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Flashcards in CV Test 1 Deck (292):
1

Phase 0 of Fast Action Potential

Rapid upstroke due to Na entry into the cell

2

Phase 1 of Fast Action Potential

Partial repolarization to OmV
Due to inactivation of Na channels and activation of IKTO to have K efflux

3

What channel is responsible for Phase 1 of Fast AP?

IKto channel; Kv.4.3 tetramer with Khip2 - voltage dependent activation and inactivation

4

Phase 2 of Fast AP

Prolonged Plateau phase. Balance between Outward Potassium flow (IKR and IKS) through delayed rectifier channel and inward Calcium flow though LTCC.

5

Delayed Rectified K channels

delayed in activation and are responsible for the plateau phase of Fast AP and the rapid repolarization of Phase 3

6

Phase 3 of Fast AP

Rapid hyperpolarization due to inactivation of Ca Channel and increasing activation of IKR and IKS

7

Phase 4 of Fast AP

Absolute refractory period. Deactivation of IKR and IKS, activation of inward rectifier IKI to keep near Ek.

8

Channel more active in Phase 4 of Fast AP

IKI (inward rectifier K )

9

Where are slow Cardiac Action Potentials located?

SA and AV nodes

10

What are the major channels differences between slow and fast AP producing cells?

Reduced expression if INa and IKI chennels; increased expression of IF and ICaT.

11

Phase 0 of slow AP

slow upstroke due to activation of ICaT and ICaL. NO activation of Na channels

12

Phase 1 of slow AP

does not exist!

13

Phase 2 of slow AP

does not exist

14

Phase 3 of slow AP

Repolarization - balance between Ca and delayed rectifier current IKR and IKS.

15

Phase 4 of slow AP

Pacemaker Potential due to hyperpolarized triggered IF (cation fluxes to drive slow depolarization to -30mV).

16

Na Channel

Nav1.5 - voltage dependent actiation and inactivation

17

Calcium Channels

L type and T Type

18

DHPR

L type Ca Channel; Cav1.2 and Cav1.3 that are high voltage activated, and voltage and [Ca} deactivated.

19

T type Ca Channels

Cav 3.1 and 3.2; Low voltage activated and voltage deactivated; only present in nodal cells

20

Potassium channels

IKto, Delayed Rectifier (IKR and IKS), Inward rectifiers - IKi and GIRK

21

IKto

Kv4.3 tetramer with KCHIP2, voltage dep act and inactivation; only in fast AP to cause brief hyperpolarization

22

IKr and IKs

delayed rectifier K channels. HERG (IKr) and KvLQT (IKs)

23

IF channel

Time dependent Cation channel in pacemaker cells that are Na and K permeable; activated with hyperpolarization.

24

IK1

Kir tetramer - inward rectifier channel, inward K whens lighly above Ek

25

GIRK

IKACh, activated by muscarinic recpetors, slows pacemaking

26

What does the R phase correspond to in the channel cycle?

Phase 0 - opening of Na Channels

27

What does ST phase correspond to in the channel cycle?

Phase 2

28

What does T phase correspond to in the channel cycle?

phase 3

29

P wave

atrial depolarization/contraction 0.08-.1 seconds

30

QRS wave

vent. contraction 0.06-0.10

31

T wave

Vent. relaxation

32

PR interval

Conduction time across AV node 0.12-0.2 sec

33

QT interval

Total depol and repol of ventricle times less than 0.44 sec

34

Path of depolarization of ventricles

1) in upper septum, left to right ventricle
2) down septum to apex
3) depolarization from endocardium to epicardium
4) apex upward
5) ends at base of ventricles

35

Repolarization of ventricles

in opposite direction becuase endocardium depolarizes before epicardium, but epicardium repolarizes before endocardium.

36

what causes first degree AV node block?

transiet reversible influence or structural defect; heightened vagal tone, transient AV node ischemia, drugs that depress conduction of AV node, MI degeneration

37

what causes a second degree AV node block?

Intermittent failure of AV node - also transient, acute MI in AV node region; Type II: is due to conduction block beyond AV node in bundle of his or purkinje.

38

What causes third degree AV node block?

acute MI and chronic degeneration that causes separation between conduction of atria and ventricles

39

Sympathetic regulation of Inotropy

NE binds to Beta-Andrenergic receptors to activate GalphaS to target AD and increase cAMP and PKA activation..
1) DHPR
2) RyR
3) Tn-I
4) Phospholamban (PLB)

40

Phosphorylation of DHPR

by PKA to increase inotropy... the effect is slowed deactivation to increase calcium entry and increase Calcium induced calcium release.

41

Phosphorylation of RyR

Increases sensitivity to calcium and increases calcium release to increase inotropy and chronotropy

42

Phosphorylation of Tn-I

Phosphorylation of Tn-I by PKA decreases Tn-C's sensitivityt to calcium to cause faster dissociation and increase lusitropy. Does not effect inotropy.

