Endogenous and Agonist-induced Opening of Mitochondrial Big Versus Small Ca2+-sensitive K+ Channels on Cardiac Cell and Mitochondrial Protection

Document Type

Article

Language

eng

Publication Date

11-2017

Publisher

Lippincott Williams & Wilkins, Inc.

Source Publication

Journal of Cardiovascular Pharmacology

Source ISSN

1533-4023

Abstract

Both big (BKCa) and small (SKCa) conductance Ca2+-sensitive K+ channels are present in mammalian cardiac cell mitochondria (m). We used pharmacological agonists and antagonists of BKCa and SKCa channels to examine the importance of endogenous opening of these channels and the relative contribution of either or both of these channels to protect against contractile dysfunction and reduce infarct size after ischemia reperfusion (IR) injury through a mitochondrial protective mechanism. After global cardiac IR injury of ex vivo perfused Guinea pig hearts, we found the following: both agonists NS1619 (for BKCa) and DCEB (for SKCa) improved contractility; BKCa antagonist paxilline (PAX) alone or with SKCa antagonist NS8593 worsened contractility and enhanced infarct size; both antagonists PAX and NS8593 obliterated protection by their respective agonists; BKCa and SKCa antagonists did not block protection afforded by SKCa and BKCa agonists, respectively; and all protective effects by the agonists were blocked by scavenging superoxide anions (O2·−) with Mn(III) tetrakis (4-benzoic acid) porphyrin (TBAP). Contractile function was inversely associated with global infarct size. In in vivo rats, infusion of NS8593, PAX, or both antagonists enhanced regional infarct size while infusion of either NS1619 or DCEB reduced infarct size. In cardiac mitochondria isolated from ex vivo hearts after IR, combined SKCa and BKCa agonists improved respiratory control index and Ca2+ retention capacity compared with IR alone, whereas the combined antagonists did not alter respiratory control index but worsened Ca2+ retention capacity. Although the differential protective bioenergetics effects of endogenous or exogenous BKCa and SKCa channel opening remain unclear, each channel likely responds to different sensing Ca2+ concentrations and voltage gradients over time during oxidative stress-induced injury to individually or together protect cardiac mitochondria and myocytes.

Comments

Journal of Cardiovascular Pharmacology, Vol. 70, No. 5 (November 2017): 314-328. DOI.

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