cerebral blood flow and metabolism › ... › cerebral › cbfm_part6.pdf · cerebral circulation...
TRANSCRIPT
![Page 1: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/1.jpg)
CEREBRAL BLOOD FLOW AND METABOLISM Part 6
Supported by: HURO/0901/069/2.3.1 HU-RO-DOCS
![Page 2: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/2.jpg)
Cerebral Circulation
¨ Blood flow to CNS ¤ delivers O2, glucose, nutrients ¤ removes CO2, lactic acid, metabolites
¨ Cerebral vasculature ¤ unique anatomy & physiology ¤ safety mechanisms
¨ Brain highly vulnerable to disrupted blood flow
![Page 3: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/3.jpg)
Vasoactive metabolites neurotransmitters
ENDOTHELIUM
Vascular smooth muscle
PARENCHYMA
LUMEN
Vascular Regulation
![Page 4: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/4.jpg)
Vascular Regulation
![Page 5: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/5.jpg)
Nurovascular Unit at Work
Neurology 2007;68:1730-1732
![Page 6: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/6.jpg)
Topic Contents
• Structure and functions of vascular endothelial cell.
• The endothelial dysfunction. • The oxidant- stress induced endothelial
dysfunction. • How to assess endothelial functions. • Summary
![Page 7: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/7.jpg)
Components: ¤ Endothelial cells ¤ Basement membrane ¤Glia
Transport: ¤Diffusion ¤Receptor mediated
transport ¤ Ion channels
Blood-Brain Barrier (BBB)
![Page 8: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/8.jpg)
The Normal Vascular Endothelium
Historically viewed as a passive vascular lining
![Page 9: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/9.jpg)
Vascular Endothelium
It has many important roles to maintain vascular homeostasis: ¤ Vascular tone regulation ¤ Vascular smooth muscle cell proliferation ¤ Inflammatory responses ¤Haemostasis
It produces and releases vasoactive, thromboregulatory and growth factor substances
![Page 11: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/11.jpg)
Endothelial Cell Function
• Maintaining the vascular tone:
Vasodilation and Vasoconstriction
Tousoulis et al., Heart 2005; 91: 353-358.
![Page 12: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/12.jpg)
Endothelial Cell Functions
Functional targets Physiological action/Mediators
Growth Stimulation Inhibition
PDGF, FGF, IGF-1, ET, AII NO, PGI2, TGF
Inflammation Proinflammatory Antiinflammatory
Adhesion molecules Selectin-E, VCAM-1, ICAM-1, PECAM-1
![Page 13: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/13.jpg)
Endothelial cell functions
Calles-Escandon and Cipolla, Endocrine Rev 2001; 22: 36-52.
Functional targets Physiological action/Mediators
Hemostasis Prothrombotic Antithrombotic
PAI-1 PGI2, TPA
![Page 14: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/14.jpg)
Factors Affecting Vascular Tone and Structure
Dilation Growth inhibition
Atithrombotic Anti-inflammatory
Antioxidant Constiction
Growth promotion Prothrombotic
Proinflammatory Pro-oxidant
Endothelium maintains vascular health
![Page 15: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/15.jpg)
- pathological conditions
- altered anticoagulant & anti-inflammatory properties
- impaired modulation of vascular growth & dysregulation of vascular remodeling
An impairment of endothelium-dependent vasorelaxation caused by a loss of NO bioactivity in the vessel wall
Endothelial Dysfunction
![Page 16: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/16.jpg)
Causes and Consequences of Endothelial Dysfunction
Endothelial dysfunction
Vasospasm (coronary, cerebral)
Atherosclerosis
Inflammatory disease
Peripheral artery disease
Reperfusion injury
Hypertension
Reocclusion Heart failure
Diabetes
Hyperhomocysteinemia
Hyperlipidemia
Immune reaction
Rubanyi GM. J Cardiovasc Pharmacol. 1993;22(suppl 4):S1-S4.
