1. Peripheral circulation I: Physiology of the vascular wall

2. Regulation of regional blood flow
Resistance vessels (arterioles): changes in diameter
Vasodilation
Vasoconstriction
Changes in the diameter of open vessels
Changes in the number of open vessels („recruitment“)
Prerequisite: basal tone
nerve-independent
sympathetic tone
1:22 PM
Vascular wall physiology

3. Vascular smooth muscle contraction
Actin (thin filaments)
attached to dense bodies made of -actin (in cytoplasm & inner side of membrane)
Myosin (thick filaments)
hexamere of 2 heavy & 2 different pairs of light chains
1:22 PM
Vascular wall physiology

4. Vascular smooth muscle (VSM) contraction
1:22 PM
Vascular wall physiology

5. Vascular wall physiology
VSM contraction
Slow
Strong
Lasting
w/o ATP, the N-terminal (catalytic) myosin head is attached to actin filament (maintains tone with minimal energy)
Intercellular communication via gap junctions
1:22 PM
Vascular wall physiology

6. Activation of VSM contractile apparatus a
Ca2+
Ca-calmodulin
Calmodulin
MLC phosphorylation
MLC
kin
ase
Ca-calmodulin-MLCK
unblocks
its
ATP
ase activity
Light
(regulatory)
myosin chain (MLC)
MLC-P  a
ATP
ase
activity
of myosin
Actin
Contraction
1:22 PM
Vascular wall physiology

7. Vascular wall physiology
VSM inactivation
 [Ca2+]i
 influx
pumping outside
Ca2+ ATPase
Na/Ca antiport
pumping to reticulum (SERCA)
Ca2+-independent MLC phosphatase prevails over MLCK   MLC phosphorylation ( activity)
1:22 PM
Vascular wall physiology

8. Excitation-contraction coupling
Electromechanical
voltage-gated Ca2+ channels (VOC)
Pharmacomechanical
receptor-operated Ca2+ channels (ROC)
Ca2+ from sarcoplasmic reticulum
Sensitization
Rho kinase  MLC phosphorylation
A, C, G kinases  MLC phosphatase inhibition
1:22 PM
Vascular wall physiology

9. Phospholipase C  IP3 + DAG
from membrane phospholipids
IP3 activates Ca channel of endoplasmic reticulum
DAG  PKC affinity to Ca
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Vascular wall physiology

10. Vascular wall physiology
cAMP
Vasodi -lation
MLC phosphatase
MLCP
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Vascular wall physiology

11. Vascular wall physiology
cGMP
Vasodi -lation
MLC phosphatase
MLCP
1:22 PM
Vascular wall physiology

12. Vascular tone regulation
Local (mainly , brain, kidney): autoregulation of blood flow
Neural (mainly skin, GIT): inter-organ distribution
important where local flow can be reduced for the sake of the whole body (blood pressure maintenance)
almost not at all in brain & 
Humoral - total PVR
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Vascular wall physiology

13. Local autoregulation of blood flow
(ml/min/kg)
Perfusion pressure (mmHg)
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Vascular wall physiology

14. Blood flow autoregulation
Importance:
Adjusts perfusion to metabolic needs
Constant flow during pressure alterations
Rises towards periphery
Mechanisms:
Myogenic response
Metabolic regulation
1:22 PM
Vascular wall physiology

15. Myogenic response to pressure changes
Normalized
diameter
Transmural pressure (cmH2O)
Flow = 0
1:22 PM
Vascular wall physiology

16. Vascular wall physiology
Myogenic response
Mechanisms unclear
Stretch-activated cation channel
Ca2+ influx
Important e.g. for orthostasis
upright   transmural pressure in legs
myogenic vasoconstriction prevents excessive redistribution of blood to legs & edema
1:22 PM
Vascular wall physiology

17. Vascular wall physiology
Metabolic regulation
Candidates (complement each other): O2
CO2 H+
lactate K+
adenosine
(probably also  NE release from SNS terminals)
Flow
Pressure
1:22 PM
Vascular wall physiology

18. Organs without autoregulation (skin,…)
Metabolic component minimal due to low metabolism
Myogenic component suppressed by NO
NO inhibition unmasks skin myogenic autoregulation
1:22 PM
Vascular wall physiology

19. Coordination of arterial & arteriolar dilation
Vasodilation of peripheral arterioles accelerates flow in larger feeding arteries
Shear stress 
NOS activation
Arterial relaxation
NO in this situation indispensable
Intact
Normalized diameter
Without endothelim
Pohl U., de Wit C.: News Physiol. Sci. 14: 74-80, 1999.
Pressure gradient (cmH2O) (~ flow)
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Transmur. pressure =konst.

