Methylene blue potentiates vascular reactivity in isolated rat lungs

Mazmanian, Guy-Michel; Baudet, Bruno; Brink, Charles; Cerrina, Jacques; Kirkiacharian, S; Weiss, Martin

doi:10.1152/jappl.1989.66.3.1040

Cited by 68 publications

(38 citation statements)

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“…Thus, if NO were continuously released, NOS blockade should raise Ppa, as it does in the systemic circulation. As described earlier, we and others found that NOS blockade did not raise Ppa in normoxic isolated perfused rat lungs (Mazmanian et al 1989;Archer et al 1990;Hasunuma et al 1991;Barer et al 1993). However, we found that it did raise Ppa during relatively mild hypoxia (7% Oµ ventilation; Barer et al 1993).…”

Section: Rat Lungssupporting

confidence: 79%

“…The circumstances which cause their release are not fully worked out and may differ with species. In isolated rat lungs perfused at constant flow, blockade of either NOS with the ¬_arginine analogues (Mazmanian et al 1989;Archer et al 1990;Hasunuma et al 1991;Barer et al 1993) or COX with sodium meclofenamate (Russell et al 1993) caused little or no rise in pulmonary artery pressure (Ppa); however, if the vasculature was in a state of vasoconstriction caused by vasoconstrictor agents or chronic exposure to hypoxia, ¬_NAME did cause a substantial rise in Ppa. These results suggest that, in these circumstances, there is no constant release of NO or dilator prostaglandins in the rat.…”

Section: Discussionmentioning

confidence: 99%

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Role of Nitric Oxide Synthase and Cyclooxygenase in Pulmonary Vascular Control in Isolated Perfused Lungs of Ferrets, Rats and Rabbits

Liu

Bee

Barer

1999

Experimental Physiology

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summaryDilator products of nitric oxide synthase (NOS) and cyclooxygenase (COX) may contribute to the low normal pulmonary artery pressure (Ppa). In isolated perfused lungs of ferrets, rabbits and rats we investigated this hypothesis by blockade of NOS with ¬_NAME (l-nitro-arginine methyl ester) and COX with meclofenamate. There were species differences. Inhibition of either enzyme caused little rise in Ppa in ferrets and rats but inhibition of both enzymes caused huge increases in Ppa. We suggest this might be due to intracellular connections between the excitatory pathways for NOS and COX dilators, such that inhibition of one enzyme leads to activation of the other. Impairment of these endothelial-based enzymes in pulmonary vascular disease might lead to severe pulmonary hypertension. By contrast, in rabbits, comparable doses of ¬_NAME lead to large rises in Ppa which were reversed rather than amplified by COX blockade. NO seems to protect against some pressorÏoedema forming product of COX in this species. introduction Nitric oxide synthase (NOS) and cyclooxygenase (COX) are present in pulmonary vascular endothelium and their dilator products nitric oxide (NO) and prostacyclin (PGIµ) contribute to pulmonary dilatation. The circumstances which cause their release are not fully worked out and may differ with species. In isolated rat lungs perfused at constant flow, blockade of either NOS with the ¬_arginine analogues (Mazmanian et al. 1989;Archer et al. 1990;Hasunuma et al. 1991;Barer et al. 1993) or COX with sodium meclofenamate (Russell et al. 1993) caused little or no rise in pulmonary artery pressure (Ppa); however, if the vasculature was in a state of vasoconstriction caused by vasoconstrictor agents or chronic exposure to hypoxia, ¬_NAME did cause a substantial rise in Ppa. These results suggest that, in these circumstances, there is no constant release of NO or dilator prostaglandins in the rat. Cremona et al. (1994) who used a similar preparation, also found that ¬_NAME did not alter pulmonary vascular resistance (PVR) during normoxia in dog lungs but raised it in the lungs of sheep, pigs and humans; in all four species, ¬_NAME raised pulmonary vascular resistance during hypoxic vasoconstriction (HPV). In rabbits, in vivo, Persson et al. (1990) and, in intact cats Hyman et al. McMahon et al. (1991) found that NOS blockade raised Ppa during normoxia. However, in conscious dogs, Nishiwaki et al. (1992) found no evidence that NO was released in the absence of experimental stimuli. The work of Barnard et al. (1993) suggested that either NOS or COX may be the predominant pulmonary dilator enzyme in different species. They used isolated lungs perfused at constant pressure and found that NOS but not COX

