Effects of Rho kinase, prostacyclin and L-arginine on microvascular permeability and perfusion

Cornelia Lundblad

Effects of Rho kinase, prostacyclin and L-arginine on microvascular permeability and perfusion

Cornelia Lundblad

Department of Immunotechnology

Research output: Thesis › Doctoral Thesis (compilation)

Abstract

This thesis presents some effects of Rho kinase, prostacyclin (PGI2) and nitric oxide (NO) in relation to trauma and inflammation by evaluating their effects on microvascular perfusion and permeability in mouse brain and in cat skeletal muscle. PGI2 and NO are endogenous vasoactive substances produced by the endothelium. They are vasodilators with antiaggregatory/antiadhesive and permeability-reducing properties, and exert their effects via cAMP and cGMP, respectively.

Earlier studies indicate that both PGI2 and NO are beneficial by improving perfusion in the traumatized brain. Rho kinase is an intracellular kinase, known to increase the contractility of the endothelial cells and thereby the intercellular distance and may, therefore, be involved in regulation of microvascular permeability. cAMP and cGMP are also suggested to exert their permeability-reducing effects by affecting the intercellular distance between the endothelial cells. PGI2, NO and Rho kinase affect the contractility of smooth muscle cells and thereby contributes to the regulation of vascular resistance.

The effects on fluid and protein microvascular permeability of the Rho kinase inhibitor Y-27632 and PGI2 were analysed in cat skeletal muscle. Y-27632 reduced permeability following the surgical trauma, as shown previously for PGI2, but neither PGI2 nor Y-27632 counteracted the endotoxin-induced increase in fluid and protein permeability. These results suggest that mechanisms behind increased permeability during inflammation differ partly from those responsible for normal regulation of permeability.

To investigate cerebral hemodynamic effects of brain trauma, a controlled cortical impact injury was evaluated regarding trauma-induced effects on cortical blood flow, number of perfused capillaries, permeability-surface area product, brain oedema and contusion volume. The model was then used to evaluate effects of L-arginine and endogenous PGI2 (using transgenic mice with deficient PGI2 receptor) on these parameters following trauma. L-arginine improved cerebral perfusion in the contusion areas, and endogenous PGI2 is important for cell survival as the contusion was larger in animal with deficient PGI2 receptor.

Original language	English
Qualification	Doctor
Awarding Institution	Department of Experimental Medical Science
Supervisors/Advisors	Grände, Per-Olof, Supervisor
Award date	2006 Mar 3
Publisher	Department of Clinical Sciences, Lund University
ISBN (Print)	91-85481-48-3
Publication status	Published - 2006

Bibliographical note

Defence details

Date: 2006-03-03
Time: 09:15
Place: GK-salen, BMC, Sölvegatan 19, Lund

External reviewer(s)

Name: Koskinen, Lars-Owe
Title: Docent
Affiliation: Avd Neurokirurgi, Umeå Universitet

---

<div class="article_info">Cornelia Lundblad, Peter Bentzer and Per-Olof Grände. <span class="article_issue_date">2003</span>. <span class="article_title">Inhibition of Rho kinase decreases hydraulic and protein microvascular permeability in cat skeletal muscle.</span> <span class="journal_series_title">Microvasc Res</span>, <span class="journal_volume">vol 66</span> <span class="journal_pages">pp 126-33</span>.</div>
<div class="article_info">Cornelia Lundblad, Peter Bentzer and Per-Olof Grände. <span class="article_issue_date">2004</span>. <span class="article_title">The permeability-reducing effects of prostacyclin and inhibition of Rho kinase do not counteract endotoxin-induced increase in permeability in cat skeletal muscle.</span> <span class="journal_series_title">Microvasc Res</span>, <span class="journal_volume">vol 68</span> <span class="journal_pages">pp 286-94</span>.</div>
<div class="article_info">Cornelia Lundblad, Per-Olof Grände and Peter Bentzer. <span class="article_issue_date">2004</span>. <span class="article_title">A mouse model for evaluation of capillary perfusion, microvascular permeability, cortical blood flow, and cortical edema in the traumatized brain.</span> <span class="journal_series_title">J Neurotrauma.</span>, <span class="journal_volume">vol 21</span> <span class="journal_pages">pp 741-53</span>.</div>
<div class="article_info">Cornelia Lundblad and Peter Bentzer. <span class="article_issue_date"></span>. <span class="article_title">Effects of L-arginine on cerebral blood flow, microvascular permeability, number of perfused capillaries and brain water content in the traumatized mouse brain.</span> (submitted)</div>
<div class="article_info">Cornelia Lundblad, Per-Olof Grände and Peter Bentzer. <span class="article_issue_date"></span>. <span class="article_title">Effects of traumatic brain injury on cerebral hemodynamics and cortical cell loss in mice lacking the IP-receptor for prostacyclin.</span> (manuscript)</div>

