• Cardiovascular research · Jan 2008

    Infarct size limitation by adrenomedullin: protein kinase A but not PI3-kinase is linked to mitochondrial KCa channels.

    • Hirofumi Nishida, Toshiaki Sato, Masaru Miyazaki, and Haruaki Nakaya.
    • Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan.
    • Cardiovasc. Res. 2008 Jan 15; 77 (2): 398-405.

    AimAdrenomedullin (ADM) has been shown to protect the heart against ischaemic injury, but little is known of the underlying mechanism. Mitochondrial Ca(2+)-activated K(+) (mitoK(Ca)) channels play a key role in cardioprotection. This study examined whether mitoK(Ca) channel is involved in the protection afforded by ADM.MethodsFlavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoK(Ca) 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.ResultsThe mitoK(Ca) channel opener NS1619 (30 microM) 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 microM). The mitoK(Ca) channel blocker paxilline (PX, 2 microM) 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%).ConclusionsADM augments the opening of mitoK(Ca) channels by PKA activation, but not by PI3-K activation. ADM treatment prior to ischaemia reduces infarct size via PKA-mediated activation of mitoK(Ca) channels. On the other hand, ADM treatment upon reperfusion reduces infarct size via a PI3-K-mediated pathway without activating mitoK(Ca) channels.

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