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Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm C. Frank Starmer Medical University of South Carolina
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Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

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Page 1: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Making Complex Arrhythmias from Simple Mechanisms:

Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade

with the Guarded Receptor Paradigm

C. Frank Starmer

Medical University of South Carolina

Page 2: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

LVRV

RA LA

15.5 mm

shock

tachycardia fibrillation

Dynamics of transmembrane potential

(monophasic cathodal truncated exponential shock, -100 V, 8 ms)

Page 3: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

How To Initiate Reentry or Fibrillation:The cardiac vulnerable period

Refractory: s1s2 = 2.1

Vulnerable: s1s2 = 2.2

Excitable: s1s2 = 2.3

refractoryconduction

Partial Conduction (arrhythmia)

Page 4: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Ion Channel Blockade Reduces Excitability (Anti- effect) and Slows Conduction (Pro- effect)

Historical observations that provided a foundation for a model of ion channel blockade:

Johnson and McKinnon (1957) (memory)

West and Amory (1960) (use-dependence)

Armstrong (1967) (open channel block)

Heistracher (1971) (frequency-dependence)

Carmeliet (1988) (trapping)

Page 5: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Steady-state Frequency-dependent AP Alterations: Quinidine

Johnson and McKinnon JPET 460-468, 1957

dV/dt(max) decreaseswith increased stim rate

AP amplitude decreaseswith increased stim rate

Page 6: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Freq-dependent Quinidine Block:

Alteration of AP Duration

West and Amory: JPET 130:183-193,1960

Increased stimrate slows repolarization

Page 7: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

An Early Model of Use-dependent Blockade

West and Amory: JPET 130:183-193,1960

Page 8: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Frequency- as well as Use-dependence: Detailed Characterization of Ajmaline Blockade

Heistracher. Naunyn-Schmeideberg’s Archiv Fur Pharmakologie 269:199-213, 1971

dV/dt(max) reduced withrepeated stimulation: note approxexponential decrease with stimulationnumber

Steady-state dV/dt(max)Reduced with faster stimulation

Page 9: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Voltage and Time-dependent TEA Block of K+

Channels

Armstrong. J. Gen Physiol 54:553-575, 1969

+90 mV

-46 mV

CP

Control: no “inactivation” + TEA: Apparent “inactivation”

IK

Page 10: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Once a Drug Molecule Blocks the Channel, Can it Escape?

i.e. is it possible to trap it in the channel

Page 11: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Is use-dependent channel blockade a “special” process or is it simply a variant of ordinary

ligand-receptor interactions?

If it’s a variant - what variant?

From These Observations, One Wonders:

Page 12: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Ordinary (not use-dependent) Chemistry:Reacting with a Continuously Accessible Site

No possibility of use- or frequency dependence

Ligand + Receptor LR-Complex

b =

b(t) = b + (b0 - b) e- t

(b- b0)/2 = Kd =

Page 13: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

How to Build a Model that Displaysuse- and frequency dependence?

Unblocked + Drug Blocked(V)

(V)

A necessary condition:Either a Real or Apparent Voltage-dependent

Equilibrium Dissociation Constant:Kd = (V) / (V)

Page 14: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Modeling Apparent Voltage DependenceOf the Equilibrium Dissociation Constant

Voltage-dependent Access to the Binding Site

Inaccessible Blocked kD

l

Page 15: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Hypothesis: Control of Binding Site Access by Channel Conformation

accessible inaccessible

Page 16: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Blockade During Accessible and Inaccessible Intervals:

Channel + D BlockedChannel + D Blocked

Accessible Conformation Inaccessible Conformation

Page 17: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Characterization of Access Control:Guarded Receptor Model

(when channel transition time << drug binding time)

Unblocked Channel + Drug Blocked Channel

where G and T act as “switches” that control binding site accessibility

G*k

l

G = “guard function” controls drug ingress: e.g. h, m, m3h, d, n, n4

T = “trap function” controls drug egress: e.g. m3h, h

In reality, the guard and trap functions are hypothesized to reflect specificchannel protein conformations, and not arbitrary model parameters

