Unit 1 - regulation Flashcards
How does sympathetic nervous system stimulation increase inotropy
Beta-1 receptors --> Gs --> cAMP --> PKA PKA phosphorylates 1. L-Type calcium channels (DHPR) 2. RyR Receptors of SR 3. PLB = Phospholambam 4. TP-I (luistropy)
So in follow up, why would a beta-adrenergic receptor antagonist decrease heart contractile force?
- decreased ca2+ influx from L-type –> decrease for storage
- decrease RyR receptor sensitivity - decrease release
- decrease PLB-p –> more inhibition of SERCA
- decrease TP-I-p –> reduced cycle velocity
How does sympathetic activation lead to increased chronotropy?
Beta-1 receptors –> Gs –> cAMP –> PKA
cAMP directly binds If (HCN) channel
-increasing likelihood of opening (raise resting)
PKA phosphorylates
- L-type channel and RyR which both act to increase intracellular calcium
Increased intracellular calcium causes the NCX exchanger to pump out 1 Ca2+ for pumping in 3Nat+
So in follow up, why would a beta adrenergic receptor antagonist decrease heart rate?
It would inhibit the production of cAMP and thus prevent increased opening of If
I would inhibit the production of PKA and thus prevent the elevated intracellular Ca2+ that enables the NCX to enable depolarization
Now recall the If is for pacers, not makers
How does the parasympathetic nervous system decrease chronotropy?
Acetylcholine binds to muscarinic acetylcholine receptors (M2) which are the G coupled ones (Gi/o)
The Gi inhibits adenyl cyclase from making cAMP so the funny current can flow as easily
cAMP can’t activate PKA
PKA can’t phosphorylate it’s targets (Ca-L, Ryr)
Intracellular Calcium is not as easily elevated –> NCX not as active
IN ADDITION
G-by subunit opens GIRK - the g-couple inward potassium rectifier - which further increases outward K+ (hyperpolarizes)
what is the primary mechanism for parasympathetic control of chronotropy?
Activation of GIRK via M2 G-ay
How many nuclei are in VSMC?
1
Do vascular smooth muscle cells have sarcomeres?
no, the contractile units in smooth muscle are not organized into sarcomeres - however, they are still comprised of actin and myosin - just not organized
Do vascular smooth muscle cells have troponin / tropomyosin
no, they do not have and are not regulated by troponin / tropomyosin - which surround the thin filament in striated muscle - rarher vascular smooth muscle cells are regulated via myosin light chain
Do vascular myocytes require SR Ca2+ release for contraction?
No
how are smooth muscle cells’ contractile properties regulated?
via phosphorylation of myosin light chain via myosin light chain kinase which is activated by calcium-calmodulin
How does cAMP influence smooth muscle cell contracility
ACTUALLY - cAMP inhibits myosin light chain kinase and thus, prevent contraction
How is contraction halted in smooth muscle cells?
when myosin light chain is dephosphorylated by myosin light chain phosphatase
adranergic targets on vascular smooth muscle cells?
! NOTABLE UNIQUE QUALITY OF SKELETALE MUSCLE?!
alpha receptors!
alpha receptors activate Gq –> cleaves phosphotidylinosotol –> IP3/DAG –> IP3 can then increase cytosolic Ca2+ via receptors on SR–> bind calmodulin –> MLCK –> vasoconstriction
Unique skeletal muscle targets - beta-2 receptors - which activate Gs and cause increase cAMP via adenyl cyclase activation –> inhibits MLCK –> vasodilation
decrease sympathetic tone on heart?
cause decreased heart rate and inotropy
decrease sympathetic tone on vasculature?
increase in vasodilation
baroreceptor reflex response to increases in blood pressure?
sense increase pressure in aortic arch and carotid sinus –> increase firing –> decrease sympathetic and increase parasympathetic tone
what is the primary mechanism of the body to match the blood it gets with the blood it needs?
via vasoactive metabolites
what are 4 metabolites that influence peripheral vasculature? cause it it dilate?
low O2
High CO2 (low pH)
High K+
High adenosine
via what mechanism does adenosine increase vasodilation?
it binds A2 purinergic receptors of vascular smooth muscle (GPCR) - increasing cAMP
Recall cAMP has inhibitory effect in VSMC inhibiting MLCK and thus vasodilating
myogenic response of VSMC?
In response to being stretched, the vascular smooth muscle cells will contract! (via activation of Trp non-selective Ca2+ channels)
Thus if if the flow is excessive, their contraction will lower it
endothelail mediated regulation of vasculature
what causes dilation
what cause contraction
NO = potent vasodilator Endothelin = potent vasoconstrictor
- both these mediators are produced in the endothelial cells and then effect the VSMCs
what is the primary mechanism for long term control of blood pressure?
RAA- system
Angiotensin II direct effects?
systemic vasoconstriction via GPCRs of VSMCs (must increase cAMP)
Angiotensin II indirect effects?
sympathetic stimulation
aldosterone release
endothelin release
ADH release
Aldosterone effect?
promotes Na+ resorption in kidney collecting duct (K+ secretion)
So… spironolactone competes for aldosterone receptors, what effects would it have?
inhibits aldosterone sensitive Na+ resorption in kidney collecting duct - here if we don’t resorb sodium we don’t dump K+
so potassium sparing diuretic
also aids in inhibiting heart remodeling
ADH effects?
increased water resorption in collecting duct
can cause vasoconstriction
where and how do thiazide diuretics (e.g.chlorothiazide) act?
distal convoluted tubule
block Na+Cl- channel –> blocking Na+ resorption
consequence of thiazeide (e.g. chlorothiazide) site of action?
increased Na+ delivery (in lumen) to collecting duct –> more K+ exchange –> hypokalemia possible
pre-requisite for thiazide diuretics?
normal GFR
not hypokalemic :)
What is atrial natriuretic peptide?
major effects? (3)
peptide hormone released in response to atrial stretch
vasodilation
natriuresis (+ diuresis)
inhibit renin and aldosterone release
ANP moa of vasodilation
receptor binding –> cGMP –> cGMP activates SERCA
