title: A non-cardiomyocyte autonomous mechanism of cardioprotection involving the SLO1 BK channel.
abstract: Opening of BK-type Ca(2+) activated K(+) channels protects the heart against ischemia-reperfusion (IR) injury. However, the location of BK channels responsible for cardioprotection is debated. Herein we confirmed that openers of the SLO1 BK channel, NS1619 and NS11021, were protective in a mouse perfused heart model of IR injury. As anticipated, deletion of the Slo1 gene blocked this protection. However, in an isolated cardiomyocyte model of IR injury, protection by NS1619 and NS11021 was insensitive to Slo1 deletion. These data suggest that protection in intact hearts occurs by a non-cardiomyocyte autonomous, SLO1-dependent, mechanism. In this regard, an in-situ assay of intrinsic cardiac neuronal function (tachycardic response to nicotine) revealed that NS1619 preserved cardiac neurons following IR injury. Furthermore, blockade of synaptic transmission by hexamethonium suppressed cardioprotection by NS1619 in intact hearts. These results suggest that opening SLO1 protects the heart during IR injury, via a mechanism that involves intrinsic cardiac neurons. Cardiac neuronal ion channels may be useful therapeutic targets for eliciting cardioprotection.
authors: Department of Medicine, University of Rochester Medical Center , Rochester, NY , USA.
authors: Andrew P
authors: AP
authors: Wojtovich
authors: Sergiy M
authors: SM
authors: Nadtochiy
authors: William R
authors: WR
authors: Urciuoli
authors: Charles O
authors: CO
authors: Smith
authors: Morten
authors: M
authors: Grunnet
authors: Keith
authors: K
authors: Nehrke
authors: Paul S
authors: PS
authors: Brookes
keywords: Cardiac neurons; Ischemia; Large conductance potassium channel; NS11021; NS1619; Preconditioning; Reperfusion
references: Pharmacol Rep. 2011;63(1):176-83
references: 21441626
references: J Physiol. 2012 Dec 1;590(23):5937-47
references: 22930268
references: Naunyn Schmiedebergs Arch Pharmacol. 2010 Mar;381(3):271-83
references: 19798481
references: PLoS One. 2011;6(12):e28287
references: 22145034
references: J Biol Chem. 2001 May 11;276(19):16232-9
references: 11278440
references: J Pharmacol Exp Ther. 2005 Feb;312(2):644-50
references: 15345753
references: Curr Pharm Des. 2011 Nov;17(34):3744-52
references: 22103845
references: Neuroscience. 2008 May 2;153(2):446-60
references: 18359571
references: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10072-7
references: 15226510
references: Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2070-7
references: 15217801
references: Heart Rhythm. 2011 Mar;8(3):448-54
references: 21075216
references: Peptides. 1996;17(6):1047-52
references: 8899826
references: Circ Res. 2010 Apr 16;106(7):1190-6
references: 20185796
references: Annu Rev Physiol. 2007;69:19-49
references: 17059356
references: Pflugers Arch. 1986 Apr;406(4):424-6
references: 2423954
references: Nat Rev Neurosci. 2006 Dec;7(12):921-31
references: 17115074
references: Science. 2002 Nov 1;298(5595):1029-33
references: 12411707
references: Annu Rev Physiol. 2007;69:51-67
references: 17007587
references: Cardiovasc Res. 2011 Feb 15;89(3):643-9
references: 20823277
references: Circ Res. 2004 Mar 5;94(4):420-32
references: 15001541
references: J Biol Chem. 2005 Sep 30;280(39):33599-609
references: 16081418
references: Biochem Pharmacol. 2003 Jun 1;65(11):1827-34
references: 12781334
references: Cardiovasc Res. 2008 Aug 1;79(3):377-86
references: 18456674
references: Nat Med. 2001 Apr;7(4):471-7
references: 11283675
references: Basic Res Cardiol. 2009 Mar;104(2):121-9
references: 19242645
references: Circulation. 2010 Aug 24;122(8):771-81
references: 20697027
references: J Interferon Cytokine Res. 2011 Jun;31(6):509-13
references: 21332365
references: Biochim Biophys Acta. 2009 May;1787(5):351-63
references: 19111672
references: Eur J Pharmacol. 2009 Sep 15;618(1-3):37-44
references: 19619521
references: Br J Pharmacol. 1996 Jan;117(1):119-29
references: 8825352
references: Am J Physiol Cell Physiol. 2010 Mar;298(3):C530-41
references: 20053924
references: PLoS One. 2010 Jan 14;5(1):e8698
references: 20090847
references: Anat Rec. 1994 May;239(1):75-87
references: 8037379
references: Pflugers Arch. 2009 Mar;457(5):979-88
references: 18762970
references: Biochem Biophys Res Commun. 2007 Oct 12;362(1):31-36
references: 17698036
references: Neuron. 1994 Dec;13(6):1315-30
references: 7993625
references: Cardiovasc Res. 1999 Jan;41(1):41-54
references: 10325952
references: Biochim Biophys Acta. 2010 Jan;1797(1):71-80
references: 19744465
references: Toxicol Mech Methods. 2004;14(1-2):59-61
references: 20021124
references: J Pharmacol Exp Ther. 2003 Sep;306(3):980-7
references: 12766260
references: Circulation. 2011 Feb 15;123(6):594-604
references: 21282498
references: J Mol Cell Cardiol. 2009 Jun;46(6):960-8
references: 19339206
references: J Pharmacol Exp Ther. 2007 Jun;321(3):1075-84
references: 17347326
references: Cardiovasc Res. 2000 Aug;47(2):367-75
references: 10946073
references: Int J Mol Sci. 2009 Mar;10(3):1104-20
references: 19399240
references: Am J Physiol. 1994 Apr;266(4 Pt 2):R1127-35
references: 8184954
references: J Neurosci Methods. 2007 Jan 30;159(2):244-51
references: 16959326
references: Neuron. 2001 Dec 6;32(5):867-81
references: 11738032
references: J Mol Cell Cardiol. 2009 Jun;46(6):858-66
references: 19118560
references: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5562-7
references: 10792058
references: Genomics. 1999 Jan 1;55(1):57-67
references: 9888999
references: Am J Physiol. 1996 Apr;270(4 Pt 2):R906-13
references: 8967421
references: Can J Cardiol. 1997 Mar;13(3):277-84
references: 9117916
references: Pflugers Arch. 2001 Feb;441(5):629-38
references: 11294244
references: Am J Physiol Cell Physiol. 2007 Jan;292(1):C148-56
references: 16870831
references: Am J Physiol. 1995 Feb;268(2 Pt 2):R403-13
references: 7864235
references: J Biol Chem. 2004 Aug 27;279(35):36746-52
references: 15184377
references: Cardiovasc Drugs Ther. 1997 Jan;10(6):657-65
references: 9110108
references: Biochim Biophys Acta. 2006 Feb;1762(2):202-12
references: 16026967
references: Mol Pharmacol. 2007 Oct;72(4):1033-44
references: 17636045
references: Biochim Biophys Acta. 2008 Jun;1777(6):540-8
references: 18471430
references: Biochem Biophys Res Commun. 1999 Apr 13;257(2):549-54
references: 10198249
references: Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1635-42
references: 16113069
references: J Biol Chem. 1998 Jul 17;273(29):18092-8
references: 9660766
references: Am J Physiol. 1997 Mar;272(3 Pt 2):R766-75
references: 9087638
references: Cardiovasc Res. 2007 Mar 1;73(4):720-8
references: 17208207