Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension

Pepke‐Zaba, Joanna; Higenbottam, T. W.; Dinh-Xuan, Anh Tuan; Stone, David L.; Wallwork, J.

doi:10.1016/0140-6736(91)92033-x

Cited by 964 publications

(216 citation statements)

References 10 publications

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“…Thus NO has more than 10 3 -fold stronger affinity for deoxy Hb than CO. However, several doses of 1-h inhalation of ϳ80 ppm NO have been successfully prescribed for clinical treatments of persistent pulmonary hypertension for the newborn and other pulmonary distress syndrome for the adult with no apparent adverse effect (34). Therefore, one must wonder why there have been neither observation nor report of NO poisoning.…”

Section: (L Is An Allosteric Parameter Defined As [T O ]/[R O ] Ormentioning

confidence: 99%

Electron Paramagnetic Resonance and Oxygen Binding Studies of α-Nitrosyl Hemoglobin

Yonetani

Tsuneshige

Zhou

et al. 1998

Journal of Biological Chemistry

135

110

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␣-Nitrosyl hemoglobin, ␣(Fe-NO) 2 ␤(Fe) 2 , which is frequently observed upon reaction of deoxy hemoglobin with limited quantities of NO in vitro as well as in vivo, has been synthetically prepared, and its reaction with O 2 has been investigation by EPR and thermodynamic equilibrium measurements. ␣-Nitrosyl hemoglobin is relatively stable under aerobic conditions and undergoes reversible O 2 binding at the heme sites of its ␤-subunits. Its O 2 binding is coupled to the structural/functional transition between T-(low affinity extreme) and R-(high affinity) states. This transition is linked to the reversible cleavage of the heme Fe-proximal His bonds in the ␣(Fe-NO) subunits and is sensitive to allosteric effectors, such as protons, 2,3-biphosphoglycerate, and inositol hexaphosphate. In fact, ␣(Fe-NO) 2 ␤(Fe) 2 is exceptionally sensitive to protons, as it exhibits a highly enhanced Bohr effect. The total Bohr effect of ␣-nitrosyl hemoglobin is comparable to that of normal hemoglobin, despite the fact that the oxygenation process involves only two ligation steps. All of these structural and functional evidences have been further confirmed by examining the reactivity of the sulfhydryl group of the Cys ␤93 toward 4,4-dipyridyl disulfide of several ␣-nitrosyl hemoglobin derivatives over a wide pH range, as a probe for quaternary structure. Despite the halved O 2 -carrying capacity, ␣-nitrosyl hemoglobin is fully functional (cooperative and allosterically sensitive) and could represent a versatile low affinity O 2 carrier with improved features that could deliver O 2 to tissues effectively even after NO is sequestered at the heme sites of the ␣-subunits. It is concluded that the NO bound to the heme sites of the ␣-subunits of hemoglobin acts as a negative allosteric effector of Hb and thus might play a role in O 2 /CO 2 transport in the blood under physiological conditions.

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Section: (L Is An Allosteric Parameter Defined As [T O ]/[R O ] Ormentioning

confidence: 99%

Electron Paramagnetic Resonance and Oxygen Binding Studies of α-Nitrosyl Hemoglobin

Yonetani

Tsuneshige

Zhou

et al. 1998

Journal of Biological Chemistry

135

110

View full text Add to dashboard Cite

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“…nates, infants, and adults with pulmonary hypertension or acute respiratory failure combined with pulmonary hypertension (12)(13)(14)(15)(16)(17)(18)(19). Inhaled NO improves ventilationlperfusion mismatch by selectively vasodilating pulmonary vessels of ventilated areas.…”

Section: Inhaled No Versus Pgi In Respiratory Failure 199mentioning

confidence: 99%

“…However, our results did not show any effect on Raw either during PGI, infusion or aerosol therapy. Inhaled NO has been demonstrated to be beneficial in adults with pulmonary hypertension (19) and ARDS (18), infants and children with ARDS (17) and pulmonary hypertension associated with congenital heart disease (33), and neonates with pulmonary hypertension (13). Inhaled NO has been shown to reverse acute pulmonary vasoconstriction induced by hypoxia, by a thromboxane analog, or by the heparin-protamin reaction (7,8).…”

Section: -I -mentioning

confidence: 99%

Inhaled Nitric Oxide versus Inhaled Prostacyclin and Intravenous versus Inhaled Prostacyclin in Acute Respiratory Failure with Pulmonary Hypertension in Piglets