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Section: Rat Lungssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Role of Nitric Oxide Synthase and Cyclooxygenase in Pulmonary Vascular Control in Isolated Perfused Lungs of Ferrets, Rats and Rabbits

Liu

Bee

Barer

1999

Experimental Physiology

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“…[2][3][4][5]7,8,15,16 Recently, we verified that these effects were due to scavenging of NO by Hb, particularly when Hb is in the free form. 6 These findings are not surprising given the high affinity and rapid reaction rate of NO with Hb, and the inhibition of the vascular relaxant effect of NO by free Hb.…”

Section: Hb No and The Pulmonary Circulationmentioning

confidence: 59%

“…1 In the pulmonary circulation, this is manifest as increased pulmonary vascular resistance (PVR) and augmentation of hypoxic pulmonary vasoconstriction (HPV) by red blood cells (RBCs) and free Hb. [2][3][4][5][6][7][8] An additional reaction of NO with Hb is S-nitrosation at the ␤-cysteine 93 (␤-cys93) residue to form S-nitrosoHb (SNO-Hb). 9 This reaction is also reversible, particularly in the presence of low-molecular weight thiols such as glutathione (GSH), 9,10 and/or under the allosteric influence of deoxygenation.…”

mentioning

confidence: 99%

Effects of S-Nitrosation and Cross-Linking of Hemoglobin on Hypoxic Pulmonary Vasoconstriction in Isolated Rat Lungs

Deem

Kim

Manjula

et al. 2002

Circulation Research

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Abstract-Free hemoglobin (Hb) and red blood cells augment hypoxic pulmonary vasoconstriction (HPV) by scavenging nitric oxide (NO). S-nitrosation of Hb (SNO-Hb) may confer vasodilatory properties by allowing release of NO during deoxygenation and/or by interaction with small-molecular weight thiols. Likewise, cross-linking of free Hb may limit its vasoconstrictive effect by preventing abluminal movement of the molecule. We compared the effects of free SNO-Hb and Hb intramolecularly cross-linked at the ␤-cysteine 93 residue [Bis(maleidophenyl)-polyethylene glycol2000HbA (Bis-Mal-PEGHb)] to those of free oxyHb on pulmonary artery pressure (PAP), HPV, and exhaled NO (eNO) in isolated, perfused rat lungs. Ventilation of lungs with anoxic gas for 5 minutes reduced perfusate PO 2 to 11Ϯ1.0 Torr. Addition of SNO-Hb or Bis-Mal-PEGHb (100 mol/L) to buffer perfusate increased normoxic PAP and augmented HPV in similar magnitude as free oxyHb, but had no effect on eNO. Addition of the allosteric modulator inositol hexaphosphate to increase Hb P50 and the thiol glutathione (GSH) to allow removal of NO from Hb via transnitrosation to the perfusate did not reduce augmentation of HPV by SNO-Hb or increase eNO. GSH resulted in an Ϸ50% reduction in perfusate [S-nitrosothiol] T he rapid oxidation of nitric oxide (NO) by oxyhemoglobin (oxyHb) to form methemoglobin (metHb) and nitrate acts to limit the magnitude and duration of the vasorelaxant effects of NO. 1 In the pulmonary circulation, this is manifest as increased pulmonary vascular resistance (PVR) and augmentation of hypoxic pulmonary vasoconstriction (HPV) by red blood cells (RBCs) and free Hb. [2][3][4][5][6][7][8] An additional reaction of NO with Hb is S-nitrosation at the ␤-cysteine 93 (␤-cys93) residue to form S-nitrosoHb (SNO-Hb). 9 This reaction is also reversible, particularly in the presence of low-molecular weight thiols such as glutathione (GSH), 9,10 and/or under the allosteric influence of deoxygenation. 9,11,12 This dynamic, oxygen-linked property of SNO-Hb has led to the theory that Hb may act as a carrier of NO from the lung to the peripheral circulation, where it is released on deoxygenation of Hb. That free and intraerythrocytic SNO-Hb results in systemic and cerebral vasodilation supports this hypothesis. 9,11 Recently, we showed that free SNO-Hb is a potent a vasoconstrictor in the pulmonary circulation. 6 In addition, we were unable to demonstrate an allosteric effect of deoxygenation on NO release from SNO-Hb, although this observation was limited by the low P 50 of free SNO-Hb and the inability to reduce perfusate PO 2 below Ϸ38 Torr despite ventilation with anoxic gas in this model.In the present work, we again studied the effects of SNO-Hb on PVR and HPV. However, we expanded on our previous work by using a different animal model (isolated, perfused rat lungs), which allowed a reduction in the perfusate PO 2 to Ϸ10 Torr during anoxic ventilation, a level that should promote deoxygenation of SNO-Hb. In addition, we studied both lower and higher conce...

