Faculty Collaboration Database

Endogenous and Agonist-induced Opening of Mitochondrial Big Versus Small Ca2+-sensitive K+ Channels on Cardiac Cell and Mitochondrial Protection. J Cardiovasc Pharmacol 2017 Nov;70(5):314-328

Date

08/05/2017

Pubmed ID

28777255

Pubmed Central ID

PMC5726766

DOI

10.1097/FJC.0000000000000524

Scopus ID

2-s2.0-85041528923 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

Both big (BKCa) and small (SKCa) conductance Ca-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 Ca retention capacity compared with IR alone, whereas the combined antagonists did not alter respiratory control index but worsened Ca 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 Ca concentrations and voltage gradients over time during oxidative stress-induced injury to individually or together protect cardiac mitochondria and myocytes.

Author List

Stowe DF, Yang M, Heisner JS, Camara AKS

Authors

Amadou K. Camara PhD Professor in the Anesthesiology department at Medical College of Wisconsin
David F. Stowe MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

1-Naphthylamine
Animals
Benzimidazoles
Cardiotonic Agents
Female
Guinea Pigs
Male
Mitochondria, Heart
Myocytes, Cardiac
Potassium Channels, Calcium-Activated
Rats
Rats, Sprague-Dawley