Oral prostacyclin enhances the pulmonary vasodilatory effect of nitric oxide in children with pulmonary hypertension

1997 ◽  
Vol 7 (4) ◽  
pp. 362-369 ◽  
Author(s):  
Kei-ichiro Uese ◽  
Fukiko Ichida ◽  
Shin-ichi Tsubata ◽  
Ikuo Hashimoto ◽  
Yuji Hamamichi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Vascular Resistance ◽  
Cyclic Gmp ◽  
Venous Blood ◽  
Combined Treatment ◽  
Systemic Resistance ◽  
Pulmonary Vasodilation ◽  
Beraprost Sodium ◽  
Combined Administration

AbstractTo evaluate the potential efficacy of the combined administration of inhaled nitric oxide and oral beraprost sodium in producing pulmonary vasodilation, we studied 20 patients with pulmonary hypertension during cardiac catheterization. We also evaluated some of the mechanisms of vasodilation under these circumstances by investigating the levels of cyclic GMP and AMP in the pulmonary venous blood. A significant decrease in pulmonary vascular resistance was observed after the administration of nitric oxide (−37 ± 6%, p<0.01), and more intense decrease was observed after the combined administration of nitric oxide and beraprost sodium (−46 ± 6%, p<0.05). In addition, the ratio of pulmonary-to-systemic resistance also decreased to a greater extent with combined administration than with nitric oxide alone (−34 ± 6% vs −42 ± 7%, p<0.05). Conversely, systemic vascular resistance showed no change, neither after loading with nitric oxide nor after combined administration. Although equivalent increases in levels of cyclic GMP were observed after inhalation of nitric and the combined administration (mean 78% vs 65%), greater increases in levels of cyclic AMP were observed with the combined use (mean 15% vs 69%). Combined treatment with nitric oxide and beraprost sodium may prove markedly beneficial in patients with primary and postoperative pulmonary hypertension who do not respond adequately to inhalation of nitric oxide alone or conventional modes of treatment.

Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension

1998 ◽  
Vol 84 (2) ◽  
pp. 435-441 ◽  
Author(s):  
Christophe Adrie ◽  
Fumito Ichinose ◽  
Alexandra Holzmann ◽  
Larry Keefer ◽  
William E. Hurford ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Half Life ◽  
Hemodynamic Effects ◽  
Pulmonary Vasodilation ◽  
Short Half Life ◽  
Acute Pulmonary Hypertension ◽  
Inhaled No

Adrie, Christophe, Fumito Ichinose, Alexandra Holzmann, Larry Keefer, William E. Hurford, and Warren M. Zapol. Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension. J. Appl. Physiol. 84(2): 435–441, 1998.—Sodium 1-( N, N-diethylamino)diazen-1-ium-1,2-diolate {DEA/NO; Et2N[N(O)NO]Na} is a compound that spontaneously generates nitric oxide (NO). Because of its short half-life (2.1 min), we hypothesized that inhaling DEA/NO aerosol would selectively dilate the pulmonary circulation without decreasing systemic arterial pressure. We compared the pulmonary selectivity of this new NO donor with two other reference drugs: inhaled NO and inhaled sodium nitroprusside (SNP). In seven awake sheep with pulmonary hypertension induced by the infusion of U-46619, we compared the hemodynamic effects of DEA/NO with those of incremental doses of inhaled NO gas. In seven additional awake sheep, we examined the hemodynamic effects of incremental doses of inhaled nitroprusside (i.e., SNP). Inhaled NO gas selectively dilated the pulmonary vasculature. Inhaled DEA/NO produced nonselective vasodilation; both systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were reduced. Inhaled SNP selectively dilated the pulmonary circulation at low concentrations (≤10−2 M), inducing a decrease of PVR of up to 42% without any significant decrease of SVR (−5%), but nonselectively dilated the systemic circulation at larger doses (>10−2 M). In conclusion, despite its short half-life, DEA/NO is not a selective pulmonary vasodilator compared with inhaled NO. Inhaled SNP appears to be selective to the pulmonary circulation at low doses but not at higher levels.