43

Phosphorylation of PLB

relieves the inhibition on SERCA, so that SR uptakes Ca faster. Increase Inotropy and lusitropy.

44

what controls HR at rest?

both parasympathetic and sympathetic neuronal control

45

Sympathetic control of chronotropy

Ne acts on B-adrenergic receptor to active G alpha S to activate AC and increase cAMP and PKA.
cAMP --> 1) binds to Hyperpolarization Activated cyclic nucleotide channels, pKA phosphorylates 1) DHPR 2) RyR, both of which increase activity of NCX

46

cAMP binding to HCN

causes increased depolarization (If - inward movement of Na and K) and increase excitability to lead to more APs

47

parasympathetic control of Chronotropy

ACh binds to M2 repetor to activate G alpha I to inhibit AC, cAMP, and PKA. So these all promote hyperpolarization. The primary method is break away of Beta-gamma to activate GIRK channels (outward flow of K) to stabalize near Ek and decrease excitability.

48

Sympathetic Control of Vasculature

NE from the sympathetic neuron acts on alpha - AR to activate Gq to activates Phospholipase C and IP3. IP3 causes activation of IP3R on SR and increased Calcium release. This causes vasoconstriction.

49

Baroreceptors

Sense stretch in the aortic arch and carotid sinus. when stretched, activate eNaC channels that cause inward movement of Na to generate an action potential via the IX and X nerves to act on the cardiovascular control center in the medulla. This center regulates HR and Vasodilation levels.

50

What controls vasodilation

not necessary parasympathetic response, but less sympathetic activation.

51

bainbridge response

low pressure in atria and vena cava trigger baroreceptors to mediate increase in Heart rate

52

Vasoactive Metabolites in vasocontrol

local feedback to control vasodilation and constriction. Triggered by PO2, PCO2, pH, extracellular K, adenosine.

53

why does extracellular K act as a metabolite

ATPase can't keep up and indicates lots of activity and vasodilation

54

adenosine

acts on A2 purogenic receptor on VSMC to activate Galpha S to increase cAMP. cAMP inhibits MLCkinase to cause vasodilation. It also activates Protein Kinase to hyperpolraize cell by activating K ATPase channels.
In cardiac cells, it binds to A1 Receptors that are tied to Gi, proteins to decrease cAMP and hyperpolarize the cell to decrease HR.

55

Myogenic Response

Stretch causes activation of Trp Channels in Vascular Smooth muscle cells that leads to non-selective depolarization and Ca entry. This maintains flow despite changes in pressure via vasoconstriction

56

NO synthesis

ACh or Bradykinin bind to surface of endothelial cell to activate IP3 and trigger Ca release. Calcium activates calmodulin to activate NO synthetase to convert Arginine into NO. NO diffuses across membrane into smooth muscle cell to activate gunaylyl cyclase to increase cGMP to activate PKG to activate SERCA and inhibit L type Ca Channels. Both decrease cytosolic Ca and lead to vasodilation and ultiatmly decreased Major Light Chain Kinase activity.

57

Endothelin

in the Endothelial cell, Big Endothelin is converted to active ET-1 by ECE in membrane. ET-1 binds to ETR on SMC membrane and activate Gq to actiate IP3 and Ca release. Increase calcium causes increase contraction and vasoconstriction

58

Control mechanism for endothelin

ET-1 binds to ETR receptor on endothelial cell to act on NO synthase enzyme to promote production of NO - vasodilator

59

what triggers Renin release

sympathetic stimulation, hypotension, decrease Na delivery (kidney secretes its)

60

Effects of Angiotensin II

Cardiac and Vasculature hypertrophy
Systemic vasoconstriction
increased thirst
stimulate adrenal cortex to increase aldosterone release
stimulate pituitary to release anit-diuretic hormone/vasopressin

61

Aldosterone

hormone released from adrenal cortex in response to AnII to cause Na and Fluid retention.

62

ADH

Anti-diuretic Hormone or Vasopressin released from pituitary with AnII to cause Na and Fluid retention, as well as vasoconstriction

63

ANP

Atrial Natiruetic Peptide is a vasodilator that is released due to atrial stretch

64

effects of ANP

decreases renin release to decrease vasopressin and aldosterone release.
drecreases endothelin release
decreases vascular resistance
Increase fluid egress
Increase natiuresis

65

ANP action

ANP bind to NPrecpetor to active gunylate cyclase direction (Not GPCR) to increase cGMP and activate SERCA and Na and H20 excretion.

66

Forward Heart Failure

inability for CO to meet metabolic demands of the body, due to low Cardiac output

67

Backward heart Failure

filling pressures are abnormally high to meet demands of the body, increased congestion.

68

what fails in HF?