Starmer, Grant, Strauss. Biophys J 46:15-27, 1984Starmer and Grant. Mol Pharm 28:348-356,1985

Starmer. Biometry 44:549-559, 1989

Page 18: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Combining Gated Access with Repetitive Stimulation makes Use-dependent Blockade:

Switched Accessibility to a Binding Site

brecov = rss - (b0 - rss) e-n

bactivated = ass - (a0 - ass) e-n

b(t) = b - (b0 - b) e-k + lt

= a ta + r tr

tr

ta

U B

U B

a

r

Starmer and Grant. Mol. Pharm 28:348-356, 1985

Page 19: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Dissecting the Mechanism of Use-Dependent Blockade:

Using Voltage Clamp Protocols to Amplify or Attenuate Blockade

Page 20: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Continuous Access Associated with Channel Inactivation (shift in “apparent” h)

V(cond)

Unblocked + Drug Blocked(1-h)

Starmer et. al. Amer. J Physiol 259:H626-H634, 1990

block

Page 21: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Transient Access Associated with Channel Opening

Pulse duration: 2 ms

2 ms150350 ms550

Gilliam et al Circ Res 65:723-739, 1989

Page 22: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Shift in Apparent Activation:Evidence of Open (?) Channel Access Control

10 ms

Starmer et. Al. J. Mol Cell Cardiol 23:73-83, 1991

Page 23: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Exploring a Model of Use-Dependent Blockade

Are the Analytical Predictions Testable?

Analytical Description:

block associated with the nth pulse: bn = bss + (b0 - bss) e -(a ta + r tr)n

Use-dependent rate = a ta + r tr

Steady-state block: bss = a + (r + a)

Steady-state slope(1 - e-r tr) / (1 - e-)

Page 24: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Testing the Model

• Pulse-train stimulation evokes an exponential pattern of use-dependent block

• There is a linear relation between exponential rate and stimulus recovery interval

• There is a linear relation between steady-state block and a function of the recovery interval ()

• There is a shift in the midpoint of channel availability and / or activation (depending on the access control mechanism)

Page 25: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Test 1. Frequency-dependent Lidocaine Uptake:Exponential Pulse-to-pulse Blockade (50 ms)

Gilliam et al Circ Res 65:723-739, 1989

.15

.65

.35

Page 26: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Test 2: Linear Uptake Rate, Linear Steady State Block ta constant and tr variable

= a ta + r tr

bss = a + (r- a)

Linear Uptake Rate

Linear Steady-State Block

Page 27: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Test 3: Shifting Apparent Inactivation(channel availability)

Unblocked + Drug Blocked(1-h)

V = s ln(1 + D/KD) = 10.76 mV

K = 3940 /M/sl = .678 /sKD = 18.8 M

sVVVsVV

sVV

hh

h

eel

kDh

bhh

eh

/)(/)(

*

*

/)(

1

1

)1(1

1

)1(

1

1

Obs V = 9 mV

Page 28: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Test 4: Shifting Apparent Channel ActivationNimodipine Blockade of Ca++ Channels

Unblocked + Drug Blockedd

V = 40.1 mV

V = k (1 + D/KD) = 43.4 mV

KD = .38 nM

Page 29: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Exploiting the “Therapeutic” Potential of Use-dependent Blockade

Cellular Antiarrhythmic ResponseMulticellular Proarrhythmic Response

Page 30: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Therapeutic Potential: Cellular Effects of Blockade (Antiarrhythmic)

Prolonging Recovery of Excitability:Control and with Use-dependent Blockade

Page 31: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Therapeutic Potential: Multicellular Effects of Blockade (Proarrhythmic)

Slowed Conduction, Increased Vulnerable Period

Why?