et al. 1995

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This study was a prospective, randomized design to compare oxygenation and pulmonary hemodynamics between inhaled nitric oxide (NO) and inhaled prostacylcin (PGI,), and between inhaled and i.v. PGI, in acute respiratory failure with pulmonary hypertension. Acute respiratory failure with pulmonary hypertension was induced in 12 piglets weighing 9-12 kg by repeated lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. Thereafter the animals were randomly assigned either for NO or PGI, application. All animals were treated with different concentrations of NO or different doses of PGI, applied i.v. and inhaled in random order. Continuous monitoring included ECG, central venous pressure (CVP), mean pulmonary artery pressure (MPAP), mean arterial pressure (MAP), artertial oxygen saturation (SaO,), and mixed venous oxygen saturation (SvO,) measurements. NO inhalation of 10 ppm resulted in a significant increase in Pao,/fraction of inspired oxygen (FiO,) from 7.5 2 1.34 kPa to 46.1 2 9.7 kPa. MPAP decreased significantly from 5.1 -t 0.26 kPa to 3.7 i 0.26 kPa during inhaled NO of 40 ppm; i.v. infusion of PGI, slightly increased oxygenation parameters. A significant increase in Pao,/ FiO, up to 32.4 2 3.lkPa was observed during PGI, aerosol delivery (11 < 0.01); i.v. PGI, decreased MAP from 11.5 -+ 0.39 kPa to 9.8 2 0.66 kPa ( p < 0.05) and MPAP from 5.8 -+ 0.53 kPa to 4.5 2 0.66 kPa, respectively ( p < 0.05). PGI, aerosol delivery significantly decreased the MPAP to 3.7 2 0.53 kPa ( p < 0.05) without influencing the MAP. It was concluded that inhaled NO and inhaled PGI, act as selective pulmonary vasodilators in acute respiratory Cdilure with pulmonary hypertension In 1987 N O was reported to be an important endotheliumderived relaxing factor (1, 2). NO is synthesized in the vascular endothelial cell from L-arginine by NO synthase. It rapidly diffuses into the vascular smooth muscle cell and acts by stimulation of guanylate cyclase producing cGMP which me-

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“…Recent studies have demonstrated that nitric oxide inhalation produces selective pulmonary vasodilation without affecting systemic blood pressure in patients with PH. 5,6) However, since the safety of nitric oxide inhalation has not been established, 7) its doses have been restricted. Phosphodiesterases (PDEs) are enzymes, which break down cAMP and/or cGMP, and they play a key role in the regulation of intracellular cyclic nucleotide levels.…”

mentioning

confidence: 99%

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Inoue

Yano

Noto

et al. 2002

Biological & Pharmaceutical Bulletin

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Pulmonary hypertension (PH) is a fatal disease, characterized by the progressive elevation of pulmonary arterial resistance. Although the causes of this disorder are complicated, abnormal vasoconstriction appears to be a primary factor in the development of PH. 1,2) Although some kinds of vasodilators, such as calcium blockers and prostacyclin, have been used in the treatment of PH, 3,4) they cause several side effects due to systemic vasodilation. Recent studies have demonstrated that nitric oxide inhalation produces selective pulmonary vasodilation without affecting systemic blood pressure in patients with PH. 5,6) However, since the safety of nitric oxide inhalation has not been established, 7) its doses have been restricted. Phosphodiesterases (PDEs) are enzymes, which break down cAMP and/or cGMP, and they play a key role in the regulation of intracellular cyclic nucleotide levels. A phosphodiesterase type 5 (PDE5) is classified as cGMP-bind, cGMP-specific phosphodiesterase. 8,9) PDE5 is abundantly expressed in some specific tissues, including the lung and pulmonary artery.10-12) Therefore, the inhibition of PDE5 is considered to produce an increase in cGMP levels in the lung and pulmonary artery. It has been reported that PDE5 inhibitors such as zaprinast, E-4021 and sildenafil preferably dilate the pulmonary artery in vivo and in vitro experimental conditions. [13][14][15][16][17][18] T-1032 (methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate) is a novel inhibitor of PDE5 (IC 50 ϭ0.001 mM; canine lung). The selectivity for PDE5 over other PDEs in T-1032 is similar to that of sildenafil (IC 50 : PDE1; 3 mM, PDE2; 9.7 mM, PDE3; Ͼ100 mM, PDE4; 3.3 mM).19) T-1032 shows potentiating effects on the nitric oxide/cGMP signaling pathway in isolated rat aorta and rabbit corpus cavernosum. 20) In addition, an intraduodenal administration of T-1032 potentiates the penile tumescence induced by pelvic nerve stimulation, probably through the blockade of PDE5 in anesthetized dogs.21) These results suggest that T-1032 potentiates a nitric oxide/cGMP pathway inhibitor and is orally active compound in animal studies.The acute hemodynamic effects by PDE5 inhibitors on pulmonary circulation have been examined in animal models with PH. 13,15,18) However, only a few studies have reported whether the chronic treatment is effective for improving cardiac remodeling and its related death in an animal model with PH. 22) In this study, we first examined the hemodynamic properties of T-1032 in MCT-induced PH rats, and we next evaluated the chronic effect of T-1032 on cardiac remodeling and its related death in MCT-induced PH rats. MATERIAL AND METHODSThis study was approved by the Animal Research Committee of Tanabe Seiyaku Co., Ltd.Animal Preparation Monocrotaline (MCT, 70 mg/kg) was subcutaneously administered in male Wistar rats weighing 94-107 g, as described previously. 23)Acute Hemodynamic Effects in MCT Rats Twenty-six days after MCT (70 mg/kg) or vehicle...

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Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension

Cited by 964 publications

References 10 publications

Electron Paramagnetic Resonance and Oxygen Binding Studies of α-Nitrosyl Hemoglobin

Electron Paramagnetic Resonance and Oxygen Binding Studies of α-Nitrosyl Hemoglobin

Inhaled Nitric Oxide versus Inhaled Prostacyclin and Intravenous versus Inhaled Prostacyclin in Acute Respiratory Failure with Pulmonary Hypertension in Piglets

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

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