Subject classification (UKÄ)

Basic Medicine

Free keywords

Fysiologi
Physiology
skeletal muscle
Rho kinase
prostacyclin
permeability
NO
experimental brain trauma
brain edema
brain contusion
microcirculation
cerebral perfusion

Cite this

@phdthesis{cf40b323f74d4441a6e876c3fdbbdcf5,

title = "Effects of Rho kinase, prostacyclin and L-arginine on microvascular permeability and perfusion",

abstract = "This thesis presents some effects of Rho kinase, prostacyclin (PGI2) and nitric oxide (NO) in relation to trauma and inflammation by evaluating their effects on microvascular perfusion and permeability in mouse brain and in cat skeletal muscle. PGI2 and NO are endogenous vasoactive substances produced by the endothelium. They are vasodilators with antiaggregatory/antiadhesive and permeability-reducing properties, and exert their effects via cAMP and cGMP, respectively. Earlier studies indicate that both PGI2 and NO are beneficial by improving perfusion in the traumatized brain. Rho kinase is an intracellular kinase, known to increase the contractility of the endothelial cells and thereby the intercellular distance and may, therefore, be involved in regulation of microvascular permeability. cAMP and cGMP are also suggested to exert their permeability-reducing effects by affecting the intercellular distance between the endothelial cells. PGI2, NO and Rho kinase affect the contractility of smooth muscle cells and thereby contributes to the regulation of vascular resistance. The effects on fluid and protein microvascular permeability of the Rho kinase inhibitor Y-27632 and PGI2 were analysed in cat skeletal muscle. Y-27632 reduced permeability following the surgical trauma, as shown previously for PGI2, but neither PGI2 nor Y-27632 counteracted the endotoxin-induced increase in fluid and protein permeability. These results suggest that mechanisms behind increased permeability during inflammation differ partly from those responsible for normal regulation of permeability. To investigate cerebral hemodynamic effects of brain trauma, a controlled cortical impact injury was evaluated regarding trauma-induced effects on cortical blood flow, number of perfused capillaries, permeability-surface area product, brain oedema and contusion volume. The model was then used to evaluate effects of L-arginine and endogenous PGI2 (using transgenic mice with deficient PGI2 receptor) on these parameters following trauma. L-arginine improved cerebral perfusion in the contusion areas, and endogenous PGI2 is important for cell survival as the contusion was larger in animal with deficient PGI2 receptor.",

keywords = "Fysiologi, Physiology, skeletal muscle, Rho kinase, prostacyclin, permeability, NO, experimental brain trauma, brain edema, brain contusion, microcirculation, cerebral perfusion",

