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Inhibition of Lung Phosphodiesterase Improves Responsiveness to Inhaled Nitric Oxide in Isolated-Perfused Lungs from Rats Challenged with Endotoxin

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Inhibition of Lung Phosphodiesterase Improves Responsiveness to Inhaled Nitric Oxide in Isolated-Perfused Lungs from Rats Challenged with Endotoxin Intensive Care Med (2001) 27: 251±257 DOI 10.1007/s001340000774 EXPERIMENTAL Alexandra Holzmann Inhibition of lung phosphodiesterase Claire Manktelow Jörg Weimann improves responsiveness to inhaled nitric Kenneth D.Bloch Warren M.Zapol oxide in isolated-perfused lungs from rats challenged with endotoxin Abstract Objectives: To investigate was also not improved. In contrast, Received: 10 March 2000 Final revision received: 27 September 2000 the ability of phosphodiesterase zaprinast (3.7, 7.4, 14.8 mM) aug- Accepted: 20 October 2000 (PDE) selective inhibitors to im- mented the pulmonary vasodilatory Published online: 15 December 2000 prove responsiveness to inhaled ni- effect of inhaled NO in lungs from Springer-Verlag 2000 tric oxide (NO) in isolated-perfused LPS-pretreated rats from lungs of rats pretreated with endo- 0.25 0.25, 0.5 0.25, toxin/lipopolysaccharide (LPS). 0.75 0.25 mmHg to 0.75 0.25, This study was supported by the Deutsche Forschungsgemeinschaft (DFG) grant Design and setting: Prospective, 1.5 0.5, 1.75 0.75 mmHg, respec- HO1651/1+2 (A.H.) and by United States controlled animal study in the ani- tively (p < 0.05). Public Health Service (USPHS) grants HL- mal research facility of a university Conclusions: Our results demon- 42397 (W.M.Z.) and HL-55377 (K.D.B.). hospital. strate that inhibition of pulmonary K.D.B. is an Established Investigator of Interventions: Sixteen hours after PDE enzyme activity with zaprinast the American Heart Association. Disclo- adult Sprague-Dawley rats were in- increases vasodilator responsiveness sure: The Massachusetts General Hospital has been granted patents on the inhalation jected intraperitoneally with 0.4 mg/ to inhaled NO in lungs obtained of nitric oxide, and the authors have a right kg E. coli 0111:B4 LPS administra- from rats 16 h after LPS challenge. to receive royalties. tion, lungs were isolated and perfus- ed, and the thromboxane mimetic Key words Nitric oxide ´ U46619 was employed to increase Hyporesponsiveness ´ the mean pulmonary artery pressure Phosphodiesterase ´ Isolated A.Holzmann by 5±7 mmHg. The lungs were then perfused lung Department of Anaesthesiology, ventilated with or without 0.4 ppm University of Heidelberg, NO, and erythro-9-(2-hydroxy-3- Im Neuenheimer Feld 100, 69120 Heidelberg, Germany nonyl) adenine (EHNA; PDE type 2 inhibitor), milrinone (PDE type 3 C.Manktelow ´ J.Weimann ´ W.M.Zapol inhibitor), or zaprinast (inhibitor of Department of Anaesthesia and Critical PDE types 5 and 9) were added to Care, Massachusetts General Hospital and the perfusate. Harvard Medical School, Fruit Street, Measurements and results: In the Boston, MA 02114, USA presence of EHNA (12.5, 25, 50 mM) K.D.Bloch ()) the vasodilator response to inhaled Cardiovascular Research Center, NO was not greater than in its ab- Massachusetts General Hospital and sence (0.25 0.25, 0.5 0.25, Harvard Medical School, Fruit Street, 0.75 0.25 mmHg vs. 0.25 0.25, Boston, MA 02114, USA 0.5 0.25, 0.75 0.25 mmHg, re- E-mail: [email protected]. harvard.edu spectively). In the presence of mil- Phone: +1-617-726 3030 rinone (125, 250, 500 nM), the va- Fax: +1-617-7263032 sodilator response to inhaled NO 252 Introduction In the mammalian lung at least six different isoforms of PDE metabolize cGMP, including PDE1 (calcium/ Inhalation of nitric oxide (NO) selectively dilates the calmodulin-activated PDE), PDE2 (cGMP-stimulated), pulmonary circulation and improves arterial oxygen- PDE3 (cGMP-inhibited), and PDE5 (cGMP-specific), ation in patients with adult respiratory distress syn- as well as the recently discovered isoforms PDE9 and drome (ARDS). In many ARDS patients minimal or PDE10 [5, 6, 7, 8] (Table 1). All of these isoforms with no pulmonary vasodilatory response to inhaled NO is the exception of PDE5 and PDE9 also promote the con- measured [1, 2, 3]. The precise mechanisms responsible version of 3¢,5¢-cyclic adenosine monophosphate for hyporesponsiveness to inhaled NO are unknown, (cAMP) to adenosine monophosphate (AMP) [7, 9]. but clinical evidence suggests that Gram-negative bacte- We examined whether cGMP-specific inhibition of remia and endotoxemia, the most common causes of PDE enzyme activity can augment the decrease in pul- ARDS, are associated with NO hyporesponsiveness. In monary vasodilation in response to NO after LPS chal- septic patients with ARDS, 60 % had little or no pulmo- lenge. We studied the effects of specific PDE inhibitors nary artery pressure reduction upon inhaling 18 or on pulmonary vasoreactivity after LPS challenge in the 36 ppm NO [2]. absence and presence of inhaled NO. We report here NO is a lipid-soluble free radical molecule with a that inhibition of pulmonary PDE enzyme activity by short half-life in biological fluids. In the