ISCHAEMICPRE-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 STIMULIIN 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-CONDITIONINGB. MEDIATORS
B-1ATP sensitive K+
channels(K+ ATPS)
B-2Protein Kinase C
(PKC)
ISCHAEMIC PRECONTITIONGB. Mdiators
B-1 K+ ATP Channels
Sarcolemal “Blocked by”
SalfonylureaS-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 PRECONTITIONGC. END EFFECTORS
Sodium proton
exchange.
Cytoskeleton changes.
TNF down regulation
Energy demand.
Catbolite acumulation.
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 activityHeat 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 IMPLICATIONSUse of Nicorandil
K+ATD. No donors. Sulfonylurea. COX-2. Cogeners of adenosine. Adenosis agonists. PKC agonists.
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 ?
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.
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) ?
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
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
PreconditioningPreconditioning
AT1-receptor antagonists
Statins
Lovastatin, pravastatin, via activation of ecto-5'-nucleotidase
Flumazenil
Amrinone
Digoxin
Gadolinium
Aprotinin
COX-2 inhibitors
EFFECT OF MEDICATION
Factors/disease statesIschaemic
preconditioningAnaesthetic
preconditioning
Diabetes
Medication
Increased age
?
Raised plasma cholesterol ?
Coronary artery disease (ischaemic cardiac remodelling)
?
Arterial hypertension (hypertrophic cardiac remodelling)
?
ICU – NISHTAR HOSPITAL