1) displacement pumps (systole and diastole)
2) L or R side
3) coordinated electrical system
4) Valves: regurgitation or stenosis (resistance)
5) Coronary Dysfunction (regurg or stenosis)
6) Pericardium

69

What contributes to SV?

Increased inotropy and preload and decreased afterload

70

systolic HF

Loss of contractility due to weak or damaged myocardium. Decreased inotropy to cause increase ESP and decreased SV.

71

examples of systolic HF

Decreased ejection fractio (HFrEF, LV systolic dysfunction); Ventricular enlargement (dilated cardiomyopathy).

72

Systolic HF is due to..

direct destruction of Heart muscle cells via MI or other cuases
2) Overstressed Heart muscle - meth, cocaine
3) Volume Overload - mitral regurgitation

73

Diastolic HF

Stiff or non-compliant heart due that decreases pre-load and lusitropy. Requires increased pressure to achieve same filling volume and ultimately increases ESP

74

Diastolic HF samples

Normal ejection fraction : HFpEF, preserved systolic function
LV hypertrophy

75

Diastolic HF is due to..

Increaesed afterload - hypertension, aortic stenosis, dialysis
Myocardial fibrosis - hypertrophic cardiomyopathy
External compression - pericardial fibrosis, effusion

76

Right sided HF is due to..

Left sided HF
Lung disease or pulmonary Hypertension, "cor pulmonale"
RV overload - due to shunt, tricuspid regurgitation
RV myocardium damage

77

Neurohormonal action in heart failure

the short term solution to increase EDV pressure to preserve the SV. Sensed by Juxtaglomeruluar reflex for AAR system and baroreceptors to increase adregneric activation.

78

Physiological Hyptertrophy

During pregnancy and chronic exercise. Myocyte length> myocyte width with no fibrosis. General increase in chamber size and no dysfunction.

79

What leads to cardiac dilation?

MI, Dilated cardiomyopathy, pregressio from pathological hypertrophy.

80

Cardiac Dilation

increase in chamber size via myocyte loss via apoptosis. Due to increase in NE and AII, and mechanical strain. Myocyte length is greater than myocyte width with excessive fibrosis and cardiac dysfunction.

81

What causes pathological hypertrophy

chronic hypertension and aortic stenosis

82

Pathological hypertrophy

no change in chamber size, but increased wall stress due to deposition of ECM to maintain CO in an attempt to decrease stress. Myocyte width is greater than length. Some fibrosis and some cardiac dysfunction.

83

alpha myosin

high ATPase acitivity, more effective at contraction

84

beta myosin

low ATPase activity, less effectie at contraction. In HF shift to Beta myosin

85

Changes in calcium regulation in HF

increase Ltype Ca Channel and decrease in SERCA function (increased PLB), to cause increased cyto Calcium levels and decrease lusitropy.

86

Changes in gene expression in HF

early acute: PKA and PKC activation
chronic: PKE, PKD, CAMK (calcineurin)

87

Calcineurin

A Ca dependent phosphatase that remove Phosphate from NFAT to dead to cardiac remodeling

88

Smooth vs. Striated Muscle

VSMC is mononucleated, with gap junction and no sarcomere. It does not require the SR to release Ca to contract. has similar SERCA reuptake system, but delivers slower and sustained cotnraction. Contraction is dependent on phsophroylation of Myosin Head (not directly Ca dependent)

89

VSMC activation

1) Ca entry into cyto from SR and Ca Channel
2) Ca binds to calmodulin
3) Ca-CaM bind ot myoslin light chain kinase to activate
4) Myosin Light Chain kinase phosphorylates light myosin head to facilitate cross bridge
5) myosin-light chain phosphatase dephosphorylates myosin to inactivate.

90

PKA in cardiac vs VSCM?

PKA promotes contraction via phosphroylation of Ca entry into cyto (cardiac cells)
IN VSMC pKA regulates phosphorylation of MLCK to influence contraction.

91

Class I Anti-arrhythmics

Na Channel blockers that mostly affect fast response cell. Decrease conduction velocity and increases effective refractory period. Use Dependent.

92

Class Ia

Quinidine, procainamide, dispyramide
Blocks Na Channes - slow upstroke
Delays repolarization by blocks K channels (class III action).
Together these prolong refractory period by prolonging depolarization.

93

Decreasing conduction velocity - class I

converts unidirection block into bidirectinla block - so signal cant propagate into a depressed region.

94

Two conditions necessary for re-entry

1) unidirectional block 2) conduction time > refractory

95

How to terminate re-entry?

1) convert unidirection block to bidirectional block 2) prolong refractory period

96

Use Dependent

drug that selectively targets overactive cells (channels open) and stabilize the cell in the inactive state to prolong the refractory period.