author = "Cornelia Lundblad",

note = "Defence details Date: 2006-03-03 Time: 09:15 Place: GK-salen, BMC, S{\"o}lvegatan 19, Lund External reviewer(s) Name: Koskinen, Lars-Owe Title: Docent Affiliation: Avd Neurokirurgi, Ume{\aa} Universitet --- <div class={"}article_info{"}>Cornelia Lundblad, Peter Bentzer and Per-Olof Gr{\"a}nde. <span class={"}article_issue_date{"}>2003</span>. <span class={"}article_title{"}>Inhibition of Rho kinase decreases hydraulic and protein microvascular permeability in cat skeletal muscle.</span> <span class={"}journal_series_title{"}>Microvasc Res</span>, <span class={"}journal_volume{"}>vol 66</span> <span class={"}journal_pages{"}>pp 126-33</span>.</div> <div class={"}article_info{"}>Cornelia Lundblad, Peter Bentzer and Per-Olof Gr{\"a}nde. <span class={"}article_issue_date{"}>2004</span>. <span class={"}article_title{"}>The permeability-reducing effects of prostacyclin and inhibition of Rho kinase do not counteract endotoxin-induced increase in permeability in cat skeletal muscle.</span> <span class={"}journal_series_title{"}>Microvasc Res</span>, <span class={"}journal_volume{"}>vol 68</span> <span class={"}journal_pages{"}>pp 286-94</span>.</div> <div class={"}article_info{"}>Cornelia Lundblad, Per-Olof Gr{\"a}nde and Peter Bentzer. <span class={"}article_issue_date{"}>2004</span>. <span class={"}article_title{"}>A mouse model for evaluation of capillary perfusion, microvascular permeability, cortical blood flow, and cortical edema in the traumatized brain.</span> <span class={"}journal_series_title{"}>J Neurotrauma.</span>, <span class={"}journal_volume{"}>vol 21</span> <span class={"}journal_pages{"}>pp 741-53</span>.</div> <div class={"}article_info{"}>Cornelia Lundblad and Peter Bentzer. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Effects of L-arginine on cerebral blood flow, microvascular permeability, number of perfused capillaries and brain water content in the traumatized mouse brain.</span> (submitted)</div> <div class={"}article_info{"}>Cornelia Lundblad, Per-Olof Gr{\"a}nde and Peter Bentzer. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Effects of traumatic brain injury on cerebral hemodynamics and cortical cell loss in mice lacking the IP-receptor for prostacyclin.</span> (manuscript)</div>",

year = "2006",

language = "English",

isbn = "91-85481-48-3",

publisher = "Department of Clinical Sciences, Lund University",

type = "Doctoral Thesis (compilation)",

school = "Department of Experimental Medical Science",

}

TY - THES

T1 - Effects of Rho kinase, prostacyclin and L-arginine on microvascular permeability and perfusion

AU - Lundblad, Cornelia

N1 - Defence details Date: 2006-03-03 Time: 09:15 Place: GK-salen, BMC, Sölvegatan 19, Lund External reviewer(s) Name: Koskinen, Lars-Owe Title: Docent Affiliation: Avd Neurokirurgi, Umeå Universitet --- <div class="article_info">Cornelia Lundblad, Peter Bentzer and Per-Olof Grände. <span class="article_issue_date">2003</span>. <span class="article_title">Inhibition of Rho kinase decreases hydraulic and protein microvascular permeability in cat skeletal muscle.</span> <span class="journal_series_title">Microvasc Res</span>, <span class="journal_volume">vol 66</span> <span class="journal_pages">pp 126-33</span>.</div> <div class="article_info">Cornelia Lundblad, Peter Bentzer and Per-Olof Grände. <span class="article_issue_date">2004</span>. <span class="article_title">The permeability-reducing effects of prostacyclin and inhibition of Rho kinase do not counteract endotoxin-induced increase in permeability in cat skeletal muscle.</span> <span class="journal_series_title">Microvasc Res</span>, <span class="journal_volume">vol 68</span> <span class="journal_pages">pp 286-94</span>.</div> <div class="article_info">Cornelia Lundblad, Per-Olof Grände and Peter Bentzer. <span class="article_issue_date">2004</span>. <span class="article_title">A mouse model for evaluation of capillary perfusion, microvascular permeability, cortical blood flow, and cortical edema in the traumatized brain.</span> <span class="journal_series_title">J Neurotrauma.</span>, <span class="journal_volume">vol 21</span> <span class="journal_pages">pp 741-53</span>.</div> <div class="article_info">Cornelia Lundblad and Peter Bentzer. <span class="article_issue_date"></span>. <span class="article_title">Effects of L-arginine on cerebral blood flow, microvascular permeability, number of perfused capillaries and brain water content in the traumatized mouse brain.</span> (submitted)</div> <div class="article_info">Cornelia Lundblad, Per-Olof Grände and Peter Bentzer. <span class="article_issue_date"></span>. <span class="article_title">Effects of traumatic brain injury on cerebral hemodynamics and cortical cell loss in mice lacking the IP-receptor for prostacyclin.</span> (manuscript)</div>

