2.08 - Local Control Of Blood Flow Flashcards
Describe the contraction and relaxation of VSMCs
Contraction is slow and different to skeletal muscles
Calcium activates MLCK which phosphorylates MLC. MLC then allows the cross-bridge cycling of myosin heads
To save energy, contraction in VSMCs can be kept in a “latched state”
Describe the neural signalling of sympathetic fibres at the neuro-muscular junction
Vesicles contain NA & ATP. NA binds to alpha1 receptors, ATP to P2X receptors.
Both result in an excitatory junction potential. ATP evokes a fast EJP (as P2X receptor is ionotropic), NA a slow EJP (as alpha1 adrenoreceptor is metabotropic). Together they produce force.
Signal terminated by reuptake (80%) and capillary clearance.
Describe the AP in VSMC contraction
Not a normal action potential. Calcium based (L-Type VGCC), smaller and slower. Blocked by nifedipine.
Describe the stages of voltage dependent contraction in VSMCs
NA activates the alpha1 adrenoreceptor (a GPCR). The cytosolic portion of the receptor interacts with Qq protein –> activation of Phospholipase C-beta (PLC-b). PLC-b convertes PIP2 to diacylglycerol (DAG) and inositol triphosphate (IP3). DAG activates TRPC channels (influx of calcium). This results in increased intracelluar calcium and a partial depolarisation –> slow EJP.
This partial depolarisation then activates voltage sensitive L-type calcium channels –> calcium AP –> large calcium influx –> MLCK activation –> contraction
IP3 also releases calcium from sarcoplasmic reticulum stores –> increased intracellular calcium
Describe the stages of voltage independent exciation in VSMCs
Mainly occurs in large arteries.
Similar to that in voltage dependent except no slow EJP seen and DAG actives protein kinase c (PKC) –> calcium sensitisation via inhibition of MLC-P –> increased phosphorylated MLC –> increased contractility
Describe the relaxation of VSMCs via adrenaline
Adreanline activates beta2 adrenoreceptor (GPCR) –> Gs activation –> adenylyl cyclase activation –> production of cAMP –> PKA activation.
PKA then: activates calcium pumps (efflux from cell and also in to SR stores, an active process); opens K+ channels –> K efflux –> hyperpolarisation –> closure of L-type voltage dependent calcium channels –> less calcium influx; inhibition of MLCK –> fall in calcium sensitivity. These three factors then result in vascular smooth muscle cell relaxation
What is the hierarchy of vascular control?
Vascular control is regulated by a three tier hierarchy
Bottom: intrinsic. autoregulation by myogenic response (in resistance vessels)
Middle: intrinsic. autoregulation can be modulated by locally produced vasoactive agents
Top: extrinsic. regulation by nerves and circulating hormones
Describe the myogenic response
Its purpose is to maintain constant perfusion.
When there is increased blood flow, this increases stretch on the vascular wall –> activated of stretch activated channels (TRPM/C channels) –> calcium influx –> intracellular calcium –> constriction –> decreased blood flow
Describe the middle tier of extrinsic vascular control
Interaction between endothelial cells (ECs) and VSMCs
shear stress in ECs and receptor binding is the stimulus for dilation.
Relaxation via three mechanisms:
Sheer stress resulting in activation of eNOS –> increased production of NO –> movement of NO in to VSMC –> activation of soluble guanylate cyclase (sGC) –> increased cGMP –> relxation
Receptor activation –> second messenger system activation –> production of PGI2 by COX-1 –> activation of GPCR on VSMC –> increased cAMP –> relaxation
Production of endothelial derived hyperpolarising factor (EDHF) –> movement of EDHF in to VSMC –> hyperpolarisation of VSMC –> closure of VDCC –> relaxation
Describe metabolic factors in the middle tier of vascular control
Work in terminal artioles
Vasoactive metabolites mainly cause relaxation.
Examples include: acidosis (H+, lactate), hypoxia (KATP), H2O2, HPO42-
Local hormones: histamine (H1), serotonin (5HT2A) –> constriction; Prostaglandin (dilation), thromboxane (constriction), both produced by COX
Vioxx, a specific COX-2 inhibitor with some blocking action on COX-1, was pulled from the market because the drug caused a higher incidence of cardiovascular complications like heart attacks. It significantly raises blood pressure. In regard to vascular function, which of the following statements could best explain the reason for the observed raised blood pressure?
A: Vioxx blocks SERCA pump activity
B: Vioxx inhibits inflammatory vasodilation
C: Vioxx blocks endothelial PGI2 production
D: Vioxx causes decreased VSM tone
E: Vioxx directly increases Ca2+ influx into smooth muscle cells
C: Vioxx blocks endothelial PGI2 production