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“…vascular resistance (I-5), but some studies have found no change in pulmonary vascular resistance during basal conditions when the action of NO is inhibited (6,7). Similarly, the role of NO during the pulmonary vasoconstrictor response to hypoxia remains unclear, with studies suggesting hypoxia-induced inhibition of NO release (4, 8-1 1) or stimulation of NO release (5-7, 12, 13).…”

mentioning

confidence: 99%

The Effect of Nω-Nitro-L-Arginine Methylester on Hypoxic Vasoconstriction in the Neonatal Pig Lung

Nelin

Dawson

1993

Pediatr Res

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ABSTRACT. This study was carried out to determine the influence and site of action of Nu-nitro-L-arginine methylester, an L-arginine analogue, on basal pulmonary vascular tone and hypoxic vasoconstriction in neonatal pig lungs. We studied isolated lungs from pigs, age 14.5 2 0.5 (SD) d and weight 3.6 +: 0.7 kg, perfused with autologous blood a t a constant flow rate. The arterial-venous occlusion method was used to determine sites of action upstream and downstream of the double occlusion pressure (Pd) during baseline, infusion of acetylcholine, and ventilation of the lung with a hypoxic gas mixture. The measurements were then repeated during the three conditions described above after adding Nu-nitro-L-arginine methylester, a competitive inhibitor of nitric oxide synthase, to the blood. During control conditions, the vascular resistance was almost evenly divided upstream and downstream of Pd. Infusion of acetylcholine resulted in downstream dilation, and hypoxia resulted in an increase in both upstream and downstream resistance. After adding Nu-nitro-L-arginine methylester to the blood, there was an increase in both upstream and downstream resistances; acetylcholine infusion resulted in an increase in total vascular resistance, which was entirely due to upstream constriction; and the hypoxia response was much larger both upstream and downstream of Pd. These results suggest that nitric oxide synthase helped maintain a low level of basal pulmonary vascular tone both upstream and downstream of Pd in these neonatal pig lungs; that the vascular effect of acetylcholine was changed from downstream dilation to upstream constriction by Nu-nitro-L-arginine methylester; and that nitric oxide synthase activity modulated both the upstream and downstream vasomotor response to hypoxia. (Pediatr Res 34: 349-353,1993) Abbreviations Ach, acetylcholine NO, nitric oxide NAME, Nw-nitro-L-arginine methylester Pa, pulmonary artery pressure Pd, double occlusion pressure Pv, left atrial pressureThe release of NO from the endothelial cell has been implicated in the maintenance of the normally low resting pulmonary vascular resistance (I-5), but some studies have found no change in pulmonary vascular resistance during basal conditions when the action of NO is inhibited (6, 7). Similarly, the role of NO during the pulmonary vasoconstrictor response to hypoxia remains unclear, with studies suggesting hypoxia-induced inhibition of NO release (4, 8-1 1) or stimulation of NO release (5-7, 12, 13). There is currently no available information on how NO synthase inhibitors, such as NAME, influence the arterial venous distribution of pulmonary vascular resistance or the arterial venous site of action of pulmonary vasomotor stimuli. These questions are of particular importance in the neonate, where the pulmonary vasculature appears to be particularly reactive (14). Furthermore, recent studies (2, 15, 16) have suggested a role for NO in modulating pulmonary vascular resistance in the early neonatal period. Thus, the present study was designed to ...

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Methylene blue potentiates vascular reactivity in isolated rat lungs

Cited by 68 publications

References 0 publications

Role of Nitric Oxide Synthase and Cyclooxygenase in Pulmonary Vascular Control in Isolated Perfused Lungs of Ferrets, Rats and Rabbits

Role of Nitric Oxide Synthase and Cyclooxygenase in Pulmonary Vascular Control in Isolated Perfused Lungs of Ferrets, Rats and Rabbits

Effects of S-Nitrosation and Cross-Linking of Hemoglobin on Hypoxic Pulmonary Vasoconstriction in Isolated Rat Lungs

The Effect of Nω-Nitro-L-Arginine Methylester on Hypoxic Vasoconstriction in the Neonatal Pig Lung

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