Mechanisms of ischemic preconditioning in rat hearts. Involvement of alpha 1B-adrenoceptors, pertussis toxin-sensitive G proteins, and protein kinase C.

Abstract:

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 alpha 1-adrenoceptors with prazosin prevented the effects of ischemic preconditioning. Whereas alpha 1B-receptor blockade with chloroethylclonidine blocked ischemic preconditioning, alpha 1A-receptor blockade with 5-methylurapadil had no effect. The alpha-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 alpha 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 alpha 1-adrenoceptor agonists, may play a central role in ischemic preconditioning mediated by protein kinase C across a broad range of species.

journal_name

Circulation

journal_title

Circulation

authors

Hu K,Nattel S

doi

10.1161/01.cir.92.8.2259

subject

Has Abstract

pub_date

1995-10-15 00:00:00

pages

2259-65

issue

8

eissn

0009-7322

issn

1524-4539

journal_volume

92

pub_type

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