Unit 1 Day 3 Flashcards
inoptropy
-contractility or contractile force of heart
lusitropy
-relaxation or ability of heart to relax
PKA phosphorylation of L-Type Ca2+ Channels
- GPCR activation
- slows inactivation
- inc. entry of trigger Ca2+
- inc. Ca2+-induced Ca2+ release increases inotropy
PKA phosphorylation of Ryr
- GPCR activation
- inc. Ca2+ sensitivity
- inc. inotropy by increasing SR Ca2+ release
PKA phosphorylation of Phospholamban
- GCPR activation
- relieves inhibition of SERCA
- faster Ca2+ reuptake into SR
- inc. lusitropy
- inc. inotropy by inc. SR Ca2+ load
PKA phosphorylation of Troponin 1
- GPCR activator
- P-Tn1 decreases Ca2+ sensitivity of troponin C
- allows faster dissociation of Ca2+ so faster filling = inc. lusitropy (not inotropy)
HCN Channels
- HCN channels produce If current
- sympathetic regulation of chronotropy
- norepinephrine binds B adrenergic receptor, activates G protein, activates cAMP, activates HCN channel
- HCN channel allows net inward (depolarizing) current= If
- promotes spontaneous action potentials
- highly expressed in SA node
- activity inc. by sympathetic stimulation via cAMP binding
L-Type Ca2+ Channels
- norepinephrine binds B adrenergic receptor, activates G protein, activates cAMP, activates PKA, activates L-Type Ca2+ channel
- net inward (depolarizing) current
- promotes excitability and spontaneous action potentials
- activity inc. by sympathetic stimulation
GIRK Channels
- G-protein coupled Inwardly Rectifying K+
- beta/gamma subunit complex of GPCR can bind GIRK channels
- parasympathetic regulation of chronotropy
- primary mechanism for parasympathetic control of heart rate
- stabilizes Vm near K+ equilibrium potential
- inc. outward K+ current decreases excitability
Chronotropy
heart rate
Vascular Smooth Muscle
- small mononucleate cells
- no sarcomeres = smooth (NOT STRIATED)
- no troponin complex, no tropomyosin
- different contractile mechanism from striated muscle
- THICK filament regulation
- Ca2+ enters cytoplasm from SR/plasma
- Ca2+ binds to Calmodulin
- Ca2+-CaM binds to myosin light chain kinase to activate it
- MLCK phosphorylates myosin head- permits cross-bridge cycling
- myosin light chain phosphatase (MLCP) dephosphorylates MLC and halts contraction
- cAMP inhibits MLCK-causes VSMC relaxation
a1 adrenergic receptors
- sympathetic stimulation alters vascular tone
- type of GPCR
- PKC inc. intracellular Ca2+ and causes vasoconstriction
- vasoconstriction via IP3 and inc. Ca2+
arterial baroreceptor reflex arc
- stretch of arterial wall activates mechanosensitive eNac Na+ channels on baroreceptor cells
- low pressure baroreceptors in atria and vena cavae mediate bainbridge reflex (inc. HR in response to stretch)
- SHORT TERM, rapid negative feedback mechanism for sudden changes in blood pressure
- inc. in pressure causes inc. in firing of baroreceptors
- CV control centers dec. sympathetic output and inc. parasympathetic output
- causes dec in HR and in inotropy
- in vasculature, dec. tone causes vasodilation
4 tissue metabolites that control local flow to a capillary bed
- primary mechanism to match blood flow in capillaries to metabolic demand
- adenosine
- lactic acid
- CO2
- K+
- H+
- PO4-
Myogenic Response
- autoregulation
- feedback mechanism to maintain constant flow despite changes in pressure
- ex. postural changes
- myogenic response produces vasoconstriction to reduce flow
- can be overcome by vasoactive metabolites
Nitric Oxide
-potent vasodilator
-basal NO release helps set resting vascular tone
-anti-atherogenic- dec. NO associated with greatly inc. risk for atherosclerosis
-NO synthase highly susceptible to CV disease risk factors (smoking)
-NO diffuses across membranes to VSMCs, where it activates guanylate cyclase to produce cGMP
-cGMP activates PKG
-PKG reduces intracellular Ca2+ via activation
of SERCA, and inhibition of L-type Ca2+ channels
Endothelin
- vasoconstrictor, produced in vascular endothelium
- inhibited by NO, ANP
- binds to ET receptors on VSMC
- vasoconstriction via IP3 and inc. Ca2+
Renin-Angiotensis-Aldosteron System
- primary system for long term control of blood pressure
- dec mean arterial pressure (hemorrhage) causes inc. renin, causes inc. angtiotensin, causes inc. aldosterone, causes inc. blood volume
- angiotensin 1 cleaved by angiotensin converting enzyme (ACE) to antiotensin 2 (A2) = vasoconstrictor
atrial natriuretic peptide
- vasodilator peptide released by atria
- released in response to stretch in heart
- natriuretic = sodium excretion
- lowers blood pressure
The sequence of events during excitation and contraction of cardiac muscle cells is:
• Ca2+ enters via DHPR (L-type Ca2+ channel) and activates RyR2 to cause larger
flux of Ca2+ from SR into myoplasm
• Ca2+ activates contraction by binding to troponin on thin filaments.