![Page 17: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/17.jpg)
![Page 18: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/18.jpg)
Unifying Model: Endothelial Dysfunction to Cardiovascular Disorder
Xanthine oxidase, NADP/NADPH oxidase uncoulpled eNOS
NO bioavailability
![Page 19: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/19.jpg)
The Role of Endothelium in Leukocyte Function
![Page 20: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/20.jpg)
How Can We Assess the Endothelial Function?
![Page 21: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/21.jpg)
Furchgott, R., Zawadzki, J., “The Obligatory Role of Endothelial Cells in the Relaxation of Arterial Smooth Muscle by Acetylcholine,” Nature, vol. 288, Nov. 27, 1980, pp. 373-376;
The Nobel Prize in Physiology or Medicine 1998 Robert F. Furchgott, Louis J. Ignarro, Ferid Murad
![Page 22: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/22.jpg)
Furchgott's Sandwich
![Page 23: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/23.jpg)
The L-arginine: Nitroc Oxide Pathway
Vallance P , Chan N Heart 2001;85:342-350
![Page 24: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/24.jpg)
What is Nitric Oxide (NO)?
¨ NO is one of the most powerful, endogeneous vasodilators
¨ Vasodilators improve circulation throughout the body
¨ In 1998 The Nobel Prize in Physiology or Medicine was awarded to 3 Americans for their discoveries concerning the Nitric Oxide molecule in the cardiovascular system Robert F. Furchgott
Louis J. Ignarro
Ferid Murad
![Page 25: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/25.jpg)
Why Does the Body Need NO?
The Answer: Better Circulation ¤ Dilates existing vessels;
arterioles, venules and lymphatics
¤ Angiogenesis - the growth of new blood and lymph vessels
¤ Decreases edema and swelling ¤ Increases nutritional flow to
cells ¤ Increases antibiotic delivery
and action ¤ Restores blood flow to nerves
![Page 26: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/26.jpg)
(A) In most, if not all, vessels nitric oxide is synthesised within the endothelium.
Vallance P , Chan N Heart 2001;85:342-350
©2001 by BMJ Publishing Group Ltd and British Cardiovascular Society
![Page 27: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/27.jpg)
Regulation of NO Synthesis
![Page 28: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/28.jpg)
Methods for exploring endothelial function. (Guerci et al., Diabetes Metab 2001; 27: 425-434.)
![Page 29: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/29.jpg)
Flow-mediated Vasodilation
![Page 30: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/30.jpg)
Endothelial Function
Dilation Growth inhibition
Atithrombotic Anti-inflammatory
Antioxidant
Constiction Growth promotion
Prothrombotic Proinflammatory
Pro-oxidant
![Page 31: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/31.jpg)
Endothelial Dysfunction the sine qua non of the atherogenic process
Age Family history
Smoking Hypertension
Low HDL-C High LDL-C
Diabetes Mellitus
Dilation Growth inhibition
Atithrombotic Anti-inflammatory
Antioxidant
Constiction Growth promotion
Prothrombotic Proinflammatory
Pro-oxidant
![Page 32: CEREBRAL BLOOD FLOW AND METABOLISM › ... › cerebral › CBFM_Part6.pdf · Cerebral Circulation ¤ Blood flow to CNS ⁄ delivers O. 2, glucose, nutrients ⁄ removes CO. 2, lactic](https://reader033.vdocuments.mx/reader033/viewer/2022052723/5f0d4d8a7e708231d439ad61/html5/thumbnails/32.jpg)
Hypercapnia-induced Vasodilation is Endothelium-dependent and Sensitive to Ischemia
Perc
ent C
hang
e fro
m B
asel
ine
0
5
10
15
20
25
30
35
40
10% CO2
5% CO2
control 1 hr 2 hr 4 hr Post - Ischemia
+
+
+ * *
*
+
+
+
Bari et al, Brain Res, (1998)