97

Quinidine

First antiarrhythmic drug - Class Ia
In addition to Na block; Blocks K channels to prolong AP
Anti Cholinergic (vagal inhibitor)
Alpha-Adrenergic antagonists

98

Class IB

Lidocaine, Mexiletine, Phenytoin
Mild slowed upstroke due to Na block,
decreased duration of action potential (decreased plateau phase - shortened repolarization)
prolonged refractory - use dependent.
Purely Class I effect - Lidocaine is least toxic.

99

Class IC

Propafenone, Flecainide, Encainide
Markedly slow upstroke
prolonged phase 2
delayed repolarization due to K channel block
Highly pro-arrhythmic.

100

so of the Class I drugs, which on has the slowest upstroke?

C>A>B

101

which Class I shows delayed repolarization

A > C, B is shortened repolarization

102

Class I drugs - which ones have extended refractory period?

all - all are use dependent.

103

Class II anti-Arrhythmic

Beta blockers - to reduce If, LTC current, and K current.
Reduced upstroke, slow repolarization at AV node, Decreased Phase 4 slope to prolong refractory period.
Specifically reduces pacing rate.
Used at AV nodal re-entry and controlling A fib.

104

Class II examples

Propanolol, Metorpolol, Esmolol

105

Class III

K channel blockers - block Rapid K channels to prolong Phase 2.
Prolongs refractory period because long phase 2 causes increased Na channel inactivation and leads to decreased re-entry.
NOT use dependent.

106

Examples of Class III

Ibutilide, Dofetilide, Amiodarone, Sotalol, Bretylium

107

Amiodarone

Class III, but with class I effect at reducing conduction velocity by decreasing phase 4 slope.
Side effects: bradycardia, heart block, corneal depoits, hypo/hyperthyroidism, pulmonary fibrosis
T1/2 13-100 days.

108

Sotolol

Class III, but also acts as beta blocker

109

Class IV

Calcium Channel blockers
Use Dependent of L type Ca Channel located primarily in nodal cells.
Slow upstroke to slow conduction velocity.
Prolongs refractory period.
Side effect: hypotension

110

Class IV examples

Verapamil
Diltiazen

111

Adenosine

Binds to A1 receptor to increase K current and decrease LTCC and IF. To cause decreased SA and AV firing rate and reduced conduction at AV node.
Resembles Beta Blockers (both reduced cAMP).
Short half life of 10 seconds.
Causes flushing chest burning, SOB

112

What cell types are in the heart

Endothelial cells>cardiac fibroblasts>mycocytes

113

Cardiac fibroblasts

mediate ECM of heart, lay down foundation upon which myocytes function

114

ECM in heart it made up of..

fibrillar collagen type I and III

115

Cardiac vs. skeletal muscle

1) both striated
2) not under direct neural control - autonomic
3) shorter, narrower, richer in to mitochondria, mononucleated
4)slower ATPase than skeltal muscle (faster than smooth)
5)Thin filament regulated (Ca binding to troponin regultes actin-myosin interaction

116

Intercalated Discs

connect cardiac muscle cells, coincide with Z discs and contain desmosones and gap junctions.

117

Desmosomes -

adhesion and assures force generated in one cell is transfered to the other, connects to ECM

118

what makes up the maorjity of the heart cell volume?

myofibril and mitochondria. The rest is sarc, T tubule, SR, intercalated disks, gap junctions

119

Myocyte

single muscle cell containing the usually orgnaless plus many myofibrils

120

Myofibril

end to end array of idential sarcomeres

121

Sarcomere

unit of contractile activity - composed of actin and mysoin and estends from Z line to Z line.

122

does tropomysin and troponin interact with actin or myosin?

actin

123

Troponin C

dumbell shaped; N lobe with ONE Ca binding site.

124

Troponin I

N terminal extension of 32 amino acids that contain PKA phosphoryltion site for adregnergic responsiveness. Interacts with TN-C but is released with phosphorylation.

125

Troponin T

binds to tropomysin. N terminal regulated with Calcium sensitivity.

126

Tropomysin

alpha form in heart; lies over myosin binding sites.

127

Relaxation cycle on contraction - molecular mechanism

1) AP leads to Ca release
2) Ca bind to Troponin C
3) Troponin undergoes structure change to move tropomysin out the way
4) myosin binds to actin and crossbridge moves
5) calcium is released, tropomysin reblocks binding sites - relaxation.

128

Diastole - Actin Myosin Relationship

1) Resting state: No Ca, non force generating
2) Transition state: Ca bound, non force generating

129

Systole Actin Myosin relationship

3) Active State: Ca bound force generating
4) Active state: No Ca bound, force generating

130

Titin

giant protein that functions as an elastic spring that extends form the M line to the Z line to prevent over stretching. Responsible for muscle tension at rest.

131

Titin Isoforms

N2B and N2Ba

132

N2B

titin isoform that is stiff

133

N2Ba

titin isoform that is not very stiff

134

length tension relationship

increasing muscle length increases muscle tension

135

Mechanisms behind the Length Tension Relationship

1) extent of overlap
2) change in calcium sensitivity
3) increased calcium release

136

How does extent of overlap affect length tension relationship

peak tension develops at lengths of 2.3 an 2.2 uM. This indicates that muscles are a prime length for tension development.

