Heart Failure Mechanisms Flashcards
Positive chronotropy
Increased heart rate
Positive inotropy
Increased contractility
Positive lusitropy
Faster cardiac relaxation
Positive dromotropy
Enhanced conduction velocity through the conduction system
Beta adrenergic effects on the SA node and conduction system contribute to __
Increased chronotropy and dromotropy
Beta adrenergic effects on myocytes are responsible mainly for ___
Inotropy and Lusitropy
Parasympathetic (vagal) innervation is strongest in the ____, where local release of ____ activates _____ receptors and causes _____ (???-tropic effect(s))
Conduction system
Acetylcholine
Muscarinic
Negative chronotropy and negative dromotropy
The ____ inotropic response to ____ receptor stimulation by albuterol occurs, at least in part, through ___ receptors on the terminal neurons of cardiac sympathetic nerves, thereby releasing _____, which in turn exerts dominant ___ receptor effects.
Positive
Beta-2
Beta-2
Norepinephrine
Beta-1
Beta-1 receptors are linked to the stimulatory G protein G() whereas Beta-2 receptors are linked to both G() and G(_)
G(s)
G(s)
G(i)
List the order of Beta-1 agonist activity for the following:
Norepinephrine, Epinephrine and Isoproterenol
Isoproterenol > Epinephrine = Norepinephrine
List the order of Beta-2 agonist activity for the following:
Norepinephrine, Epinephrine and Isoproterenol
Isoproterenol > Epinephrine > Norepinephrine
List the order of Alpha-1 agonist activity for the following:
Norepinephrine, Epinephrine and Isoproterenol
Norepinephrine > Epinephrine > Isoproterenol
The ___ subunit of G(s) combines with GTP and then separates from the beta-gamma subunits to ____ the activity of ____
Alpha
Enhance
Adenylyl cyclase
How does G(i) cause inhibition of adenylyl cyclase?
Beta-gamma subunit stimulates GTP-ase to breakdown alpha subunit of G(s)
Adenylyl cyclase catalyzes formation of ____
The second messenger cAMP
What is the overarching effect of cAMP?
Acts through multiple intracellular signals (importantly PKA) to mediate the chronotropic, inotropic, lusitropic and dromotropic effects of cardiac beta-adrenergic agonists
cAMP has very rapid turnover as a result of a constant dynamic balance between its formation by ____ and conversion to ____ by ____
Adenylyl cyclase
AMP
Phosphodiesterases (PDEs)
What is the function of Epac?
Epac is a GTP exchange protein activated by cAMP that is activated in parallel to cAMP-dependent PKA activation. This allows additional parallel signaling downstream of beta-adrenergic activation
What is the purpose of the PKA(c) subunits?
The PKA(c) or catalytic subunits are responsible for transferring the terminal phosphate of ATP to protein substrates
What is the purpose of the PKA(r) subunits?
The PKA(r) or regulatory subunits bind to A-kinase anchoring proteins (AKAPs) on activation by cAMP. AKAPs target PKA-dependent phosphorylation at specific sub-cellular targets
List the sequence of events for PKA activation:
1) Catecholamine stimulation
2)
3)
4)
5)
6)
7) Phosphorylation of target proteins
1) Catecholamine stimulation
2) Activation beta receptor
3) Binding of GTP to alpha subunit of G(s)
4) G(s) stimulation of adenylyl cyclase
5) Formation of cAMP from ATP
6) Activation of cAMP-dependent PKA, locally bound by an AKAP
7) Phosphorylation of target proteins
The _______ calcium channel is rapidly phosphorylated by the PKA activation cascade, which results in both a large ____ in the amount of peak I(Ca) and a shift in the activation voltage to more _____ potentials. This _____ the amount of calcium that enters the cell at each beat and also _______ excitability (including in pacemaker cells).
L-type
Increase
Negative
Increases
Enhances
What is the normal function of phospholamban?
Inhibits the calcium pump by reducing its affinity for calcium
What does phosphorylation of phospholamban (PLB) cause?
It relieves the inhibitory effect on the Calcium pump and greatly enhances its function. This allows more calcium to accumulate inside the SR (sarcoplasmic reticulum) during the cardiac cycle - which enhances inotropy and lusitropy
Describe the beta-adrenergic receptor desensitization process involving GRK2.
Sustained beta-agonist stimulation recruits GRK2 which phosphorylates a site on the carboxy terminal of the beta-adrenergic receptor. This by itself does not switch off signaling but it increases beta receptor affinity for arrestins which uncouple receptor signaling
Name the protein kinase that is often co-activated with PKA to phosphorylation downstream targets synergistically.
Calmodulin-dependent protein kinase II (CaMKII)
Nitrous Oxide (NO) facilitates ____ signaling at two levels, the _____ and the activity of the enzyme system that produces ___
cholinergic
Nerve terminal
cGMP
Muscarinic ___ activation ____ adenylyl cyclase which _____ cAMP formation
G(i)
Inhibits
Reduces
Vagal activity has ____ strong effects on atrial or ventricular myocyte electrophysiology than on conduction system cells, in part because of the ____ density of vagal innervation at ____ but also because of the intrinsic properties of the cells (e.g. ____ major pacemaker function).
Less
Lower
Myocytes
Lacking
List the following in order where vagal innervation is highest to lowest
SA and AV nodes, atrial myocardium, ventricular myocardium
SA and AV nodes > atrial myocardium > ventricular myocardium
cGMP typically has ___ inotropic effects in the heart
Negative
cAMP is to PKA as cGMP is to ___
PKG
What does activation of PKG cause?
Inhibitory cardiac effects such as decreased chronotropy and negative inotropic response
List whether the following PDE subtypes break down cAMP, cGMP or both:
PDE1
PDE2
PDE3
PDE4
PDE5
PDE1: Both
PDE2: Both
PDE3: Both
PDE4: cAMP
PDE5: cGMP
The anchoring protein for PKG may be the same ____ as for PKA, thus allowing tight subcellular co-localization
AKAP