The sequence of events during relaxation of cardiac muscle cells is:
• Ca2+ is removed from the myoplasm by:
(i) SERCA2 pump located in longitudinal SR (2 Ca2+ per cycle); Ca2+ diffuses within SR
to terminal cisternae, where it binds to calsequestrin (low affinity, high capacity)
(ii) NCX Na+
/Ca2+ exchanger in junctional domains of plasma membrane and t-tubules.
• SERCA2 dominates since SR surrounds each myofibril; requires less energy since VSR≈0.
• NCX is next in importance and can be arrhythmogenic, as will be discussed later.
• In steady-state, Ca2+ released from SR is recycled back into SR by SERCA2, and surface
extrusion balances L-type Ca2+ current.
EC Coupling in Cardiac vs. Skeletal Muscle
-Cardiac: requires entry of external Ca2+ DHPR: CaV1.2 (α1C), β2a or β2b, α2δ1, Ca2+ released from SR via RyR2
-Skeletal: does NOT require entry of external Ca2+ DHPR: CaV1.1 (α1S), β1a, α2δ1, γ1
Ca2+ released from SR via RyR1
-Both: Ca2+ binds to troponin on thin filaments and activates contraction
NCX Na/Ca Exchanger
- exchanges 2 Na+ for 1 Ca2+
- can run in either direction, depending on both membrane potential and gradients of Na and Ca
- sudden inc. Ca could cause cell to Ca to be released from SR and cause cell to depolarize
calcium-dependent inactivation
- if amount of Ca in SR inc., great CDI causes less Ca to enter via L-type channel
- if amount of Ca is dec. then there is less CDI and greater Ca entry via the L type channel
- helps maintain constant SR Ca contant
Stimulation of β-adrenergic Receptors
-increases both contraction strength (pos inotropy), and rate of relaxation (pos lusitropy), of cardiac muscle
Catecholaminergic Polymorphic Ventricular Tachycardia (CVPT)
- CVPT pts do not display ECG abnormalities at rest but do display them upon exercise or upon infusion of catecholamines
- mutations in RyR2, that inc. resting leak of Va out of SR or render RyR2 more sensitive to activation of Ca
- caseuqestirin regulates function of RyR2 and this may also be altered in CVPT
- CVPT mutations together w/ inc. SR Ca content that is caused by activation of b adrenergic receptors results in releases of Ca
- occurs shortly or long after repolarization
- extrusion of this Ca via NCX results in depolarizations that can trigger ectopic action potentials and initiate arrhythmias
Timothy Syndrome*
- de novo mutations of the Cav1.2 subunit of the L-type Ca2+ channel result in a lengthened cardiac action potential
- mutation suppresses voltage-dependent inactivation
- TS and TS2 pts display AV block, PROLONGED QT INTERVALS, and polymorphic ventricular tachycardia
- results in syncope, cardiac arrhythmias and sudden death
Brugada Syndrome*
- sudden unexplained death syndrome
- linked to mutations of cardiac Na channel Nav1.5, KChip2, and Cav1.2
- these mutations cause large reduction in magnitude of L-type Ca current, impairing membrane trafficking
- these pts have significantly shortened QT interval
HFrEF
-due to coronary artery disease most commonly
HFpEF
-due to hypertension most commonly
