Copyright © 2007, European Society of Cardiology
Activation of 
1B-adrenoceptors alleviates ischemia/reperfusion injury by limitation of mitochondrial Ca2+ overload in cardiomyocytes
Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China
* Corresponding author. Laboratory of Molecular Cardiology, Institute of Health Sciences, SIBS, CAS and SJTUSM, 225 Chong Qing Nan Rd., #1 Bulg., Shanghai 200025, China. Tel./fax: +86 21 63852593. htyang{at}sibs.ac.cn
Objective Activation of 
1-adrenergic receptors (1-ARs) mimics ischemic preconditioning (IP). However, the subtypes of 1-ARs involved and the protective mechanisms are not entirely clear. Here we tested the hypothesis that preservation of mitochondrial integrity, in particular, Ca2+ homeostasis via the epsilon isoform of protein kinase C (PKC
) and mitoKATP channels, may underlie the basis of 1B-AR-triggered cardioprotection.
Methods Indo-1 fluorescence in adult rat cardiomyocytes was used as an index of cytosolic ([Ca2+]c) or mitochondrial free Ca2+ concentration ([Ca2+]m), and cell shortening was measured simultaneously. Cells were subjected to 20 min of simulated ischemia followed by 30 min of reperfusion (I/R).
Results Activation of a1-ARs by phenylephrine significantly decreased I/R-induced [Ca2+]c and [Ca2+]m overload, mitochondrial cytochrome c release and ATP reduction, and improved Ca2+ transients and cell shortening. These protective effects were markedly inhibited by blockade of 1B-AR (chloroethylclonidine) but not 1A-AR (5'-methylurapidil) or 1D-AR (BMY 7378). Moreover, phenylephrine-afforded protection on the [Ca2+]m, [Ca2+]c, and cell shortening was lost when mitoKATP channels were inhibited with 5-hydroxydecanoate and PKC with PKC V1–2. However, PKC V1–2 did not affect the mitoKATP channel opener diazoxide-induced protection on these parameters.
Conclusions These findings indicate that phenylephrine-induced protection on [Ca2+]m homeostasis is mediated by selective activation of 1B-AR via mitoKATP channel opening and PKC activation. Mitochondrial function appears to be a determinant of [Ca2+]c and contractile function during I/R injury.
KEYWORDS 1-adrenergic receptors; Intracellular Ca2+ concentration; Mitochondria; Cell contraction; Protein kinase C
1 These authors contributed equally to this work.
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