Propagation: Responses to Excitation

1) no response

2) front propagates away from stimulation site

3) front propagates in some directions and fails to propagate in other direction (proarrhythmic)

Page 32: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Premature Excitation:The Vulnerable Period

• Normal excitation: cells are in the rest state

• Premature excitation: Following a propagating wave is a refractory region that recovers to the resting state. Stimulation in the transition region can be proarrhythmic

Page 33: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.
Page 34: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

The Dynamics of Vulnerability

Using a simple 2 current model (Na: inward; K: outward) we can demonstrate role of introducing a stimulus within and outside the interval of vulnerability:

We demonstrate the paradox of channel blockade: block extends the refractory period, slows conduction and increases the VP

Here, we switch to Matlab, to demonstrate the dynamic events defining the Vulnerable Period

Page 35: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Demonstrating the Vulnerable Period: ControlRefractory Period = 352 ms VP = 3 ms

Page 36: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Demonstrating Extension of the VP: DrugRefractory Period = 668 ms VP = 59 ms

Page 37: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Use-dependent Extension of the VP

Page 38: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

2-D Responses to Premature Excitation:Note geometric distance between 1st and 2nd fronts

(refractory, unidirectional conduction, bidirectional conduction)

Refractory: s1s2 = 2.1

Vulnerable: s1s2 = 2.2

Excitable: s1s2 = 2.3

refractoryconduction

unidirectional conduction

Page 39: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Extending the VP with Na Channel Block:

Fact or Fantasy?

Starmer et. al. Amer. J. Physiol 262:H1305-1310, 1992

Page 40: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

More Apparent Complexity: Monomorphic and Polymorphic Reentry and ECG

Monomorphic PolymorphicgNa = 2.25 gNa = 4.5

Polymorphic gna = 2.3

Page 41: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Major Lessons Learned FromIdeas Originating in Studies of

Johnson, Heistracher and Carmaliet

Page 42: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Use caution when “repairing” channels that aren’t broken:Blockade of normal Na Channels

• Antiarrhythmic– Extended refractory

interval and reduced excitability leading to PVC suppression

• Proarrhythmic– Extends the vulnerable

period (increases the probability of a PVC initiating reentry)

– Slowed conduction increase the probability of sustained reentry

– Increases probability of wavefront fractionation

Page 43: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Repairing Channels that are Broken (e.g. SCN5A) may have Clinical Utility:

Blockade of “defective” channels diminishes EADs in LQT Syndrome, Heart Failure, Epilepsy

Page 44: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Long QT Syndrome:Links to Mutant Na and K Channels

Q T

Page 45: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Stable and Unstable Action Potentials

Beeler-Reuter ModelHuman Ventricular Cells

Page 46: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Yet Another Variant: Epilepsy

Page 47: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Summary

• Use- and Frequency Na channel block are consistent with “ordinary” binding to a periodically accessible site

• Tonic block is compatible with block of inactivated channels at the rest potential.

• Tests are available to validate the applicability of the guarded-receptor paradigm to observations of drug-channel interactions

Page 48: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

• For individual cells: use-dependent Na channel block reduces excitability (prolongs the refractory period (antiarrhythmic effect)

• For connected cells (tissue): reduced excitability ALSO slows propagation which extends the vulnerable period (proarrhythmic effect)

• The guarded receptor paradigm is a tool for “in numero” exploration of channel blockade in both cellular and multicellular preparations and direct characterization of anti- and proarrhythmic effects

Page 49: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.
Page 50: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Apparent Trapping of Quinidine and Disopyramide

Zilberter et. Al. Amer. J. Physiol 266:H2007-H2017, 1994

100 uM Diso

5 uM Quinidine

Page 51: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Demonstrating the Trap

Zilberter et. Al. Amer. J. Physiol 266:H2007-H2017, 1994

Page 52: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Examples of Recent State-Transition Models

Balser et al J. Clin Invest. 98:2874-2886, 1996

Vedantham and Cannon J. Gen Physiol 113:7-16, 1999

Page 53: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Transforming a State-transition Model to a Macroscopic Model:

The Importance of “Rapid Equilibration”

Unblocked Channel + Drug Blocked ChannelG

Page 54: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Reducing a Complex State-Transition Model to a Simple “Macro” GRH