137

How does changing calcium sensitivity affect length tension relationship?

a short lengths - only a portion of potential cross bridges can be activated. At longer lengths, more cross-bridges become activated and there is no time delay.

138

How does increased calcium release affect the length tension relationship?

occurs several minutes after changing muscle length - due to stretch sensitive channels in cell membrane.

139

What factors regulate calcium sensitivity of the myofilament?

TnI phosphorylation
TnT Isoform composition
Sarcomere length

140

TnT Isoform and Calcium sensitivity

N-terminal extension of TnT decreases sensitivity to calcium

141

PKA phosphorylation of TnI and calcium sensitivity

Phosphorylation decreases Ca sensitivity to TnC, to promote lusitropy.

142

Force Velocity Relationship

increasing preload enables muscle to contract faster against a given afterload

143

what change velocity at sarcomere level?

Phosphorylation of MLC
Phosphorylation of MyBPC

144

Ventricle Geometry and Muscle Fibers

Increase in ventricular volume causes increased ventricular circumference and increase in length of individual muscle cells.
2) Increase in tension on individual cell sin wall --> increases intraventricular pressure.
3) as ventricular volume increases, a greater force is require from each muscle cell to produce a given intraventricular pressure.
La of Laplace: Wall stress equals tranmural pressure X radius of chamber/wall thickness.
To compensate for increase in pressure, wall thickness increases.

145

Concentric Vs Eccentric hypertrophy

Concentric - increase n muscle width - pathological hypertrophy
Eccentric: increase in muscle length - dilation

146

Working Myocytes

in atria and ventricles that are quire large -20 um in diameter

147

Nodal myocytes

in SA and AV nodes and are smaller, specialized for electrical conduction instead of contraction.

148

What supplies Right atrium and Right ventricle with blood?

Right Main coronary Artery

149

Left main coronary Artery supplies..

left atrium and ventricle with blood and bifurcates into left anterior descending (LAD) and circumflex.

150

Aorta - Types of Vessel

Large single outflow form heart with elastic and smooth muscle fibers in wall to dampen pulsatile flow. 2mm thickness 12 mm radius

151

Arteries - type of vessel

Thick walled (1mm) and resistnat to expansion.
Diameter 4 mm
Distribute blood to organs

152

Arterioles - type of vessel

Relatively thick wall with lots of VSMC (20um);
diameter 15 um
highly innervated - primary site of regulation of vascular resistance.

153

Thickness of arteries.

Arterioles>Artery>aorta.

154

Venules and Veins type of Blood Vessles

Thin walls of similar diameters of arteries.
Capacitance vessels that hold most of the blood volume.
Low pressure - one-way valves

155

Vena Cavae

Large diameter 50 mm with very thin walls 1.5 mm, very low pressure.

156

Tunica Adventitia

outermost layer of vessel that contains connective tissue like collagen and elastin

157

Tunica Media

mIddle layer of vessel that innervated smooth muscle cells. Controls vessel diameter

158

Tunic Intima

Inner layer with connective tissue and vascular endothelium.
Important site of signaling
Site of plaque formation.

159

Pre-Capillary sphincters

smooth muscle bands at junction of arterioles and capillaries to regulate blood flow through capillary beds

160

lymphatic system

Lymph is filtered interstitial fluid that is filter and is run through the lymphatic system which is low pressure with one-way valves.

161

What promotes flow of lymph?

increased interstitial pressure, smooth muscle contraction of lymph vessels, contraction of surrounding skeletal muscles

162

overdrive suppression

when SA node is overtaken by an ectopic pacemaker to trigger contraction independently.

163

AV node

located a right side of heart near opening of coronary sinus to regulate action potential propagation through ventricles.

164

How does signal spread from AV node"?

through conducting pathways that propagate to L and right ventricles that are larger in diameter and able to spread the signal rapidly.

165

what prevents the depolarization from spreading from atria to ventricles, besides AV node?

CT electrical insulation

166

Ena

+58

167

NCa

+124

168

Ek

-90

169

T-Tubule Lumen Ca Concentration

less than 2 mM

170

Calcium regulation/cycle

1) Ca enters via DHPR and activates RyR to cause larger flux of Ca from SR.
2) Ca activates contraction by binding to troponin
3) Ca is removed from cytoplasm by SERCA pump on longitudinal SR (2 Ca per cycle) where it diffuses to bind to calsequestrin at terminal cisternae.
4) Ca is also removed by NCX at junctional domain and via PMCA transporters.

171

Calsequestrin

binds to Ca in terminal SR with low affinity and high capacity. Low binding affinity, but high storage capacity of calcium.

172

why isn't calcium entry from DHPR sufficient for contraction?

