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Adenosine A 1 receptor activation reduces opening of mitochondrial permeability transition pores in hypoxic cardiomyocytes
Author(s) -
Xiang Fei,
Huang Yuesheng,
Zhang Dongxia,
Chu Zhigang,
Zhang Jiaping,
Zhang Qiong
Publication year - 2010
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2009.05300.x
Subject(s) - mptp , ccpa , mitochondrial permeability transition pore , cardioprotection , agonist , chemistry , microbiology and biotechnology , adenosine , mitochondrion , pharmacology , apoptosis , biochemistry , adenosine receptor , biology , receptor , programmed cell death , medicine , endocrinology , ischemia , dopaminergic , dopamine
Summary 1. Adenosine A 1 receptors (A 1 R) play an important role in cardioprotection against hypoxic damage and the opening of mitochondrial permeability transition pores (MPTP) is central to the regulation of cell apoptosis and necrosis. However, it is still unclear whether A 1 R open MPTP in hypoxic cardiomyocytes. 2. The present study used primary cardiomyocyte cultures from neonatal rats to investigate the mechanisms of A 1 R activation and the effects of A 1 R on MPTP opening under hypoxic conditions. 3. Hypoxia increased both MPTP opening and the production of reactive oxygen species (ROS), while decreasing cell viability and mitochondrial membrane potential (Δψ). The A 1 R agonist 2‐chloro‐ N 6 ‐cyclopentyladenosine (CCPA; 500 nmol/L) blocked the increase in MPTP opening and ROS production and maintained cell viability and Δψ under hypoxic conditions. 4. The protective effects of CCPA were eliminated by both the protein kinase C (PKC) inhibitor chelerythine (2 μmol/L) and the mitochondrial ATP‐sensitive K + channel (mitoK ATP ) inhibitor 5‐hydroxydecanoate (500 μmol/L). Moreover, CCPA significantly increased the PKC content in both total protein and membrane protein of cardiomyocytes. 5‐Hydroxydecanoate did not prevent these CCPA‐induced increases in PKC. 5. These results demonstrate that CCPA reduces MPTP opening in hypoxic cardiomyocytes, possibly by activating PKC, stabilizing Δψ and reducing ROS production following the opening of mitoK ATP . Consequently, fewer MPTP open.