Vascular Smooth Muscle Contraction Flashcards
VSM contraction and its regulation
Functions of vascular smooth muscle
1) regulation of arterial blood presure by controlling diameter of arterioles
2) redirect blood flow from one vascular bed to other
3) regulat fluid movement across capillary walls by controlling constrticion of pre-capillary arteriols and post-capillary venules
4) maintain the CVP or preload of heart by constricton of veins
Vasoconstriction
caused by SNS
NE causes it
VSM structure and function
thick and thin filaments randomly aligned, not striated
dense bodies connect contractile proteins
little titin
more collagen and elastin
NO troponin
sparse SR
caveolae - where SR interacts with membrane
innervated ONLY by sympathetic
VSM innervation
multi-unit - cells separtely activated by varicosity, dont need AP to contract
single unit - lots of electrical communication with gap junctions so depolarization of one leads to depolarization of adjoining
How is VSM activation controlled?
SR Ca conc low in relaxed
activation preceded by increase in Ca
regulated by control of myosin activity
when relaxes myosin light chain not phosphoylated, when phosphoylated at serine the cross bridge heads become active and contact acin, bind to it and hydrolyze ATP to produce force and shortening
myosin light chain kinase
at low intracellcular Ca - inactive
when conc Ca rises, it binds to calmodulin and forms complex. the dimer binds to inactive MLCK and activates it. it then phosphorylates myosin light chain and activates it to interact with actin
all reversible, but active form of myosin has to be dephosphorylated to be inactive and get relaxation (done by MLCP - which is always in SR)
myosin light chain phosphatase
activty can be increased by PKG (cGMP pathway)
but if phosphoylate it at different site by PKC its activity is inhibitited
How does Ca enter the VSM cytosol?
pharmaco-mechanical coupling
(can enter vsm through voltage dependent Ca channels) but NE induced release from SR is more important
Ne relased, diffuses to post synaptic membrane and binds a1 and actiavtes phospholipase C, this cleaves PI-P2 into IP3 and DAG
IP3 binds SR IP3 receptor Ca channel and ligand gated channel opens, Ca conc rises in cytoplasm, the SR Ca pump active to reduce Ca conc slowly so need constant NE stimulation to keep Ca high
DAG activates PKC and that phosphorylates L-type Ca channels and Ca goes into cell and K channesls so depolarizes membrane)
(IP3 short lived and used to remake PI-P2)
How is Ca removed from VSM cytosol?
SR Ca pump - stimulated by rise in Ca in cell
phospholamban - slows pump when bound but when phosphorylated by PKA and PKG it dissociates
VSM Membrane Ion Channels
agents depolarizing VSM cells increase flow of Ca into cell and activate contraction, agents hyperpolarizing VSM reduce Ca flow into cell and cause relaxation
Ca channels - voltage operated channels and L-type channels (important for tone) (when PKC phosphoylates L-type the time channel is open increases) (DAG increased by angiotensin ,vasopressin, histamines)
K channels - reduce conductance and depolarize cell and increase tone; gK,V - as conductance increases depolarize and incomplete inactivation; gK,ATP - modulate hypoxia and ischemia, if ATP falls channels open and get hyperpolarization and relax, can be phosphorylated by PKA and PKG and increcrease conductance and releax, if PKC phosphorylates it conductance down and contract
minoxidil, pinacidil, cromakalim - increase gK
VSM rexation modulation
initated by lots of mechanism - reduce rate of ss of vessels, reduce NE, angiotension, Ach, histamine, serotonin, vasopressin, decrease Ca conducation, increase K conductance, phosphorylate channels, phospholambad or MLCP
PKA - phosphorylates phospholamban and stimulates Ca pump rate and promotes relaxation and phosphorylates gK,ATP and hyperpolarize, and phosphorylates MLCK to reduce affinity for calmodulin
ways to increase PKA - 3 receptors
epinephrine binds B2 strongly and NE binds it weakly
exercise, increase epi and promote blood flow
A2 receports binds adenosine
H2 receptor binds histamine (increase cap permeability and pressure)
epinephrine
highest affnity for B2 but if high concentrations binds to a1 and a2 as well because more a2 receptors than B2
so at physiological concentrations get vasodilation
pharmacological concentrations get a1 activation and vasoconstriction
PKG activation
activated by NO (binds soluble guanylate cyclase, activates it and increase cGMP, activate PKG)
get relaxation - 3 ways
3 ways PKG causes relaxation
1) phosphorylates phospholamban
2) phosphorylates K channesl and increase gK,ATP (hyperpolarization closes L-type voltage dependent Ca channels and reduce flow of Ca into cell)
3) activates myosin light chain phosphatase and inhibits contraction