Filaments located far away from DHPR channel would see Ca signal later than those closer --> non-synchronous contraction.
While SR is wrapped extensively and Ca never needs to move far.

173

CaV1.2

DHPR - L Type Ca Channel.
Four homologous repeat subunits. Binds to Beta, and alpha2delta subunit.

174

RyR

enormous homo-tetramer in SR that binds to ryanidine with high affinity. From different physiological pathway than DHPR

175

Cardiac vs Skeletal muscle calcium

ECC coupling requires external Ca to trigger Ca release form RyR in heart.
Skeletal muscle does not require Ca entry for Ca to be released from RyR.
Both used Ca to bind to troponin to activate contraction.

176

Cav1.2 2-3 loops

can be replaced with Cav1.1 loop to couple cardiac to skeletal type contraction.

177

Why is SERCA most important in cardiac cytoplasmic Ca removal?

Voltage against SR is kept at 0mV so it is easier to transport vs. the cell surface membrane at -70mV.. So it is not as must work.

178

NCX

3 Na in for 2 Calcium out; net effect is that it depolarizes the membrane.
Can switch direction based on membrane potentials and concentrations.

179

Cardiac Glyocisides

former Tx for heart failure - blocks Na/K pump that extablishes the Na concentration gradient. Thus Na will build up in cell and NCX is no longer able to function and lots of Ca is stuck in cytosol..

180

Consequences of over NCX use?

depolarization triggers abnormal diastolic SR Ca release to trigger delayed afterpolarizations and gives rise to arrhythmias

181

Norepinephrine

Released by sympathetic nerves to
1) Increase HR (chronotropy) by raising firing rate at SA node.
2) increase inotropy (contractile force)
3) increase relaxation rate (lusitropy)
2-3 are due to B-adrenergic receptors to activate PKA.

182

Result of Phosphorylation of DHPR

increased inotropy - contractile force

183

Result of Phosphorylation of RyR

increase inotropy

184

Result of PLB phosphoryaltion

increase inotropy and lusitropy

185

Phosphorylation of Tn-I

Increase lusitropy

186

why are genetic disorders of EC coupling difficult to study?

requires model systems which are difficult because:
1) Splicing/associated proteins may be different in reference cells
2) transgenic/knockout/in mice are different from humans (faster HR)
3) disease manifestations take many years to develop

187

Timothy Syndrome

Cardiac Arrhythmias due to de Novo mutations in CaV1.2 (multisystem) to block voltage inactivation to PROLONG QT interval and polymorphic ventricular tachycardia.
TS: G406R Exon 8A
TS: G406R and G402S - Exon 8

188

Timothy syndrome symptomes

syncope, arrhythmia, sudden death, intermittent hypoglycemia, immune deficiency, cognitive abnormalities - autism

189

Brugada Syndrome

Sudden unexplained death syndrome
Mutations in Nav1.5 KChip2 (IKTO) and other proteins including ankyrin.
Subset iwth mutations in Cav1.2, B2B accessory of DHPR>

190

Brugada mutation - Cav1.2 and B2B mutation EKG

Shortened QT interval

191

Catecholaminergic Polymorphic ventricular Tachycardia

No ECG abnormalities at rest, but ab. with exercise of catecholamines.
Mutations in RyR, Ressesive mutaions in calsequestrin (dramatic loss of lumenal Ca buffer and ineffectie regulation of RyR).
Causes B-AR in release of Ca not triggered by DHPR during plateau or shortly after repolarization --> arrhythmias

192

CPVT - Treatment

Beta Blockers
For some patients, need to prevent release of RyR with Tetracaine OR block Na channels like Flecainide

193

Function of ANS

maintain homeostasis within a narrow physiological range amid changing external conditions.

194

ANS vs SMS

ANS: involuntary, diffuse, slow AP, innervates smooth, cardiac and gland muscles, disynaptic
Somatic: voluntary, specific projections, rapid, innervates skeletal muscle, monosynpatic

195

what does disynpatic mean for ANS?

preganglionic nuerons located in brainstem or spinal cord connect to post-ganglionic neurons in ganglia outisde CNS. PostG neurons project to smooth muscle, cardiac cells or glands.

196

Solitary Tract

located in the medulla - contains nucleus of ANS neurons that convey visceral sensory input

197

Hypothalamus

in forebrain, conveys internal goals and states.

198

Myelination of pre and post ganglionic neurons

Pre are myelinated, post are nonmyelinated

199

Sympathetic NS - where do nerves originate compared to parasympathetic

S: thoracic and lumbar spinal cord
P: brainstem and sacral spinal cord

200

Where are the ganglia located in sympathetic vs parasympathetic?

S: near spinal cord in sympathetic chain
P: near target organs

201

Ratio of Pre to post ganglionic neurons in sympathetic vs. parasympathetic

Sympathetic have many more post ganglion than pre 10:1
Parasympathetic have more post than pre as well, but only 3:1

202

White ramus

sympathetic nerves exit the spinal cord via the ventral roots and pass through this myelinated section before entering the sympathetic trunk.

