez P, Meziani F. Intensive Care Med. 2010;36:2019-2029.
3. McConnell KW, Coopersmith CM. Presse Med. 2016;45:e93-8.
Topic: Basic or Translational Science
Jahandideh, Forough1; Macala, Kimberly1,2,3; Panahi, Sareh4; Khadaroo, Rachel2,3; Gragasin, Ferrante1; Bourque, Stephane1,4
1Dept Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Canada; 2Dept Critical Care Medicine, University of Alberta, Edmonton, Canada; 3Dept Surgery, University of Alberta, Edmonton, Canada; 4Dept Pharmacology, University of Alberta, Edmonton, Canada
Introduction: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. If unimpeded, sepsis can progress to septic shock, characterized by refractory hypotension and unresponsive vasculature (i.e. vasoplegia) resulting in tissue hypoperfusion and eventually organ failure1. The overall mortality rate of septic shock is more than 30%. The vascular dysfunction and refractory hypotension in septic shock are caused, at least in part, by excess reactive oxygen species (ROS) generation and dysregulated nitric oxide (NO) production (via inducible NO synthase upregulation and increased scavenging by excess ROS)2. Moreover, excess ROS oxidizes and hence damages soluble guanylate cyclase (sGC), the downstream mediator of NO, resulting in the impaired organ blood flow3. We believe the loss of sGC-mediated vasodilation is a critical determinant of reduced organ blood flow in sepsis.
Objectives: To assess the state of vascular dysfunction and altered blood flow patterns as sepsis progresses to septic shock. We hypothesized restoring defective sGC in sepsis using cinaciguat would improve survival in a murine model of sepsis.
Methods: Studies were in accordance with Canadian Council on Animal Care guidelines and the Animal Care and Use Committee at the University of Alberta. Male C57Bl/6 mice (10-12 weeks of age) were instrumented with fibre-optic pressure sensors for direct blood pressure monitoring under anesthesia. Flow probes were placed around the left common carotid, superior mesenteric, and right renal arteries to monitor blood flow to the brain, gut, and kidney, respectively. After baseline recordings, sepsis was induced by an intraperitoneal injection of fecal slurry (FS, 1.3mg/g) or equivalent volume of vehicle. In a separate series of experiments, mice were treated with cinaciguat (15μg/kg IV) 30 minutes after FS injection and survival time was monitored.
Results: Blood pressure decreased steadily over time after FS administration (44%±4% after 4h) compared to control mice (p<0.01), but no changes in heart rate were noted (p>0.05). Blood flow in the carotid, superior mesenteric, and renal arteries reduced at 47±4%, 71±8%, and 57±13% respectively, 4h after FS injection.
Vessel reactivity, assessed by monitoring constrictor and relaxation responses to bolus doses of phenylephrine (10µg/kg body weight) and sodium nitroprusside (5µg/kg body weight) was reduced by 36±9% and 53±7% respectively, in mice administered FS compared to controls, suggesting impaired regional vascular function. These data suggest certain organs are more susceptible to vascular dysfunction and hypoperfusion with the progression of sepsis. Administration of cinaciguat 30 minutes after FS injection improved survival (3.3h vs 4.8h; p<0.001). While sGC activity was impaired in septic mice, cinacigaut administration restored its activity by 87±2% (p<0.05).
Conclusion: Vascular dysfunction occurs as sepsis progresses to septic shock. Sepsis impairs sGC activity and regional blood flow while cinaciguat administration restores defective sGC, hence improving survival in septic mice.
1. Sharawy N. J Crit Care. 2014;29:83-87.
2. Levy B, Collin S, Sennoun N, Ducrocq N, Kimmoun A, Asfar P, Perez P, Meziani F. Intensive Care Med. 2010;36:2019-2029.
3. McConnell KW, Coopersmith CM. Presse Med. 2016;45:e93-8.
Department of Anesthesiology and Pain Medicine
Topic: Basic or Translational Science
Jahandideh, Forough1; Macala, Kimberly1,2,3; Panahi, Sareh4; Khadaroo, Rachel2,3; Gragasin, Ferrante1; Bourque, Stephane1,4
1Dept Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Canada; 2Dept Critical Care Medicine, University of Alberta, Edmonton, Canada; 3Dept Surgery, University of Alberta, Edmonton, Canada; 4Dept Pharmacology, University of Alberta, Edmonton, Canada
Introduction: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. If unimpeded, sepsis can progress to septic shock, characterized by refractory hypotension and unresponsive vasculature (i.e. vasoplegia) resulting in tissue hypoperfusion and eventually organ failure1. The overall mortality rate of septic shock is more than 30%. The vascular dysfunction and refractory hypotension in septic shock are caused, at least in part, by excess reactive oxygen species (ROS) generation and dysregulated nitric oxide (NO) production (via inducible NO synthase upregulation and increased scavenging by excess ROS)2. Moreover, excess ROS oxidizes and hence damages soluble guanylate cyclase (sGC), the downstream mediator of NO, resulting in the impaired organ blood flow3. We believe the loss of sGC-mediated vasodilation is a critical determinant of reduced organ blood flow in sepsis.
Objectives: To assess the state of vascular dysfunction and altered blood flow patterns as sepsis progresses to septic shock. We hypothesized restoring defective sGC in sepsis using cinaciguat would improve survival in a murine model of sepsis.