Beneficial effect of an oral analog of prostacyclin on pulmonary hypertension secondary to congenital heart disease

1998 ◽  
Vol 8 (2) ◽  
pp. 205-210 ◽  
Author(s):  
Fukiko Ichida ◽  
Kei-ichiro Uese ◽  
Shin-ichi Tsubata ◽  
Ikuo Hashimoto ◽  
Yuji Hamamichi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Congenital Heart Disease ◽  
Pulmonary Hypertension ◽  
Heart Disease ◽  
Congenital Heart ◽  
Hemodynamic Effect ◽  
Pulmonary Vasodilation ◽  
Beraprost Sodium ◽  
Hypertension In Children ◽  
Appreciable Reduction

AbstractTo determine whether a newly synthesized oral analog of prostacyclin, called beraprost sodium, could cause pulmonary vasodilation, we studied its hemodynamic effect on pulmonary hypertension of children, comparing it to other vasodilatory agents, such as nitric oxide and tolazoline. We studied 20 children (mean age 24 months) having pulmonary hypertension secondary to congenital heart disease. A single oral dose of beraprost sodium resulted in an appreciable reduction of pulmonary vascular resistance (mean 34%), which was comparable to that induced by inhalation of nitric oxide and intravenous delivery of tolazoline (mean 41% and 31%, respectively). The results suggest that beraprost sodium may serve as a novel and safe vasodilator for the screening of pulmonary vasoreactivity, as well as the treatment of pulmonary hypertension in children.

scholarly journals Inhaled Nitric Oxide at Birth Reduces Pulmonary Vascular Resistance and Improves Oxygenation in Preterm Lambs

Children ◽  
2021 ◽  
Vol 8 (5) ◽  
pp. 378
Author(s):  
Satyan Lakshminrusimha ◽  
Sylvia F. Gugino ◽  
Krishnamurthy Sekar ◽  
Stephen Wedgwood ◽  
Carmon Koenigsknecht ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Preterm Infants ◽  
Vascular Resistance ◽  
Inhaled Nitric Oxide ◽  
Persistent Pulmonary Hypertension ◽  
Inhaled No ◽  
Birth Preterm

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147–150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

scholarly journals Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus

2009 ◽  
Vol 297 (2) ◽  
pp. L318-L325 ◽  
Author(s):  
Marc Chester ◽  
Pierre Tourneux ◽  
Greg Seedorf ◽  
Theresa R. Grover ◽  
Jason Gien ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Left Pulmonary Artery ◽  
Flow Transducer ◽  
Pulmonary Vasodilation

Impaired nitric oxide-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble guanylate cyclase (sGC) activity. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation, even in the presence of oxidized heme or heme-free sGC, but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on eight fetal (126 ± 2 days gestation) lambs (full term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery to measure blood flow, and a catheter was placed in the left pulmonary artery for drug infusion. Cinaciguat (0.1–100 μg over 10 min) caused dose-related increases in pulmonary blood flow greater than fourfold above baseline and reduced pulmonary vascular resistance by 80%. Treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an sGC-oxidizing inhibitor, enhanced cinaciguat-induced pulmonary vasodilation by >120%. The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing pulmonary vascular resistance for >1.5 h after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinaciguat after ODQ treatment resulted in a 14-fold increase in cGMP compared with non-ODQ-treated cells. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinaciguat may have therapeutic potential for severe neonatal pulmonary hypertension.

l-Arginine promotes angiogenesis in the chronically hypoxic lung: a novel mechanism ameliorating pulmonary hypertension

2009 ◽  
Vol 296 (6) ◽  
pp. L1042-L1050 ◽  
Author(s):  
K. Howell ◽  
C. M. Costello ◽  
M. Sands ◽  
I. Dooley ◽  
P. McLoughlin
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Vascular Resistance ◽  
Structural Changes ◽  
Lumen Diameter ◽  
Vascular Lumen ◽  
Arteriolar Resistance ◽  
Endogenous Nitric Oxide ◽  
Alveolar Hypoxia ◽  
Arginine Supplementation

