Positive inotropic and lusitropic effects of HNO/NO- in failing hearts:: Independence from β-adrenergic signaling

被引:273
作者
Paolocci, N
Katori, T
Champion, HC
St John, ME
Miranda, KM
Fukuto, JM
Wink, DA
Kass, DA
机构
[1] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21287 USA
[2] NCI, Radiat Biol Branch, Bethesda, MD 20892 USA
[3] Univ Calif Los Angeles, Dept Mol Pharmacol, Los Angeles, CA 90095 USA
关键词
nitroxyl; contractility; heart failure; nitric oxide; CGRP;
D O I
10.1073/pnas.0937302100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Nitroxyl anion (HNO/NO-), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO- augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts beta-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO- generated by Angelis' salt (AS) was infused (10 mug/kg per min, im.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)/NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed beta-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted beta-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO- cardiotropic action. Thus, HNO/NO- has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to beta-adrenergic stimulation and stimulates CGRIP release. This suggests potential of HNO/NO- donors for the treatment of heart failure.
引用
收藏
页码:5537 / 5542
页数:6
相关论文
共 43 条
[1]   Regulation of cardiac β-adrenergic response by nitric oxide [J].
Balligand, JL .
CARDIOVASCULAR RESEARCH, 1999, 43 (03) :607-620
[2]   Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms [J].
Barouch, LA ;
Harrison, RW ;
Skaf, MW ;
Rosas, GO ;
Cappola, TP ;
Kobeissi, ZA ;
Hobai, IA ;
Lemmon, CA ;
Burnett, AL ;
O'Rourke, B ;
Rodriguez, ER ;
Huang, PL ;
Lima, JAC ;
Berkowitz, DE ;
Hare, JM .
NATURE, 2002, 416 (6878) :337-340
[3]   The reduction potential of nitric oxide (NO) and its importance to NO biochemistry [J].
Bartberger, MD ;
Liu, W ;
Ford, E ;
Miranda, KM ;
Switzer, C ;
Fukuto, JM ;
Farmer, PJ ;
Wink, DA ;
Houk, KN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (17) :10958-10963
[4]   Chronic infusion of dobutamine and nitroprusside in patients with end-stage heart failure awaiting heart transplantation: safety and clinical outcome [J].
Capomolla, S ;
Febo, O ;
Opasich, C ;
Guazzottia, G ;
Caporotondi, A ;
La Rovere, MT ;
Gnemmi, M ;
Mortara, A ;
Vona, M ;
Pinna, GD ;
Maestri, R ;
Cobelli, F .
EUROPEAN JOURNAL OF HEART FAILURE, 2001, 3 (05) :601-610
[5]   Nitric oxide modulates myocardial oxygen consumption in the failing heart [J].
Chen, YJ ;
Traverse, JH ;
Du, RS ;
Hou, MX ;
Bache, RJ .
CIRCULATION, 2002, 106 (02) :273-279
[6]   Upregulation of functional β3-adrenergic receptor in the failing canine myocardium [J].
Cheng, HJ ;
Zhang, ZS ;
Onishi, K ;
Ukai, T ;
Sane, DC ;
Cheng, CP .
CIRCULATION RESEARCH, 2001, 89 (07) :599-606
[7]   ARTERIAL BAROREFLEX REGULATION OF BLOOD-PRESSURE IN PATIENTS WITH CONGESTIVE-HEART-FAILURE [J].
CREAGER, MA ;
CREAGER, SJ .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1994, 23 (02) :401-405
[8]   Increased myocardial expression of RAMP1 and RAMP3 in rats with chronic heart failure [J].
Cueille, C ;
Pidoux, E ;
de Vernejoul, MC ;
Ventura-Clapier, R ;
Garel, JM .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2002, 294 (02) :340-346
[9]   IMPROVED CARDIAC-PERFORMANCE WITH HUMAN CALCITONIN GENE RELATED PEPTIDE IN PATIENTS WITH CONGESTIVE HEART-FAILURE [J].
GENNARI, C ;
NAMI, R ;
AGNUSDEI, D ;
FISCHER, JA .
CARDIOVASCULAR RESEARCH, 1990, 24 (03) :239-241
[10]   Modulation of mouse cardiac function in vivo by eNOS and ANP [J].
Gyurko, R ;
Kuhlencordt, P ;
Fishman, MC ;
Huang, PL .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2000, 278 (03) :H971-H981