Methods: Studies were in accordance with Canadian Council on Animal Care guidelines and the Animal Care and Use Committee at the University of Alberta. Male C57Bl/6 mice (10-12 weeks of age) were instrumented with fibre-optic pressure sensors for direct blood pressure monitoring under anesthesia. Flow probes were placed around the left common carotid, superior mesenteric, and right renal arteries to monitor blood flow to the brain, gut, and kidney, respectively. After baseline recordings, sepsis was induced by an intraperitoneal injection of fecal slurry (FS, 1.3mg/g) or equivalent volume of vehicle. In a separate series of experiments, mice were treated with cinaciguat (15μg/kg IV) 30 minutes after FS injection and survival time was monitored.
Results: Blood pressure decreased steadily over time after FS administration (44%±4% after 4h) compared to control mice (p<0.01), but no changes in heart rate were noted (p>0.05). Blood flow in the carotid, superior mesenteric, and renal arteries reduced at 47±4%, 71±8%, and 57±13% respectively, 4h after FS injection.
Vessel reactivity, assessed by monitoring constrictor and relaxation responses to bolus doses of phenylephrine (10µg/kg body weight) and sodium nitroprusside (5µg/kg body weight) was reduced by 36±9% and 53±7% respectively, in mice administered FS compared to controls, suggesting impaired regional vascular function. These data suggest certain organs are more susceptible to vascular dysfunction and hypoperfusion with the progression of sepsis. Administration of cinaciguat 30 minutes after FS injection improved survival (3.3h vs 4.8h; p<0.001). While sGC activity was impaired in septic mice, cinacigaut administration restored its activity by 87±2% (p<0.05).
Conclusion: Vascular dysfunction occurs as sepsis progresses to septic shock. Sepsis impairs sGC activity and regional blood flow while cinaciguat administration restores defective sGC, hence improving survival in septic mice.
1. Sharawy N. J Crit Care. 2014;29:83-87.
2. Levy B, Collin S, Sennoun N, Ducrocq N, Kimmoun A, Asfar P, Perez P, Meziani F. Intensive Care Med. 2010;36:2019-2029.
3. McConnell KW, Coopersmith CM. Presse Med. 2016;45:e93-8.
Topic: Basic or Translational Science
Jahandideh, Forough1; Macala, Kimberly1,2,3; Panahi, Sareh4; Khadaroo, Rachel2,3; Gragasin, Ferrante1; Bourque, Stephane1,4
1Dept Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Canada; 2Dept Critical Care Medicine, University of Alberta, Edmonton, Canada; 3Dept Surgery, University of Alberta, Edmonton, Canada; 4Dept Pharmacology, University of Alberta, Edmonton, Canada
Introduction: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. If unimpeded, sepsis can progress to septic shock, characterized by refractory hypotension and unresponsive vasculature (i.e. vasoplegia) resulting in tissue hypoperfusion and eventually organ failure1. The overall mortality rate of septic shock is more than 30%. The vascular dysfunction and refractory hypotension in septic shock are caused, at least in part, by excess reactive oxygen species (ROS) generation and dysregulated nitric oxide (NO) production (via inducible NO synthase upregulation and increased scavenging by excess ROS)2. Moreover, excess ROS oxidizes and hence damages soluble guanylate cyclase (sGC), the downstream mediator of NO, resulting in the impaired organ blood flow3. We believe the loss of sGC-mediated vasodilation is a critical determinant of reduced organ blood flow in sepsis.
Objectives: To assess the state of vascular dysfunction and altered blood flow patterns as sepsis progresses to septic shock. We hypothesized restoring defective sGC in sepsis using cinaciguat would improve survival in a murine model of sepsis.
Methods: Studies were in accordance with Canadian Council on Animal Care guidelines and the Animal Care and Use Committee at the University of Alberta. Male C57Bl/6 mice (10-12 weeks of age) were instrumented with fibre-optic pressure sensors for direct blood pressure monitoring under anesthesia. Flow probes were placed around the left common carotid, superior mesenteric, and right renal arteries to monitor blood flow to the brain, gut, and kidney, respectively. After baseline recordings, sepsis was induced by an intraperitoneal injection of fecal slurry (FS, 1.3mg/g) or equivalent volume of vehicle. In a separate series of experiments, mice were treated with cinaciguat (15μg/kg IV) 30 minutes after FS injection and survival time was monitored.
Results: Blood pressure decreased steadily over time after FS administration (44%±4% after 4h) compared to control mice (p<0.01), but no changes in heart rate were noted (p>0.05). Blood flow in the carotid, superior mesenteric, and renal arteries reduced at 47±4%, 71±8%, and 57±13% respectively, 4h after FS injection.
Vessel reactivity, assessed by monitoring constrictor and relaxation responses to bolus doses of phenylephrine (10µg/kg body weight) and sodium nitroprusside (5µg/kg body weight) was reduced by 36±9% and 53±7% respectively, in mice administered FS compared to controls, suggesting impaired regional vascular function. These data suggest certain organs are more susceptible to vascular dysfunction and hypoperfusion with the progression of sepsis. Administration of cinaciguat 30 minutes after FS injection improved survival (3.3h vs 4.8h; p<0.001). While sGC activity was impaired in septic mice, cinacigaut administration restored its activity by 87±2% (p<0.05).
Conclusion: Vascular dysfunction occurs as sepsis progresses to septic shock. Sepsis impairs sGC activity and regional blood flow while cinaciguat administration restores defective sGC, hence improving survival in septic mice.
1. Sharawy N. J Crit Care. 2014;29:83-87.
2. Levy B, Collin S, Sennoun N, Ducrocq N, Kimmoun A, Asfar P, Perez P, Meziani F. Intensive Care Med. 2010;36:2019-2029.
3. McConnell KW, Coopersmith CM. Presse Med. 2016;45:e93-8.
