CARDIAC PRESERVATION IS ENHANCED IN A HETEROTOPIC RAT TRANSPLANT MODEL BY SUPPLEMENTING THE NITRIC-OXIDE PATHWAY

被引:132
作者
PINSKY, DJ
OZ, MC
KOGA, S
TAHA, Z
BROEKMAN, MJ
MARCUS, AJ
LIAO, H
NAKA, Y
BRETT, J
CANNON, PJ
NOWYGROD, R
MALINSKI, T
STERN, DM
机构
[1] COLUMBIA UNIV, DEPT MED, NEW YORK, NY 10032 USA
[2] COLUMBIA UNIV, DEPT SURG, NEW YORK, NY 10032 USA
[3] OAKLAND UNIV, DEPT CHEM, ROCHESTER, MI 48309 USA
[4] CORNELL UNIV, COLL MED, DEPT MED, NEW YORK, NY 10010 USA
[5] CORNELL UNIV, COLL MED, DEPT PATHOL, NEW YORK, NY 10010 USA
[6] DEPT VET AFFAIRS MED CTR, NEW YORK, NY 10010 USA
关键词
NITRIC OXIDE; CYCLIC GMP; CARDIAC; PRESERVATION; TRANSPLANTATION;
D O I
10.1172/JCI117230
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1 +/- 0.4 mu M for freshly explanted hearts to 0.7 +/- 0.2 and 0.2 +/- 0.08 mu M for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5'monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist N-G-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO. Augmentation of NO/cGMP-dependent mechanisms enhances vascular function after ischemia and reperfusion and provides a new strategy for transplantation of vascular organs.
引用
收藏
页码:2291 / 2297
页数:7
相关论文
共 38 条
[1]  
BABBS CF, 1991, AM J PATHOL, V139, P1069
[2]   PRINCIPLES OF SOLID-ORGAN PRESERVATION BY COLD-STORAGE [J].
BELZER, FO ;
SOUTHARD, JH .
TRANSPLANTATION, 1988, 45 (04) :673-676
[3]   DIMINISHED POLYMORPHONUCLEAR LEUKOCYTE ADHERENCE - FUNCTION DEPENDENT ON RELEASE OF CYCLIC-AMP BY ENDOTHELIAL-CELLS AFTER STIMULATION OF BETA-RECEPTORS BY EPINEPHRINE [J].
BOXER, LA ;
ALLEN, JM ;
BAEHNER, RL .
JOURNAL OF CLINICAL INVESTIGATION, 1980, 66 (02) :268-274
[4]  
BRITIGAN BE, 1992, BLOOD, V79, P699
[5]   INHIBITION OF HUMAN PLATELET REACTIVITY BY ENDOTHELIUM-DERIVED RELAXING FACTOR FROM HUMAN UMBILICAL VEIN ENDOTHELIAL-CELLS IN SUSPENSION - BLOCKADE OF AGGREGATION AND SECRETION BY AN ASPIRIN-INSENSITIVE MECHANISM [J].
BROEKMAN, MJ ;
EIROA, AM ;
MARCUS, AJ .
BLOOD, 1991, 78 (04) :1033-1040
[6]   COMPLEMENT AND NEUTROPHIL ACTIVATION IN THE PATHOGENESIS OF ISCHEMIC MYOCARDIAL INJURY [J].
CRAWFORD, MH ;
GROVER, FL ;
KOLB, WP ;
MCMAHAN, CA ;
OROURKE, RA ;
MCMANUS, LM ;
PINCKARD, RN .
CIRCULATION, 1988, 78 (06) :1449-1458
[7]   THE OBLIGATORY ROLE OF ENDOTHELIAL-CELLS IN THE RELAXATION OF ARTERIAL SMOOTH-MUSCLE BY ACETYLCHOLINE [J].
FURCHGOTT, RF ;
ZAWADZKI, JV .
NATURE, 1980, 288 (5789) :373-376
[8]   LUNG MYELOPEROXIDASE AS A MEASURE OF PULMONARY LEUKOSTASIS IN RABBITS [J].
GOLDBLUM, SE ;
WU, KM ;
JAY, M .
JOURNAL OF APPLIED PHYSIOLOGY, 1985, 59 (06) :1978-1985
[9]   EVALUATION OF NONRADIOACTIVE, COLORED MICROSPHERES FOR MEASUREMENT OF REGIONAL MYOCARDIAL BLOOD-FLOW IN DOGS [J].
HALE, SL ;
ALKER, KJ ;
KLONER, RA .
CIRCULATION, 1988, 78 (02) :428-434
[10]   ENDOTHELIUM-DERIVED RELAXING FACTOR PRODUCED AND RELEASED FROM ARTERY AND VEIN IS NITRIC-OXIDE [J].
IGNARRO, LJ ;
BUGA, GM ;
WOOD, KS ;
BYRNS, RE ;
CHAUDHURI, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (24) :9265-9269