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