20. Vascular wall physiology
Endothelium
Nitric oxide (NO)
vasodilation via cGMP  G kinase
Prostacyclin (PGI2)
vasodilation via cAMP  A kinase
Endothelin (mainly ET-1, also -2 a -3)
21 amino acids from pro-ET-1 (38 AA) by endothelin converting enzyme
receptors via G-proteins:
ETA on VSM (mainly intracellular Ca2+)
ETB releases NO & PGI2 from endothelium
Angiotensin conversion
1:22 PM
Vascular wall physiology

21. Neural regulation of vascular tone
Essentially only sympathicus
Mostly adrenergic
Mainly vasoconstriction
Parasympathicus only a bit in face, colon, bladder & genital (erection)
Cholinergic
Vasodilation
From pressoric & depressoric area of the cardiovascular center in medulla
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Vascular wall physiology

22. Vascular wall physiology
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Vascular wall physiology

23. Sympathicus: NA terminals
 receptors - vasoconstriction
more sensitive to NA from nerve terminals than to circulating adrenaline
predominant in skin, kidney,…
 receptors - vasodilation
more sensitive to circulating adrenaline than to NA
predominant in skeletal muscle
similar expression of  a  in coronary & GIT vessels
flow redistribution to muscle during exercise
Some SNS terminals in vessels are cholinergic
vasodilation
skeletal muscle
importance ?? ( muscle flow when exercise anticipated ?)
1:22 PM
Vascular wall physiology

24. Sympathetic regulation of vascular tone
Capacitance vessels (veins) more sensitive (& have  basal tone)
( CO before  tissue perfusion)
SNS lowers filtration to tissues ( filtration pressure)
1:22 PM
Vascular wall physiology

25. Vascular wall physiology
Baroreceptors
Carotid sinus (more sensitive) & aortic arch
Activation by stretch
Via glossopharyngeal nerve to medulla (nucleus tractus solitarius)
Sympathetic tone 
Sensitivity  in hypertension (stiffer carotid sinus)
Sometimes hypersensitivity  hypotension & fainting because of tight collar
1:22 PM
Vascular wall physiology

26. Vascular wall physiology
Chemoreceptors
Peripheral (O2 in carotid & aortic bodies): only small, supportive role
Central (CO2/pH in hypothalamus): massive vasoconstriction (protects CNS from ischemia)
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Vascular wall physiology

27. Humoral regulation of VSM: circulating hormones
Adrenaline: (importance < NA from SNS)
Skeletal muscles:  low dose,  high dose
Skin & other organs: only  vasoconstriction
Angiotensin II:
ACE from A-I, A-I from angiotensinogen by renin (released from kidny in hypotension or  volume)
mainly AT1 receptors
AT2 opposite effects, but little AT2 in vessels
(their activation can  during AT1 inhibition because of feed-back  A II - therapeutic significance)
BROWN NJ, VAUGHAN DE: Angiotensin-converting enzyme inhibitors. Circulation 97: ; 1998.
1:22 PM
Vascular wall physiology

28. Humoral regulation of VSM: circulating hormones
ANP:
atrial distention
natriuresis, vasodilation via cGMP
Endogenous ouabain (Na-K ATPase inhibitor)
Na/K ATPase is electrogenic (3 Na out, 2 K in)  its inhibition depolarizes
but  natriuresis by inhibition of Na pumping from primary urine   volume   pressure
Adrenomedullin (peptide from adrenal medulla)
 cAMP in VSM
 NO in endothelium
1:22 PM
Vascular wall physiology