The concomitant coronary vasodilator and positive inotropic actions of the nitroxyl donor Angeli's salt in the intact rat heart: contribution of soluble guanylyl cyclase-dependent and -independent mechanisms

被引:22
作者
Chin, Kai Yee [1 ,2 ]
Qin, Chengxue [1 ]
Cao, Nga [1 ]
Kemp-Harper, Barbara K. [3 ]
Woodman, Owen L. [2 ]
Ritchie, Rebecca H. [1 ,4 ]
机构
[1] Monash Univ, Baker IDI Heart & Diabet Inst, Melbourne, Vic 8008, Australia
[2] RMIT Univ, Sch Med Sci, Bundoora, Vic, Australia
[3] Monash Univ, Dept Pharmacol, Clayton, Vic 3168, Australia
[4] Monash Univ, Dept Med, Clayton, Vic, Australia
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;
关键词
cardiac relaxation; cGMP; nitroxyl; vasodilatation; ventricular function; NITRIC-OXIDE DONORS; S-NITROSYLATION; CONCISE GUIDE; IN-VIVO; ISOPROPYLAMINE-NONOATE; FAILING HEARTS; CARDIAC-MUSCLE; CYCLIC-GMP; NO; CARDIOMYOCYTES;
D O I
10.1111/bph.12568
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background and Purpose The NO redox sibling nitroxyl (HNO) elicits soluble guanylyl cyclase (sGC)-dependent vasodilatation. HNO has high reactivity with thiols, which is attributed with HNO-enhanced left ventricular (LV) function. Here, we tested the hypothesis that the concomitant vasodilatation and inotropic actions induced by a HNO donor, Angeli's salt (sodium trioxodinitrate), were sGC-dependent and sGC-independent respectively. Experimental Approach Haemodynamic responses to Angeli's salt (10 pmol-10 mu mol), alone and in the presence of scavengers of HNO (L-cysteine, 4 mM) or of NO [hydroxocobalamin (HXC), 100 mu M] or a selective inhibitor of sGC [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), 10 mu M], a CGRP receptor antagonist (CGRP(8-37), 0.1 mu M) or a blocker of voltage-dependent potassium channels [4-aminopyridine (4-AP), 1 mM] were determined in isolated hearts from male rats. Key Results Angeli's salt elicited concomitant, dose-dependent increases in coronary flow and LV systolic and diastolic function. Both L-cysteine and ODQ shifted (but did not abolish) the dose-response curve of each of these effects to the right, implying contributions from HNO and sGC in both the vasodilator and inotropic actions. In contrast, neither HXC, CGRP(8-37) nor 4-AP affected these actions. Conclusions and Implications Both vasodilator and inotropic actions of the HNO donor Angeli's salt were mediated in part by sGC-dependent mechanisms, representing the first evidence that sGC contributes to the inotropic and lusitropic action of HNO in the intact heart. Thus, HNO acutely enhances LV contraction and relaxation, while concomitantly unloading the heart, potentially beneficial actions in failing hearts.
引用
收藏
页码:1722 / 1734
页数:13
相关论文
共 71 条
[1]   THE CONCISE GUIDE TO PHARMACOLOGY 2013/14: ENZYMES [J].
Alexander, Stephen P. H. ;
Benson, Helen E. ;
Faccenda, Elena ;
Pawson, Adam J. ;
Sharman, Joanna L. ;
Spedding, Michael ;
Peters, John A. ;
Harmar, Anthony J. .
BRITISH JOURNAL OF PHARMACOLOGY, 2013, 170 (08) :1797-1867
[2]   THE CONCISE GUIDE TO PHARMACOLOGY 2013/14: ION CHANNELS [J].
Alexander, Stephen P. H. ;
Benson, Helen E. ;
Faccenda, Elena ;
Pawson, Adam J. ;
Sharman, Joanna L. ;
Catterall, William A. ;
Spedding, Michael ;
Peters, John A. ;
Harmar, Anthony J. .
BRITISH JOURNAL OF PHARMACOLOGY, 2013, 170 (08) :1607-1651
[3]   THE CONCISE GUIDE TO PHARMACOLOGY 2013/14: G PROTEIN-COUPLED RECEPTORS [J].
Alexander, Stephen P. H. ;
Benson, Helen E. ;
Faccenda, Elena ;
Pawson, Adam J. ;
Sharman, Joanna L. ;
Spedding, Michael ;
Peters, John A. ;
Harmar, Anthony J. .
BRITISH JOURNAL OF PHARMACOLOGY, 2013, 170 (08) :1459-1581
[4]   CONTROL OF CARDIAC-MUSCLE CELL-FUNCTION BY AN ENDOGENOUS NITRIC-OXIDE SIGNALING SYSTEM [J].
BALLIGAND, JL ;
KELLY, RA ;
MARSDEN, PA ;
SMITH, TW ;
MICHEL, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (01) :347-351
[5]   NITRIC-OXIDE ATTENUATES CARDIAC MYOCYTE CONTRACTION [J].
BRADY, AJB ;
WARREN, JB ;
POOLEWILSON, PA ;
WILLIAMS, TJ ;
HARDING, SE .
AMERICAN JOURNAL OF PHYSIOLOGY, 1993, 265 (01) :H176-H182
[6]   Vasorelaxant and antiaggregatory actions of the nitroxyl donor isopropylamine NONOate are maintained in hypercholesterolemia [J].
Bullen, Michelle L. ;
Miller, Alyson A. ;
Dharmarajah, Janahan ;
Drummond, Grant R. ;
Sobey, Christopher G. ;
Kemp-Harper, Barbara K. .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2011, 301 (04) :H1405-H1414
[7]   Nitric Oxide Synthases in Heart Failure [J].
Carnicer, Ricardo ;
Crabtree, Mark J. ;
Sivakumaran, Vidhya ;
Casadei, Barbara ;
Kass, David A. .
ANTIOXIDANTS & REDOX SIGNALING, 2013, 18 (09) :1078-1099
[8]   sGCα1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling [J].
Cawley, Sharon M. ;
Kolodziej, Starsha ;
Ichinose, Fumito ;
Brouckaert, Peter ;
Buys, Emmanuel S. ;
Bloch, Kenneth D. .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2011, 301 (01) :H157-H163
[9]   Comparison of responses to novel nitric oxide donors in the feline pulmonary vascular bed [J].
De Witt, BJ ;
Marrone, JR ;
Kaye, AD ;
Keefer, LK ;
Kadowitz, PJ .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2001, 430 (2-3) :311-315
[10]   Nitric oxide effects depend on different mechanisms in different regions of the rat heart [J].
Derici, Kursat ;
Samsar, Ufuk ;
Demirel-Yilmaz, Emine .
HEART AND VESSELS, 2012, 27 (01) :89-97