ISCHAEMIC
PRE-CONDITIONING
Prof. Mehdi Hasan Mumtaz
MYOCARDIAL ISCHAEMIC
PRE-CONDITIONING
“Phenomenon by which a brief
episod (s) of myocardial ischaemia
increases the ability of te heart to
tolerate a sbsequent prolonged
period of ischaemia”
‘Murry et al’
HISTORY
 1986
– Murry & colleagues.
 1993
– Marber & colleagues.
 1997
– Cason & colleagues.
Kersten & colleagues.
 1983-89 – Davis & colleagues.
ENDPOINTS
 Reperfusion arrythmias.
 Slow energy metabolism.
 Improve post-ischaemic function.
 Protect coronary endothelium.
 Post-ischaemic tension in atrial
trabeculae muscle.
 Resistance to hypoxic injury.
TIME COURSE OF ISCHAEMIC
PRECONDITIONING
 Important factors.
 Duration of ischaemia.
 Number of cycles.
 Duration of reperfusion.
 Types.
 Eary, classic.
 Lte, second window of protection.
Delayed.
TYPES
EARLY
 Immediate
 Lasts 2-3h.
LATE
 12-24h.
 Lasts 72h.
 Dpendent on:
 Cardioprotective
proteins.
 Protects against
stunning
ADDITIONAL STRESSFUL STIMULI
IN ADDITION TO ISCHAEMIC
 Oxidative (hyperoxia).
 Mecanical (stretch).
 Electrical (rapid pacing).
 Thermal.
 Chemical (harmonal).
 Ionic (calcium).
 Pharmacological.
CLASSIC/EARLY PRECONDITIONING
Putative Mecanisms
 Opening of coronary colleterals.
 Induction of oxidants.
 Synthesis of protective proteins.
 Changes in mitochondrial
ATPases.
 Not supported.
PRECONDITIONING
“Protection is receptor
mediated”
 Objective  Identification.
 Triggers.
 Tranducers.
 End effectors in myocytes.
A. TRIGGERS – ISCHAEMIC
PRECONTITIONG
RECEPTOR DEPENDENT
 Adenosine.
 Opoid receptors.
 Bradykinin.
 Bristaglandins.
 Adrenergic,
angiotension,
endothelin
receptors.
 Purine.
 Ach.
RECEPTOR INDEPENDENT
 Nitric oxide.
 Free radicals.
 Calcium.
ISCHAEMIC PRE-CONDITIONING
B. MEDIATORS
B-1
ATP sensitive K+
channels
(K+ ATPS)
B-2
Protein Kinase C
(PKC)
ISCHAEMIC PRECONTITIONG
B. Mdiators
B-1
K+ ATP Channels
Sarcolemal
 “Blocked by”
Salfonylurea
S-hydroxydecanoate
Mitochondrial
 “Opened by”
 Diazoxide.
 “Blocked by”
 5HD
ISCHAEMIC PRECONTITIONG
B – Mediators.
B-2 Protein Kinase C (PKC).
1.  “Activator”
Phorbol esters.
2.  “Inhibitor”
Polymyxin.
Stanrosporin
ISCHAEMIC PRECONTITIONG
C. END EFFECTORS
 Sodium proton exchange.
  Energy demand.
 Cytoskeleton changes.
 Catbolite acumulation.
 TNF  down regulation
  Lactate accumulation.
  Glycogen store.
  Intrcellular acidification.
DELAYED PRE-CONDITIONING
Complex polygemic phenomenon
involving activation of several
genes necessary for the synthesis
of severe proteins and channels
(K+ATD).
DELAYED PRECONDITIONING
 Latent period 12-24h.
 Duration 72h.
 Cardioprotective proteins.
 Protects MI.
 Protects M. Stunning.
STIMULI FOR DELAYED
PRE-CONDITIONING




Parmacological
Endotoxins.
Adenosine agonists
Opioid agonists.
TNF








Non-Parmacological
Ischaemia.
Stress.
Rapid ventricular
pacing.
Exercise
 Infarction.
 Stunning.
 Arrythmias.
 Endothelial dysfunction
DELAYED PRE-CONDITIONING
“MEDIATORS & END EFFECTORS”