PY - 2006

Y1 - 2006

N2 - This thesis presents some effects of Rho kinase, prostacyclin (PGI2) and nitric oxide (NO) in relation to trauma and inflammation by evaluating their effects on microvascular perfusion and permeability in mouse brain and in cat skeletal muscle. PGI2 and NO are endogenous vasoactive substances produced by the endothelium. They are vasodilators with antiaggregatory/antiadhesive and permeability-reducing properties, and exert their effects via cAMP and cGMP, respectively. Earlier studies indicate that both PGI2 and NO are beneficial by improving perfusion in the traumatized brain. Rho kinase is an intracellular kinase, known to increase the contractility of the endothelial cells and thereby the intercellular distance and may, therefore, be involved in regulation of microvascular permeability. cAMP and cGMP are also suggested to exert their permeability-reducing effects by affecting the intercellular distance between the endothelial cells. PGI2, NO and Rho kinase affect the contractility of smooth muscle cells and thereby contributes to the regulation of vascular resistance. The effects on fluid and protein microvascular permeability of the Rho kinase inhibitor Y-27632 and PGI2 were analysed in cat skeletal muscle. Y-27632 reduced permeability following the surgical trauma, as shown previously for PGI2, but neither PGI2 nor Y-27632 counteracted the endotoxin-induced increase in fluid and protein permeability. These results suggest that mechanisms behind increased permeability during inflammation differ partly from those responsible for normal regulation of permeability. To investigate cerebral hemodynamic effects of brain trauma, a controlled cortical impact injury was evaluated regarding trauma-induced effects on cortical blood flow, number of perfused capillaries, permeability-surface area product, brain oedema and contusion volume. The model was then used to evaluate effects of L-arginine and endogenous PGI2 (using transgenic mice with deficient PGI2 receptor) on these parameters following trauma. L-arginine improved cerebral perfusion in the contusion areas, and endogenous PGI2 is important for cell survival as the contusion was larger in animal with deficient PGI2 receptor.

AB - This thesis presents some effects of Rho kinase, prostacyclin (PGI2) and nitric oxide (NO) in relation to trauma and inflammation by evaluating their effects on microvascular perfusion and permeability in mouse brain and in cat skeletal muscle. PGI2 and NO are endogenous vasoactive substances produced by the endothelium. They are vasodilators with antiaggregatory/antiadhesive and permeability-reducing properties, and exert their effects via cAMP and cGMP, respectively. Earlier studies indicate that both PGI2 and NO are beneficial by improving perfusion in the traumatized brain. Rho kinase is an intracellular kinase, known to increase the contractility of the endothelial cells and thereby the intercellular distance and may, therefore, be involved in regulation of microvascular permeability. cAMP and cGMP are also suggested to exert their permeability-reducing effects by affecting the intercellular distance between the endothelial cells. PGI2, NO and Rho kinase affect the contractility of smooth muscle cells and thereby contributes to the regulation of vascular resistance. The effects on fluid and protein microvascular permeability of the Rho kinase inhibitor Y-27632 and PGI2 were analysed in cat skeletal muscle. Y-27632 reduced permeability following the surgical trauma, as shown previously for PGI2, but neither PGI2 nor Y-27632 counteracted the endotoxin-induced increase in fluid and protein permeability. These results suggest that mechanisms behind increased permeability during inflammation differ partly from those responsible for normal regulation of permeability. To investigate cerebral hemodynamic effects of brain trauma, a controlled cortical impact injury was evaluated regarding trauma-induced effects on cortical blood flow, number of perfused capillaries, permeability-surface area product, brain oedema and contusion volume. The model was then used to evaluate effects of L-arginine and endogenous PGI2 (using transgenic mice with deficient PGI2 receptor) on these parameters following trauma. L-arginine improved cerebral perfusion in the contusion areas, and endogenous PGI2 is important for cell survival as the contusion was larger in animal with deficient PGI2 receptor.

KW - Fysiologi

KW - Physiology

KW - skeletal muscle

KW - Rho kinase

KW - prostacyclin

KW - permeability

KW - NO

KW - experimental brain trauma

KW - brain edema

KW - brain contusion

KW - microcirculation

KW - cerebral perfusion

M3 - Doctoral Thesis (compilation)

SN - 91-85481-48-3

PB - Department of Clinical Sciences, Lund University

ER -

Effects of Rho kinase, prostacyclin and L-arginine on microvascular permeability and perfusion

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

Fingerprint

Cite this