Infarct size limitation by adrenomedullin: protein kinase A but not PI3-kinase is linked to mitochondrial KCa channels
1 Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
2 Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
* Corresponding author. Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel: +81 43 226 2051; fax: +81 43 226 2052.E-mail address: tsato{at}faculty.chiba-u.jp (T. Sato).
Aim: Adrenomedullin (ADM) has been shown to protect the heart against ischaemic injury, but little is known of the underlying mechanism. Mitochondrial Ca2+-activated K+ (mitoKCa) channels play a key role in cardioprotection. This study examined whether mitoKCa channel is involved in the protection afforded by ADM.
Methods: Flavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoKCa channel activity. Infarct size in the isolated perfused rabbit hearts subjected to 30-min global ischaemia and 120-min reperfusion was determined by triphenyltetrazolium chloride staining.
Results: The mitoKCa channel opener NS1619 (30 µM) partially oxidized flavoprotein. ADM (10 nM) augmented the NS1619-induced flavoprotein oxidation when applied after the effect of NS1619 had reached steady state. This potentiating effect of ADM was prevented by the protein kinase A (PKA) inhibitor KT5720 (200 nM), but not by the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 (5 µM). The mitoKCa channel blocker paxilline (PX, 2 µM) completely blocked the oxidative effects of NS1619 in the presence of ADM. Treatment with ADM for 10 min before ischaemia significantly reduced infarct size after ischaemia/reperfusion from 63 ± 3% in controls to 32 ± 4% (P < 0.01). This infarct size-limiting effect of ADM was abolished by PX (61 ± 2%), as well as by KT5720 (62 ± 3%). ADM treatment for the first 10 min of reperfusion significantly reduced infarct size compared with controls (42 ± 3%, P < 0.01). This cardioprotective effect of ADM was unaffected by PX (38 ± 4%), but was abolished by LY294002 (60 ± 4%).
Conclusions: ADM augments the opening of mitoKCa channels by PKA activation, but not by PI3-K activation. ADM treatment prior to ischaemia reduces infarct size via PKA-mediated activation of mitoKCa channels. On the other hand, ADM treatment upon reperfusion reduces infarct size via a PI3-K-mediated pathway without activating mitoKCa channels.
KEYWORDS Adrenomedullin; Ca2+-activated K+ channel; Cardioprotection; Mitochondria
Time for primary review: 29 days
This article was published online by Elsevier on 2 August, 2007.
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