(Circulation. 1995;92:2259-2265.)
© 1995 American Heart Association, Inc.
Articles |
Mechanisms of Ischemic Preconditioning in Rat Hearts
Involvement of 
1B-Adrenoceptors, Pertussis Toxin–Sensitive G Proteins, and Protein Kinase C
From the Department of Pharmacology and Therapeutics (K.H., S.N.), McGill University and the Department of Medicine (S.N.), Montreal Heart Institute and the University of Montreal, Montreal, Canada.
Correspondence to Stanley Nattel, MD, Research Center, Montreal Heart Institute, 5000 Belanger St East, Montreal, Quebec H1T 1C8, Canada.
Background Ischemic preconditioning attenuates the effects of subsequent sustained ischemia by a mechanism involving adenosine and G proteins in several species. Adenosine is not involved in ischemic preconditioning of rat hearts, the mechanisms of which are poorly understood.
Methods and Results Reduction of isometric tension development
was used as an index of the effects of ischemia in isolated,
Langendorff-perfused rat hearts. Two 5-minute periods of
ischemia followed by 10 minutes of reperfusion attenuated the
reduction of developed tension caused by 30 minutes of ischemia
and 15 minutes of reperfusion. Pretreatment with pertussis toxin (PTX),
depletion of norepinephrine stores with reserpine, or
blockade of 
1-adrenoceptors with prazosin prevented the
effects of ischemic preconditioning. Whereas
1B-receptor blockade with chloroethylclonidine blocked
ischemic preconditioning, 1A-receptor blockade
with 5-methylurapadil had no effect. The -adrenergic agonist
phenylephrine mimicked the effects of ischemic
preconditioning in a concentration-dependent manner, and
pretreatment with PTX prevented the action of maximally effective
concentrations of phenylephrine. The protein kinase C
activator phorbol 12-myristate 13-acetate mimicked
and the protein kinase C inhibitors
1-(5-isoquinolinesulfonyl)-2-methylpiperazine and bisindolylmaleimide
prevented ischemic preconditioning.
Conclusions Ischemic preconditioning in isolated,
perfused rat hearts is caused by stimulation of
1B-adrenoceptors by endogenous
catecholamines through the activation of protein kinase C
via a PTX-sensitive G protein. The PTX-sensitive inhibitory
protein Gi, which can be activated by
adenosine, muscarinic agonists, and
1-adrenoceptor agonists, may play a central role in
ischemic preconditioning mediated by protein kinase C across a
broad range of species.
Key Words: signal transduction • receptors • adrenergic • alpha • arrhythmia • catecholamines • ischemia • myocardial infarction
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