Related to changes in protein activity
Heat stress proteins.
HSP – 72.
Antioxidant enzymes.
(MnSod)
NOS (cox – 2)
Cytokine.
DELAYED PRE-CONDITIONING
 Requires.
 Myocardial protein synthesis.
 Phosphorylation of transcription
factors.
NOS.
SOD.
Heat shock protein.
 Role of ROS.
 Role of NO.
Selectivity
Agonists
Antagonists
Sarcolemmal
Long-chain CoA esters
HMR-1098
P-1075
ADP
Mitochondrial
GTP
ADP
GDP
Long-chain-CoA esters
UDP
5-Hydroxydecanoate
Superoxide anions
Diazoxide
Nicorandil
BMS-191095
Non-selective
Cromakalim
ATP
Bimakalim
Glibenclamide
Aprikalim
Glyburide
Diethylaminoethylbenzoate
Pinacidil
CLINICAL IMPLICATIONS
Use of Nicorandil
 K+ATD.
 No donors.
 Sulfonylurea.
 COX-2.
 Cogeners of adenosine.
 Adenosis agonists.
 PKC agonists.
ANAESTHETIC INDUCED
PRECONDITIONING
Anaesthetic drug
MitochondrialKATP
channel activity
Sarcolemmal KATP
channel activity

Isoflurane
Sevoflurane
?
Desflurane
Halothane
?

Enflurane
?
?
Nitrous oxide**
?
?
Morphine
?
Fentanyl
?
Sufentanil
?
?
Remifentanil
?
?
Trichloroethanol
(chloral hydrate, -chloralose)
?
Ethanol
Urethane
?
ANAESTHETIC INDUCED
PRECONDITIONING
Volatile Anaesthetics
 Characteristics of preconditioning similar to
those of ischaemic preconditioning”
 A1 adenosin receptor activation.
 KATP chanel activation.
 Reduce Ca++ loading.
 Augment post ischaemic contrctile
responsiveness to Ca++.
 infarct size.
 Delayed preconditioning.
Mitochondrial
KATP channel
activity
Sarcolemmal
KATP channel
activity
R-ketamine


S-ketamine

?
Propofol
  (#)
  (#)
Etomidate

?
Thiopental

?
Midazolam

?
Pentobarbital (used in the
laboratory)


Thiamylal (used in the
laboratory)
?


?
Anaesthetic drug
Xylazine (used in the
laboratory)
EFFECT OF MEDICATION
Preconditioning
Preconditioning
Adenosine receptor agonists
Adenosine receptor antagonists
Including nucleotide transporter
inhibitors (acadesine, dipyridamol)
Theophylline, aminophylline
KATP channel openers
KATP channel blockers
(Nicorandil, diazoxide, cromakalim,
levosimendan, minoxidil, benzocaine, pdiethylaminoethylbenzoate), including the
uncoupler of oxidative phosphorylation:
bupivacaine, ropivacaine, most NSAIDs
Sulfonylurea agents, including
antidiabetic drugs: glibenclamide,
glyburide. Much less: glimepiride, and
anticancer drugs (diarylsulfonylurea),
lidocaine, mexiletine
Opioid agonists (probably via)
Opioid antagonists
Morphine, pentazocine, fentanyl
Naloxone
ß-Adrenergic receptor agonists
ß-Adrenergic receptor antagonists
Isoproterenol, norepinephrine,
epinephrine. Some ß-blockers
with
auxiliary effects may enhance
preconditioning, such as
carvedilol, nipradilol and nebivolol
Including drugs which deplete
myocardial tissue of catecholamines,
such as reserpine
EFFECT OF MEDICATION
Preconditioning
Preconditioning
1-Adrenergic receptor agonists
1-Adrenergic receptor antagonists
Phentolamine
Phenylephrine, norepinephrine
M2-muscarinic receptor agonists
Acetylcholine esterase inhibitors
M2-muscarinic receptor antagonists
Atropine
Nitric oxide releasers
Nitric oxide scavengers
Nitroglycerin, nitroprusside, Larginine
Vitamin E?
Ca2+
Ca2+ channel blocker
B2-bradykinin receptor agonists
Angiotensin converting enzyme
inhibitors: captopril, lisinopril,
enalapril
EFFECT OF MEDICATION
Preconditioning
Preconditioning
AT1-receptor antagonists
Statins
Lovastatin, pravastatin, via activation
of ecto-5'-nucleotidase
Flumazenil
Amrinone
Digoxin
Gadolinium
Aprotinin
COX-2 inhibitors
Factors/disease states
Ischaemic
preconditioning
 
Diabetes
 
Anaesthetic
preconditioning

 
Medication
 
Increased age
Raised plasma cholesterol
?

?
 
Coronary artery disease (ischaemic
cardiac remodelling)
?
 
Arterial hypertension (hypertrophic
cardiac remodelling)
?
ICU – NISHTAR HOSPITAL