Model

R I B

kD

l

Differential Equation Description:

maxC B I R :Channels ofon Conservati

][][

][][

BlIkDdt

dB

RIdt

dR

lbbhkDdt

db

lBBkDdt

dB

)1)(1(

)C(

B) -(C I

B - I - C B - R -C I

I R :ionEquilibrat Rapid

max

max

maxmax

Guard Function: 1-h

Guarded Receptor Formulation:

Page 55: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Spontaneous Oscillation: Mutant KVLQT1 and HERG (K+) and SCN5A (Na+) Channels:

Altering Electrical Stability with Channel Blockade

Page 56: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Use- and Frequency-Dependent Blockade:Central Features

• Degree of Blockade Depends on Vclamp

• Degree of Blockade Depends on Tclamp

• Degree of Blockade Depends on Vhold

Vclamp

Vhold

Tclamp

Page 57: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

1. Frequency-dependent Lidocaine Uptake:Exponential Pulse-to-pulse Blockade (2 ms)

Test 1: Exponential UDP Block, ta = constant

Gilliam et al Circ Res 65:723-739, 1989

Page 58: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Recovery of Excitability: Drug

Page 59: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Evolution of a Spiral Wave

T = 0 T = 1

T = 5 T = 15

Page 60: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Monomorphic and Polymorphic EKGs

Role of Wavefront Energy

Page 61: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Building a Model of “Discontinuous” (Use-dependent) Drug-Channel Interaction:

Unblocked + Drug Blocked(V)

(V)

Apparent Voltage-dependent Equilibrium Dissociation Constant:Kd = (V) / (V)

Page 62: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Why Does the Guraded Receptor Model Work?

Comparing State-Transition and Macro Models

Macro Model: Unblocked + Drug BlockedG

Page 63: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Reduction in AP Duration:

CL

C Q

Colatsky Circ Res 50:17-27, 1982

Page 64: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Altering the Equilibrium Stability of a Cell: Blockade of Na Current

Can be reversed by Nablockade

Page 65: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

EADs and Suppression via Na Channel Blockade

Maltsev et al Circ 98:2545-2552, 1998

Page 66: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Frequency-dependent Lidocaine Uptake:Access Controlled by “Inactivation”

Pulse duration: 50 ms

50 ms

150

650

150250350 ms450550650

Gilliam et al Circ Res 65:723-739, 1989

Page 67: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Voltage-dependent Recovery from Blockade

Starmer, et. al. J. Mol. Cell. Card 23;73-83, 1992

Page 68: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Two Modes of Na Channel Blockade:Test 3: Linearity with variations in both ta and tr

ta = 50 ms

ta = 10 ms

tr = constant

= a ta + r tr

tclamp

.15

.25

.45

Page 69: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

A Conformation-dependent Blockade ModelClosed <===> Open <===> Blocked

Armstrong. J. Gen Physiol 54:553-575, 1969

Page 70: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Binding to Accessible Sites at Sub-threshold Vm

A single mechanism for tonic and use-dependent block

-80 mV, = 694 ms

-20 mV, t = 373 ms

Gilliam et al Circ Res 65:723-739, 1989

: Channel InactivationV (mV) (ms) -70 94 -40 9 -20 2.9

Block independent of rate ofinactivation but dependent

on potential dependence of h

Evidence that lidocaine does not compete with fast-inactivation and that slow recovery does not result from accumulated fast inactivated channels. Vedantham and CannonJ. Gen. Physiol 113:7-16, 1999

65x2x (no evidence of 2 exp)

block

% block

Page 71: Making Complex Arrhythmias from Simple Mechanisms: Exploring Anti- and Proarrhythmic Effects of Na Channel Blockade with the Guarded Receptor Paradigm.

Test 4: Exponential Binding to a Continuously Accessible Site independent of “inactivation”

Gilliam et al Circ Res 65:723-739, 1989

-20 mV

-80 mV-120 mV

tc

I = I + (I0 - I) e-2.95 t