203

How do parasympathetic pre-ganglionic nerves reach their ganglion?

In the brainstem they exit the via cranial nerve III (oculomotor), VII (facial), IX (glossopharyngeal), an X (Vagus).

204

PreGanglionic NT for Symp and Para

ACh

205

PostG NT for Sym and Para

Sym: Norepinephrine
Para: ACh

206

Gray Ramus

exit out of sympathetic trunk with unmyelinated post-ganglionic fibers that project to sweat glands, blood vessels, viscera etc.

207

Are ACh receptor inotrophic?

Yes! Nicotinic receptors are

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Type of ACh receptors?

Nicotinic *ionotropic) and muscarinic

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Nicotinic

an ionotropic ACh receptor on Post G neurons.
Ligand gated, nonselective ion channel to allow movement of Na and K into cell for depolarization and excitation.

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Muscarinic Receptor

a ACh that is present on effector cells of cardiac muscle, smooth muscle and glands.
a GPCR that either stimulates or inhibits intracellular effectors

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NE receptors

Alpha or Beta adrenergic

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Alpha 1 Receptor

responsible ror vasoconstriction of skin
Gq acts on PLC --> IP3 and DAg

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Agonist for A1

phenylephrine

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Antagonist for A1

doxazosin

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Alpha 2 Receptor

presynaptic inhibition of NE release to cause mixed effects.
Acts via Gi to inactive adenylate cyclase

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A2 agonist

Clonidine

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A2 antagonist

Trazodone

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B1 Receptor

increases HR by activating Gs to activate cAMP

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B1 Receptor agonist

dobutamine

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B1 Receptor antagonist

Atenolol

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B2 Receptor

increased HR and vasodilation in skeletal muscle, smooth muscle relaxation.
Gs

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B2 agonist

albuterol

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B2 Antagonist

Butaxamine

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Adrenal Medulla

a sympathetic ganglion that is innervated by pre-ganglionic neurons (superficial to kidney)
releases NE and E to lead to hormone like effects of widespread sympathomimetic.

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Sympathomimetic

mimics activation of sympatheic NS

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Sympathetic stimulation of HR

1) Action potential to SA node causes NE binding to Beta-1 Receptor
2) activate GPCR with G to active AC
3) AC activates PKA
4) PKA activates Ca channels to increase depolarization and amplitude
5) cAMP acts on HCN to cause increased repolarization back to baseline and decrease time between AP to increase HR and

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Parasympathetic control of HR

ACh bind to M2 receptor
2) acivates G protein i to inhibit adneylyl cyclase.
3) decrease in cAMP
4) active BY activates GIRK to cause hyperpolarization.
Shallower slope and decreased amplitude.

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sympathomimetic Drugs

mimic sympathetic activity by activating sympathetic or inhibiting parap
Atropine

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Parasympathomimetic drug

mimic para by activating para or inhibit sympth
Propranolol

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Barorceptor function

sense stretch in aortic arch and carotid sinus and send info via vagus nerve to nucleus solitary tract (NTS) in medulla. This reugulates level of sympathetic and parasymathetic output.

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High BP and baroreceptor

1) Increase in BP triggers excitatory neuron release of glutamate. Glutamate acts on parasympathetic neurons to facilitate ACh release on SA node to decrease force of contraction and BP.
2) Glutamaneric neurons also release GAGA, an inhibitor NT that binds to sympathetic neurons to inhibit the release of ACh and NE. This decreases BP.

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Hypothalamus

controls release of hormones via the pituitary and integrates information from may different signaling systems in body.

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Posterior pituitary - brain or gland?

brain

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anterior pituitary - brain or gland?

gland

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Subfornical organ

lacks a blood brain barrier so it can detect hormones and stretch receptors to detect BP --> sends signals to hypothalamus for ADH release.

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isotonic exercise

bike, jog, swim
decreases peripheral vascualr resistance and increases venous return.
Increase HR and increases inotropy
decreases afterload.

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Isometric exercise

weight training
increase peripheral vascular resistance
Increased HR
No increase in CO.

