ischaemic pre-conditioning prof. mehdi hasan mumtaz
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ISCHAEMICPRE-CONDITIONING
Prof. Mehdi Hasan Mumtaz
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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’
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HISTORY
1986 – Murry & colleagues.
1993 – Marber & colleagues.
1997 – Cason & colleagues.
Kersten & colleagues.
1983-89 – Davis & colleagues.
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ENDPOINTS
Reperfusion arrythmias.
Slow energy metabolism.
Improve post-ischaemic function.
Protect coronary endothelium.
Post-ischaemic tension in atrial trabeculae muscle.
Resistance to hypoxic injury.
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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.
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TYPES
EARLY Immediate Lasts 2-3h.
LATE 12-24h. Lasts 72h. Dpendent on:
Cardioprotective proteins.
Protects against stunning
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ADDITIONAL STRESSFUL STIMULIIN ADDITION TO ISCHAEMIC
Oxidative (hyperoxia). Mecanical (stretch). Electrical (rapid pacing). Thermal. Chemical (harmonal). Ionic (calcium). Pharmacological.
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CLASSIC/EARLY PRECONDITIONING
Putative Mecanisms Opening of coronary colleterals. Induction of oxidants. Synthesis of protective proteins. Changes in mitochondrial
ATPases.
Not supported.
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PRECONDITIONING
“Protection is receptor mediated”
Objective Identification. Triggers. Tranducers. End effectors in myocytes.
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A. TRIGGERS – ISCHAEMIC PRECONTITIONG
RECEPTOR DEPENDENT
Adenosine. Opoid receptors. Bradykinin. Bristaglandins. Adrenergic,
angiotension, endothelin receptors.
Purine. Ach.
RECEPTOR INDEPENDENT
Nitric oxide. Free radicals. Calcium.
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ISCHAEMIC PRE-CONDITIONINGB. MEDIATORS
B-1ATP sensitive K+
channels(K+ ATPS)
B-2Protein Kinase C
(PKC)
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ISCHAEMIC PRECONTITIONGB. Mdiators
B-1 K+ ATP Channels
Sarcolemal “Blocked by”
SalfonylureaS-hydroxydecanoate
Mitochondrial “Opened by”
Diazoxide. “Blocked by”
5HD
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ISCHAEMIC PRECONTITIONG
B – Mediators.B-2 Protein Kinase C (PKC).
1. “Activator”Phorbol
esters.2. “Inhibitor”
Polymyxin.Stanrosporin
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ISCHAEMIC PRECONTITIONGC. END EFFECTORS
Sodium proton
exchange.
Cytoskeleton changes.
TNF down regulation
Energy demand.
Catbolite acumulation.
Lactate accumulation.
Glycogen store.
Intrcellular
acidification.
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DELAYED PRE-CONDITIONING
Complex polygemic phenomenon
involving activation of several
genes necessary for the
synthesis of severe proteins
and channels (K+ATD).
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DELAYED PRECONDITIONING
Latent period 12-24h.
Duration 72h.
Cardioprotective proteins.
Protects MI.
Protects M. Stunning.
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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
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DELAYED PRE-CONDITIONING
“MEDIATORS & END EFFECTORS”
Related to changes in protein activityHeat stress proteins.
HSP – 72.Antioxidant enzymes.
(MnSod)NOS (cox – 2)
Cytokine.
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DELAYED PRE-CONDITIONING
Requires. Myocardial protein synthesis.
Phosphorylation of transcription factors. NOS.
SOD.
Heat shock protein.
Role of ROS.
Role of NO.
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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
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CLINICAL IMPLICATIONSUse of Nicorandil
K+ATD. No donors. Sulfonylurea. COX-2. Cogeners of adenosine. Adenosis agonists. PKC agonists.
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ANAESTHETIC INDUCEDPRECONDITIONING
Anaesthetic drugMitochondrialKATP
channel activitySarcolemmal KATP
channel activity
Isoflurane
Sevoflurane ?
Desflurane
Halothane ?
Enflurane ? ?
Nitrous oxide** ? ?
Morphine ?
Fentanyl ?
Sufentanil ? ?
Remifentanil ? ?
Trichloroethanol (chloral hydrate, -chloralose) ?
Ethanol
Urethane ?
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ANAESTHETIC INDUCEDPRECONDITIONING
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.
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Anaesthetic drug
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) ?
Xylazine (used in the laboratory) ?
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EFFECT OF MEDICATIONPreconditioning 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, p-diethylaminoethylbenzoate), 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
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Preconditioning Preconditioning
1-Adrenergic receptor agonists 1-Adrenergic receptor antagonists
Phenylephrine, norepinephrine Phentolamine
M2-muscarinic receptor agonists M2-muscarinic receptor antagonists
Acetylcholine esterase inhibitors Atropine
Nitric oxide releasers Nitric oxide scavengers
Nitroglycerin, nitroprusside, L-arginine
Vitamin E?
Ca2+ Ca2+ channel blocker
B2-bradykinin receptor agonists
Angiotensin converting enzyme inhibitors: captopril, lisinopril, enalapril
EFFECT OF MEDICATION
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PreconditioningPreconditioning
AT1-receptor antagonists
Statins
Lovastatin, pravastatin, via activation of ecto-5'-nucleotidase
Flumazenil
Amrinone
Digoxin
Gadolinium
Aprotinin
COX-2 inhibitors
EFFECT OF MEDICATION
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Factors/disease statesIschaemic
preconditioningAnaesthetic
preconditioning
Diabetes
Medication
Increased age
?
Raised plasma cholesterol ?
Coronary artery disease (ischaemic cardiac remodelling)
?
Arterial hypertension (hypertrophic cardiac remodelling)
?
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ICU – NISHTAR HOSPITAL