Chronic alveolar hypoxia, whether due to residence at high altitude or lung disease, leads to a sustained increase in pulmonary vascular resistance and pulmonary hypertension (PH). Strategies that augment endogenous nitric oxide production or activity, including l-arginine supplementation, attenuate the development of PH. This action has been attributed to inhibition of vessel wall remodeling, thus preventing structural narrowing of the vascular lumen. However, more recent evidence suggests that structural changes are not responsible for the elevated vascular resistance observed in chronic hypoxic PH, calling into question the previous explanation for the action of l-arginine. We examined the effect of dietary l-arginine supplementation on pulmonary vasoconstriction, structurally determined maximum vascular lumen diameter, and vessel length in rats during 2 wk of exposure to hypoxia. l-Arginine attenuated the development of hypoxic PH by preventing increased arteriolar resistance. It did not alter mean maximal vascular lumen diameter, nor did it augment nitric oxide-mediated vasodilatation, in chronically hypoxic lungs. However, the total length of vessels within the gas exchange region of the hypoxic lungs was significantly increased after l-arginine supplementation. These findings suggest that dietary l-arginine ameliorated hypoxic PH, but not by an effect on the structurally determined lumen diameter of pulmonary blood vessels. l-Arginine enhanced angiogenesis in the hypoxic pulmonary circulation, which may attenuate hypoxic PH by producing new parallel vascular pathways through the lung.

Search for an animal model to investigate selective pulmonary vasodilation

2016 ◽  
Vol 51 (4) ◽  
pp. 376-387
Author(s):  
Bodil Petersen ◽  
Thilo Busch ◽  
Katharina Noreikat ◽  
Lorenz Homeister ◽  
Ralf Regenthal ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Animal Models ◽  
Vascular Tone ◽  
Acute Hypoxia ◽  
Haemodynamic Instability ◽  
Time Interval ◽  
Systemic Hypotension ◽  
Pulmonary Vasodilation ◽  
Selective Pulmonary Vasodilation

Pulmonary arterial hypertension is a life-threatening disease with a poor prognosis. Oral treatment with vasodilators is often limited by systemic hypotension. Inhalation of vasodilators offers the opportunity for selective pulmonary vasodilation. Testing selective pulmonary vasodilation by inhaled nitric oxide or alternative substances in animal models requires an increased pulmonary vascular tone. The aim of this study was to identify animal models that are suitable for investigating selective pulmonary vasodilation. To do so, a haemodynamic stable pulmonary hypertension was initiated, with a 30 min duration deemed to be a sufficient time interval before and after a possible intervention. In anaesthetized and mechanically-ventilated Sprague–Dawley rats pulmonary hypertension was induced either by acute hypoxia due to reduction of the inspired oxygen fraction from 0.21 to 0.1 ( n = 6), a fixed infusion rate of the thromboxane analogue U46619 (240 ng/min; n = 6) or a monocrotaline injection (MCT; 60 mg/kg applied 23 days before the investigation; n = 7). The animals were instrumented to measure right ventricular and systemic arterial pressures. Acute hypoxia caused a short, and only transient, increase of pulmonary artery pressure as well as profound systemic hypotension which suggested haemodynamic instability. U46619 infusion induced variable changes in the pulmonary and systemic vascular tone without sufficient stabilization within 30 min. MCT provoked sustained pulmonary hypertension with normal systemic pressure values and inhalation of nitric oxide caused selective pulmonary vasodilation. In conclusion, out of the three examined rat animal models only MCT-induced pulmonary hypertension is a solid and reliable model for investigating selective pulmonary vasodilation.

Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension

1999 ◽  
Vol 277 (5) ◽  
pp. H1849-H1856 ◽  
Author(s):  
Stephen M. Black ◽  
R. Scott Heidersbach ◽  
D. Michael McMullan ◽  
Janine M. Bekker ◽  
Michael J. Johengen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Inhaled Nitric Oxide ◽  
Protein Levels ◽  
Acute Withdrawal ◽  
Inhaled No

Life-threatening increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO), although the mechanisms remain unknown. In vitro data suggest that exogenous NO exposure inhibits endothelial NO synthase (NOS) activity. Thus the objectives of this study were to determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb. Six 1-mo-old lambs were mechanically ventilated and instrumented to measure vascular pressures and left pulmonary blood flow. Inhaled NO (40 ppm) acutely decreased left pulmonary vascular resistance by 27.5 ± 4.7% ( P < 0.05). This was associated with a 207% increase in plasma cGMP concentrations ( P < 0.05). After 6 h of inhaled NO, NOS activity was reduced to 44.3 ± 5.9% of pre-NO values ( P < 0.05). After acute withdrawal of NO, pulmonary vascular resistance increased by 52.1 ± 11.6% ( P < 0.05) and cGMP concentrations decreased. Both returned to pre-NO values within 60 min. One hour after NO withdrawal, NOS activity increased by 48.4 ± 19.1% to 70% of pre-NO values ( P < 0.05). Western blot analysis revealed that endothelial NOS protein levels remained unchanged throughout the study period. These data suggest a role for decreased endogenous NOS activity in the rebound pulmonary hypertension noted after acute withdrawal of inhaled NO.

