Hyporesponsiveness to inhaled nitric oxide in isolated, perfused lungs from endotoxin-challenged rats

被引:26
作者
Holzmann, A
Bloch, KD
Sanchez, LS
Filippov, G
Zapol, WM
机构
[1] HARVARD UNIV, MASSACHUSETTS GEN HOSP, SCH MED, DEPT ANESTHESIA, BOSTON, MA 02114 USA
[2] HARVARD UNIV, MASSACHUSETTS GEN HOSP, SCH MED, CARDIOVASC RES CTR, BOSTON, MA 02114 USA
关键词
nitric oxide; phosphodiesterases; lipopolysaccharide;
D O I
10.1152/ajplung.1996.271.6.L981
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in patients with the adult respiratory distress syndrome (ARDS). Approximately 30% of ARDS patients fail to respond to iNO. Because sepsis syndrome often accompanies a decreased response to iNO, we investigated NO responsiveness in isolated, perfused lungs from rats exposed to lipopolysaccharide (LPS). Eighteen hours after intraperitoneal injection of 0.5 mg/kg LPS, rat lungs were isolated, perfused, and preconstricted with U-46619. Ventilation with 0.4, 4, and 40 parts per million by volume NO vasodilated LPS-pretreated lungs 75, 47, and 42% less than control lungs (P < 0.01 value differs at each concentration). The diminished vasodilatory response to iNO was associated with decreased NO-stimulated guanosine 3',5'-cyclic monophosphate (cGMP) release into the perfusate. Soluble guanylate cyclase activity did not differ in lung extracts from LPS-pretreated and control rats. LPS increased pulmonary cGMP-phosphodiesterase (PDE) activity by 40%. The PDE-sensitive cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate vasodilated lungs from LPS-pretreated rats less than lungs from control rats. In contrast, the PDE-insensitive 8-para-chlorophenylthioguanosine 3',5'-cyclic monophosphate vasodilated lungs equally from both groups. After LPS challenge, the rat pulmonary vasculature becomes hyporesponsive to iNO. Hyporesponsiveness to iNO appears partly attributable to increased pulmonary cGMP-PDE activity.
引用
收藏
页码:L981 / L986
页数:6
相关论文
共 25 条
[1]  
AHN HS, 1991, ADV EXP MED BIOL, V308, P191
[2]   PROLONGED INHALATION OF LOW CONCENTRATIONS OF NITRIC-OXIDE IN PATIENTS WITH SEVERE ADULT-RESPIRATORY-DISTRESS-SYNDROME - EFFECTS ON PULMONARY HEMODYNAMICS AND OXYGENATION [J].
BIGATELLO, LM ;
HURFORD, WE ;
KACMAREK, RM ;
ROBERTS, JD ;
ZAPOL, WM .
ANESTHESIOLOGY, 1994, 80 (04) :761-770
[3]   ANALYSIS OF THE FUNCTIONAL-ROLE OF CGMP-DEPENDENT PROTEIN-KINASE IN INTACT HUMAN PLATELETS USING A SPECIFIC ACTIVATOR 8-PARA-CHLOROPHENYLTHIO-CGMP [J].
BUTT, E ;
NOLTE, C ;
SCHULZ, S ;
BELTMAN, J ;
BEAVO, JA ;
JASTORFF, B ;
WALTER, U .
BIOCHEMICAL PHARMACOLOGY, 1992, 43 (12) :2591-2600
[4]   CHRONIC HYPOXIA IMPAIRS SOLUBLE GUANYLYL CYCLASE-MEDIATED PULMONARY ARTERIAL RELAXATION IN THE RAT [J].
CRAWLEY, DE ;
ZHAO, L ;
GIEMBYCZ, MA ;
LIU, SF ;
BARNES, PJ ;
WINTER, RJD ;
EVANS, TW .
AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 263 (03) :L325-L332
[5]  
FRANCIS SH, 1988, METHOD ENZYMOL, V159, P722
[6]   INHALED NITRIC-OXIDE - A SELECTIVE PULMONARY VASODILATOR REVERSING HYPOXIC PULMONARY VASOCONSTRICTION [J].
FROSTELL, C ;
FRATACCI, MD ;
WAIN, JC ;
JONES, R ;
ZAPOL, WM .
CIRCULATION, 1991, 83 (06) :2038-2047
[7]   DYSFUNCTION OF CGMP-MEDIATED PULMONARY VASORELAXATION IN ENDOTOXIN-INDUCED ACUTE LUNG INJURY [J].
FULLERTON, DA ;
MCINTYRE, RC ;
HAHN, AR ;
AGRAFOJO, J ;
KOIKE, K ;
MENG, XZ ;
BANERJEE, A ;
HARKEN, AH .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 1995, 268 (06) :L1029-L1035
[8]  
HAMET P, 1989, J BIOL CHEM, V264, P12364
[9]   PROLONGED PULMONARY VASODILATOR ACTION OF INHALED NITRIC-OXIDE BY ZAPRINAST IN AWAKE LAMBS [J].
ICHINOSE, F ;
ADRIE, C ;
HURFORD, WE ;
ZAPOL, WM .
JOURNAL OF APPLIED PHYSIOLOGY, 1995, 78 (04) :1288-1295
[10]   TNF-ALPHA AUGMENTS PULMONARY VASOCONSTRICTION VIA THE INHIBITION OF NITROVASODILATOR ACTIVITY [J].
JOHNSON, A ;
FERRO, TJ .
JOURNAL OF APPLIED PHYSIOLOGY, 1992, 73 (06) :2483-2492