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what happens during a heart attack?

loss of functional myocardium
Increasec atecholamine surge to cause sweating, tachycardia, hypertension.
Increase Inotropy to maintain CO despite increased BP
Heterogenous cellular environment (some areas alive some dead) to affect cytosolic calcium

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Flow (Q) =

Change in pressure/change in resistant

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Cardiac Output =

(Pa-Pv)/Total peripheral resistance; or SVxHR

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Flow (Q) complicated equation

Change in press x (PiX r^4)/ 8 nl (viscosityXlength)

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Velocity =

Flow Q /cross sectional area

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Velocity is small area

Increased - Aorta

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Velocity in large area

decrease - capillaries

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Resistance in parallel

decreased total resistance (1 over)

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Resistance in series

Increased total resistance (additive)

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Pulse Pressure =

Pressure Systemic - Pressure diastolic

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Systolic pressure represents

peak aortic prssure

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Diastolic Pressure represents

minimum aortic pressure

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Mean arterial pressure =

Pdiastolic + 1/3(Pulse pressure)

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Compliance represents

how stretchy something is

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compliance =

change in volume/change in pressure

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what determines compliance

relationship between elastin and smooth muscle collagen; veins are more compliant than arteries

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La of LaPlace

Wall stress (T) = change is pressure*radius/u or wall thickness

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La of laplace in practical terms..

wall stress is inversely related to wall thickness. Thicker wall is less stressed —> hypertrophy

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Rate of bulk transport

Flow * concentration of substance

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Fick equation does this..

how much substance is used by the tissue

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Fick equation

X = Q ([x]initial-[x]final)

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How to calculate myocardial oxygen consumption

CO([O2 arterial]-[O2 venous])

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Fractional Oxygen Extraction

([O2art)-[O2vein])/[O2art]

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what determines oncotic pressure?

concentration of alpha globulin and albumin

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Flux or balance of hydrostatic and oncotic pressures

k[(HPc-HPi)-(OPc-OPi)]

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When is filtration favored?

when HP in capillaries is greater than interstitial fluid

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when is absorption favored?

when OP in capillaries is greater than interstital fluid

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What is the order of the phases in contraction

1) Filing 2) isovolumetric contraction phase 3) ejection phase 4) isovolumetric relaxation phase

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What phases are diastole?

1) filling and 2) isovolumetric relaxation

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Filing phase

Mitral valve is open because Atrial Pressure is higher than Ventricular pressure. Atrial systole occurs. Blood is flowing from atria into ventricle due to mitral valve being open.

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A wave

also known as atrial systole - start of atrial contraction from SA node. Occurs during diastolic filling phase

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Isovolumetric Contraction

depolarization/contraction reaches ventricles to increase ventricular pressure greater than atrial —> closes valve. Aortic/pulmonic valves remain closed. Ventricular pressure increases dramatically and volume remains constant.

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what closes the mitral or tricuspid valve in systole?

increased ventricular pressure over atrial pressure.

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in the isovolumetric phases, why are both the valves closed?

because aortic/pulmonic pressures are greater than those in the ventricles

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Ejection phase

when contraction is increased so much that ventricular pressure exceeds aortic or pulmonic pressure to open the valve. Ventricle begins to relax and slowly pressure decreases and blood is ejected.

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Isovolumentric relaxation

when ventricular pressure decreases to be below aortic or pulmonic presure, the valve closes (delayed). The mitral or tricuspid are still closed so volume remains constant.

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End Diastolic Pressure Volume Relationship

the filling phase - pre-load. A sign of the passive elastic properties of the heart. Slope of this line is inverse of compliance. Increased EDPVR is decreased compliance.

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Systolic Pressure Volume Relationship

Pressure at peak isometric contraction - afterload.
Represents active and passive elastic properties of heart.

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Active tension of heart

difference between End Diastolic VPR and SPVR..

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Factors of Active tension

1) heart fusions on the ascending curve.
2) EVPVR increases force of contraction (CO)
3) what goes out must come in CO = VR

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Frank Starling relationship

reflects intrinsic property of heart, independent of autonomic nervous system and dependent on sarcomere length-tension relationship.

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What is the molecular basis of the Frank Starling relationship?

1) Titin to resist stretch past optimal length
2) Ca sensitivity increases at longer sarcomere length
3) increase length changes lattice spacing to allow cross-bridge to generate more force.

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Mitral valve for ESV?

Open

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Mitral Valve for EDV?

closed

282

Stroke Volume =

EDV - ESV

283

Ejection Fraction

SV/EDV or (EDV-ESV)/EDV

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Stroke work

energy per beat (J) or the area under the curve. Left works more than right.

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Increasing preload results in…

preload represents EDV. So increasing preload increases Stroke volume on next beat.

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what factors affect preload

Blood volume, filling pressure, resistance to filling - arterial pressure, AV valve stenosis, Ventricular compliance.

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Decreased compliance in terms of prelaod

decreased compliance means hypertrophy, decreased EDV/preload

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Increased compliance in terms of preload

increased compliance leads to dilation, increased EDV and preload

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What factors affect afterload?

Aortic pressure, wall thickness and radius, aortic stenosis

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Increasing after load affects stroke volume

decreases stroke volume, because must increase pressure at same EDV to overcome that pressure and this increases the ESV (volume remaining).

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Inotropy

contractility - used in exercise and due to sympathetic and hormonal agents. Increasing isotropy increases stroke volume

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Increasing inotropy

decreases ESV to increase contractility. This is long acting though.