Sildenafil for Pulmonary Hypertension

2005 ◽  
Vol 39 (5) ◽  
pp. 869-884 ◽  
Author(s):  
Audrey J Lee ◽  
Teresa B Chiao ◽  
Mildred P Tsang
Keyword(s):  
Nitric Oxide ◽  
Clinical Trials ◽  
Pulmonary Hypertension ◽  
Vascular Resistance ◽  
Resistance Index ◽  
Data Sources ◽  
Cochrane Library ◽  
Open Label ◽  
Vascular Effects ◽  
Double Blind

OBJECTIVE: To evaluate the efficacy of sildenafil for treatment of pulmonary hypertension. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1977–March 2005), Cochrane Library, and International Pharmaceutical Abstracts (1977–March 2005) using the terms sildenafil and pulmonary hypertension. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from the data sources were evaluated. Studies including >5 patients with primarily adult populations were included in the review. DATA SYNTHESIS: The treatment of pulmonary hypertension is challenging. Sildenafil has recently been studied as monotherapy and in combination with other vasodilators in the management of pulmonary hypertension. Eight hemodynamic studies and 12 clinical trials were reviewed (1 retrospective, 3 double-blind, 8 open-label). Sildenafil reduced pulmonary arterial hypertension and pulmonary vascular resistance/peripheral vascular resistance index and tended to increase cardiac output/cardiac index compared with baseline. Sildenafil was comparable to nitric oxide and at least as effective as iloprost or epoprostenol in terms of its pulmonary vasoreactivity. Combination therapy with iloprost, nitric oxide, or epoprostenol resulted in enhanced and prolonged pulmonary vascular effects. Clinical trials suggest that sildenafil improves exercise tolerance and New York Heart Association functional class, but large, randomized controlled trials are needed to confirm these findings. Overall, sildenafil was well tolerated. CONCLUSIONS: Overall, sildenafil is a promising and well-tolerated agent for management of pulmonary hypertension. Further well-designed trials are warranted to establish its place in the treatment of pulmonary hypertension.

Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension

2007 ◽  
Vol 292 (4) ◽  
pp. H1812-H1820 ◽  
Author(s):  
Girija G. Konduri ◽  
Ivane Bakhutashvili ◽  
Annie Eis ◽  
Kirkwood Pritchard
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Nitric Oxide Synthase ◽  
Pulmonary Artery ◽  
Ductus Arteriosus ◽  
Oxidant Stress ◽  
Pulmonary Arteries ◽  
Persistent Pulmonary Hypertension ◽  
Pulmonary Vasodilation ◽  
Oxide Synthase

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased NO release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O2•−) release by an uncoupled endothelial nitric oxide synthase (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to the NOS agonist ATP and the NO donor S-nitroso- N-acetylpenicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus and in sham-ligated controls in the presence or absence of the NOS antagonist nitro-l-arginine methyl ester (l-NAME) or the O2•− scavenger 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). ATP caused dose-dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. l-NAME, the NO precursor l-arginine, and Tiron restored the relaxation response of pulmonary artery rings to ATP in PPHN. Relaxation to NO was attenuated in arteries from PPHN lambs, and the response was improved by l-NAME and by Tiron. We also investigated the alteration in heat shock protein (HSP)90-eNOS interactions and release of NO and O2•− in response to ATP in the pulmonary artery endothelial cells (PAEC) from these lambs. Cultured PAEC and endothelium of freshly isolated pulmonary arteries from PPHN lambs released O2•− in response to ATP, and this was attenuated by the NOS antagonist l-NAME and superoxide dismutase (SOD). ATP stimulated HSP90-eNOS interactions in PAEC from control but not PPHN lambs. HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.

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