Effect of heptanol on heart and its mechanism

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Effect of heptanol on heart and its mechanism

• Baoping Chen
• June 25, 2004

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• 1. What is heptanol ?
• 2. Effect of heptanol on the contractile
  function
• 3. Effect of heptanol on the electrical
  function
• 4. Effect of heptanol on the infarct size in
  ischemic heart
• 5. Mechanism of these actions

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• 1?What is heptanol ?

• Gap junction

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(No Transcript)
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• 1?What is heptanol ?

(2) Heptanol is a relatively selective gap
junction uncoupler
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• 1?What is heptanol ?

• Mechanism of heptanol-induced uncoupling

Number of gap junction channel
Conductance of the individual channels
Conductance
Open probability
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• 1?What is heptanol ?

• Mechanism of heptanol-induced uncoupling
  ------three hypotheses

1) An indirect action mediated by an increase in
intracellular Ca2 concentration 2) A
conformational change in the cell-to-cell channel
resulting either from a disordering effect of the
insertion of lipid-soluble molecules into
membrane bilayer 3) A direct interaction of
heptanol with the channel proteion
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• 2. Effect of heptanol on the contractile
  function

• Effect on LVDP in normal perfused heart

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Fig1. a, b. Effects of introduction and
withdrawal of 1.0 mM heptanol in the perfusate on
LVDP
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Fig 2. Effects of heptanol on (a) LVDP, (b)
(dp/dt) and (c) (-dp/dt), normalized to baseline
values recorded in the absence of heptanol.
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• 2. Effect of heptanol on the contractile
  function

(2) Effect on LVDP in ischemic heart
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Figure 3. Effect of different concentrations of
heptanol during the first 15 minutes of
reoxygenation on LVDP(top) and LVEDP ( bottom) 75
minutes after cessation of heptanol infusion
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3. Effect of heptanol on the electrical function

• Effect on conduction

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Figure 4. The effect of heptanol on conduction
velocity of action potential of right papillary
muscle in rat
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3. Effect of heptanol on the electrical function
(2) Effect on BEG ( Bipolar electrograms )
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Fig 5. BEGs recorded from epicardial (epi,
left-hand traces) and endocardial (endo,
right-hand traces) sites in a paced
Langendorff-perfused heart before (i) and during
(ii) perfusion with 1 mM heptanol and 3 min (iii)
and 10 min (iv) after washout of heptanol
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3. Effect of heptanol on the electrical function
(3) Induction of arrhythmias in normal perfused
heart
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Fig 6. A typical example of an episode of
non-sustained ventricular tachycardia (NSVT)
induced by a premature stimulus in a heart
perfused with 0.1 mM heptanol. The dashed box
shows the BEG complex recorded following the
normal stimulus as well as the premature stimulus
immediately preceding the NSVT
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3. Effect of heptanol on the electrical function

• Effect on ventricular arrhythmias in infarced
  canine myocardium or ischemic heart
• 1) In infarcted canine myocardium, at low
  concentrations, the effect is proarrhythmic at
  higher concentrations, heptanol exerts an
  antiarrhythmic effect.
• 2) In ischemic rat heart of my previous
  study, at low concentrations, the effect is also
  proarrhythmic at higher concentrations, heptanol
  exerts an antiarrhythmic effect

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3. Effect of heptanol on the electrical function

• Decreasing defibrillation thresholds
• One study showed that electrical uncoupling
  by heptanol significantly lower defibrillation
  thresholds and temporal dispersion of VF
  activation without affecting ventricular
  refractoriness.

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3. Effect of heptanol on the electrical function

• Effect on many other channels
• Of greater significance, it is well
  recognized that heptanol at concentration ?1mM
  can exert nonspecific and nonjunctional effects,
  most notably on sodium, potassium and calcium
  channels.
• But at concentration lt 1mM, its
  nonspecific and nonjunctional effects is small.
  So in my prevous study, it had no significant
  effect on the other parameters of action
  potential of papillary muscle in the right
  ventricle of rat, including RP, APA, Vmax,APD90
  and ERP.

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4. Effect of heptanol on the infarct size in
ischemic heart

• Effect of perfusion with heptanol during
  reperfusion on infarct size

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Figure 7. Effect of the intracoronary infusion of
heptanol at a final concentration of 1 mmol/L on
infarct size
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Figure 8. Myocardial necrosis (black areas) in
the third slice from the 10 pigs included in the
study, five from the control group (A), and 5
from the heptanol group (B), as disclosed by
computer-assisted analysis of tryphenyltetrazolium
staining images.
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4. Effect of heptanol on the infarct size in
ischemic heart
(2) Effect of perfusion with heptanol before
ischemia on infarct size
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Figure 9. Effects of heptanol or IP on infarct
size in the isolated perfused rat heart
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4. Effect of heptanol on the infarct size in
ischemic heart
(3) Controversy Loading the soon-to-be
ischemic region with the gap junction uncoupler
heptanol (0.5 mM) failed to limit infarct size in
the isolated buffer-perfused rabbit heart model
of regional ischemia/reperfusion. Thus, in
contrast to results obtained in models of
reperfusion injury,'' their data, obtained with
heptanol pretreatment, suggest that cell-cell
communication via gap junctions during coronary
artery occlusion does not contribute importantly
to the development of necrosis in rabbit heart.
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4. Effect of heptanol on the infarct size in
ischemic heart

• Abrogating infarct size reduction with
  preconditioning
• In another report, an author demonstrated
  that treatment with heptanol renderd IP
  ineffective in eliciting protection, and their
  results suggest that gap junction-mediated
  transfer of an as-yet unknown survival
  factorrather than disrupted transfer of a death
  messenger may play a role in the increased
  resistance to infarction conferred by antecedent
  IP in mouse heart.

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5. Mechanism of these actions
(1) Hypothesis that chemical interaction through
gap junctions may result in cell-to-cell
progression of hypercontracture and that this
phenomenon contributes to the final extent of
reperfused infarcts.
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Figure 10. Passage of lucifer yellow from the
microinjected cell to the adjacent one.
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These results demonstrate that hypercontracture
may be transmitted to adjacent myocytes through
gap junctions and that heptanol may interfere
with this transmission and reduce the final
extent of myocarsial necrosis during
reoxygenation or reperfusion . These findings are
consistent with the hypothesis tested and open a
new approach to limitation of infarct size by
pharmacological control of gap junction
conductance.
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5. Mechanism of these actions
(2) Hypothesis that directly blocking gap
junctions preconditions the heart, and that this
protection is likely related to delayed
uncoupling in heptanol preconditioned hearts.
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5. Mechanism of these actions
In our recent study, preconditioning with brief
ischemia or heptanol decreased the maximal rate
of uncoupling during ischemia, also increased the
time required to reach a plateau in whole-tissue
resistance during ischemia, and also delayed the
onset of uncoupling during ischemia. These
findings are consistent with the hypothesis
tested
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