presence of ox- zaprinast markedly improves vasodilator responsive- ygen, nitric oxide synthase (NOS) enzymes produce ness to inhaled NO after LPS exposure. NO via the conversion of the amino acid l-arginine to l-citrulline. In pulmonary vascular smooth muscle cells, NO stimulates soluble guanylate cyclase (sGC), Materials and methods an enzyme that promotes the conversion of GTP to 3¢, 5¢-cyclic guanosine monophosphate (cGMP). cGMP ac- These investigations were approved by the Subcommittee for Re- tivates cGMP-dependent protein kinases leading to de- search Animal Studies of the Massachusetts General Hospital, creased vascular smooth muscle tone. cGMP is metabo- Boston, Massachusetts. lized to guanosine monophosphate (GMP) by a family of enzymes called phosphodiesterases (PDEs). Isolated, perfused rat lungs We previously observed that in isolated, perfused, and ventilated lungs obtained from rats challenged Lungs obtained from rats were isolated, perfused, and ventilated as with endotoxin (lipopolysaccharide, LPS) the ability of described previously [4]. Briefly, adult Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass., USA) weighing inhaled NO to reduce an elevated pulmonary vascular 450±550 g were injected intraperitoneally with 0.4 mg/kg Escheri- tone is impaired [4]. Hyporesponsiveness to inhaled chia coli 0111:B4 lPS (Difco Laboratories Detroit, Mich., USA) NO is associated with a lower NO-induced cGMP re- and 16 h later were anesthetized by an intraperitoneal injection of lease rate into the perfusate than in lungs from unchal- sodium pentothal (100 mg/kg body wt.). Following a midline thora- lenged control rats. NO hyporesponsiveness is also asso- cotomy the rats were killed by blood withdrawal via puncture of ciated with an increased lung PDE activity. Moreover, the heart. Then pulmonary artery and left atrium were cannulated. Lungs were perfused with Hank's balanced salt solution containing perfusion with a PDE-resistant cGMP analog dilates 5% dextran, 5% bovine albumin, and 30 mM indomethacin, using preconstricted lungs obtained from LPS-treated rats to a roller pump (Cardiovascular Instrument, Wakefield, Mass., the same extent as the lungs from control rats. USA) at a pulsatile flow of 0.03 ml/g body wt./min in a recirculat- Table 1 Distribution of PDE isoforms that metabolize cGMP in the lung. At least six different cGMP-metabolizing PDE isoforms are expressed in lungs. Selective inhibitors for each of these isoforms are available PDE isoform Substrate Location Inhibited by PDE1 Ca/CaM-activated [23] (calcium- cGMP/cAMP [24] Lung, heart, brain, kidney [24] Vinpocetine, IBMX [25] and calmodulin-dependent) PDE2 cGMP-stimulated [15, 26] cGMP [26] Lung, heart, brain, kidney [26] EHNA [15] PDE3 cGMP-inhibited [27] cAMP > cGMP [27] Lung, heart, brain, liver, cGMP, milrinone, smooth muscle [28, 29] amrinone [27, 29] PDE5 cGMP-specific [30, 31] cGMP [30, 31] Lung, heart, liver, skeletal Zaprinast, dipyridamole, muscle, smooth muscle, sildenafil [22, 33] brain and other [32] PDE9 cGMP-specific [7, 14] cGMP [7, 14] Lung, kidney, spleen, brain, Zaprinast [7] liver [7, 14] PDE10 cAMP-inhibited cGMP/cAMP cAMP > cGMP [9, 34] Human fetal lung, thyroid, Dipyridamole [34] PDE [9, 34] brain, testis [34] 253 ing system at 37C. The perfusate was continuously equilibrated with 95% O2,5%CO2 in the presence of NaHCO3 to maintain pH at 7.35±7.40 as well as to maintain PCO2 (35±40 mmHg) and PO2 (150±250 mmHg). The pulmonary artery pressure (PAP) and left atrial pressure (set to 3±4 mmHg) were measured via a small catheter (PE-50) placed within the lumen of the inflow and outflow perfusion catheters, respectively. The time between death and per- fusion of the lungs was about 3±5 min. Dose-response curves of PDE inhibitors The PAP in the isolated-perfused lungs was increased 5± 7 mmHg by addition to the perfusate of the stable thromboxane mimetic U46619. The amount of U46619 used to increase and maintain PAP was 2.6 0.4 mg/min and 230 140 ng/min, respectively. Ery- thro-9-(2-hydroxy-3-nonyl) adenine (EHNA; 12.5, 25, 50 mM; n = 3), milrinone (125, 250, 500 nM; n = 3), or zaprinast (3.7, 7.4, 14.8 mM; n = 3) was added to the perfusate, and values are ex- pressed as final concentrations. First, for each PDE inhibitor dose-response curves were generated to assess the threshold doses at which pulmonary vasodilation occurred. After administration of each dose of the PDE inhibitor the PAP was allowed to stabilize for 5 min. Pulmonary vasoreactivity to inhaled NO in combination with PDE inhibitors Fig.1 EHNA, a PDE2 inhibitor, decreased the PAP of lungs ob- tained from LPS-treated rats alone and with inhaled NO. Isolat- NO was added to the inspired gas mixture at a low concentration of ed-perfused lungs from LPS-treated rats were preconstricted with 0.4 ppm which decreased the PAP of preconstricted lungs from U46619 PH) and EHNA was added to the perfusate in increasing LPS-challenged rats by 10±15%. NO gas was obtained from Airco doses in the absence open circles) and presence filled circles) of (Hingham, Mass., USA) as a mixture of 800 ppm NO in pure N2.
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