Red blood cells but not platelets prolong vascular reactivity of isolated rat lungs

McMurtry, I. F.; Hookway, B. W.; Roos, S. D.

doi:10.1152/ajpheart.1978.234.2.h186

Cited by 15 publications

(17 citation statements)

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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%

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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Section: Hb No and The Pulmonary Circulationmentioning

confidence: 59%

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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“…Following pentobarbital anesthesia (30 mg/kg i.p.) the lungs were isolated as described (6,7). The lungs were ventilated with 21% 02-5% C02-74% N2 by positive pressure and perfused at constant flow (0.03 ml/g body wt) with heparinized blood that had been collected from three donor rats.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia Impairs Vasodilation in the Lung

Voelkel¹,

McMurtry²,

Reeves³

1981

J. Clin. Invest.

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A B S T R A C T Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxiainduced impairment of vasodilation after angiotensin II, bradykinin, or serotonin pressor responses. Progressive slowing of vasodilation followed angiotensin IIinduced constriction as the lung oxygen tension fell progressively below 60 Torr. KCI, which is not metabolized by the lung, caused vasoconstriction; the subsequent vasodilation time was delayed during hypoxia. However, catecholamine depletion in the lungs abolished this hypoxic vasodilation delay after KCIinduced vasoconstriction. In lungs from high altitude rats, the hypoxia-induced vasodilation impairment after an angiotensin II pressor response was markedly less than it was in lungs from low altitude rats. We conclude from these studies that (a) hypoxia impairs vasodilation of rat lung vessels following constriction induced by angiotensin II, serotonin, bradykinin, or KCI, (b) hypoxia slows vasodilation following KCIinduced vasoconstriction probably by altering lung handling of norepinephrine, (c) the effect of hypoxia on vasodilation is not dependent on its constricting effect on lung vessels, (d) high altitude acclimation moderates the effect of acute hypoxia on vasodilation, and (e) the hypoxic impairment of vasodilation is possibly the result of an altered rate of dissociation of agonists from their membrane receptors on the vascular smooth muscle.

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“…In addition to roles for endothelial and myogenic signaling in HPV (254,301), the influence of RBCs on pulmonary vascular tone has been recognized for some time (69,198). Most recently, work by several groups has established that sequestration of NO by RBCs (reactions 1 and 2) contributes importantly to HPV (58,61,287,302).…”

Section: Ventilation-perfusion Matching In the Lungmentioning

confidence: 99%

Nitric Oxide Transport in Blood: A Third Gas in the Respiratory Cycle

Doctor

Stamler

2011

Comprehensive Physiology

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The trapping, processing, and delivery of nitric oxide (NO) bioactivity by red blood cells (RBCs) have emerged as a conserved mechanism through which regional blood flow is linked to biochemical cues of perfusion sufficiency. We present here an expanded paradigm for the human respiratory cycle based on the coordinated transport of three gases: NO, O₂, and CO₂. By linking O₂ and NO flux, RBCs couple vessel caliber (and thus blood flow) to O₂ availability in the lung and to O₂ need in the periphery. The elements required for regulated O₂-based signal transduction via controlled NO processing within RBCs are presented herein, including S-nitrosothiol (SNO) synthesis by hemoglobin and O₂-regulated delivery of NO bioactivity (capture, activation, and delivery of NO groups at sites remote from NO synthesis by NO synthase). The role of NO transport in the respiratory cycle at molecular, microcirculatory, and system levels is reviewed. We elucidate the mechanism through which regulated NO transport in blood supports O₂ homeostasis, not only through adaptive regulation of regional systemic blood flow but also by optimizing ventilation-perfusion matching in the lung. Furthermore, we discuss the role of NO transport in the central control of breathing and in baroreceptor control of blood pressure, which subserve O₂ supply to tissue. Additionally, malfunctions of this transport and signaling system that are implicated in a wide array of human pathophysiologies are described. Understanding the (dys)function of NO processing in blood is a prerequisite for the development of novel therapies that target the vasoactive capacities of RBCs.

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Red blood cells but not platelets prolong vascular reactivity of isolated rat lungs

Cited by 15 publications

References 0 publications

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

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

Hypoxia Impairs Vasodilation in the Lung

Nitric Oxide Transport in Blood: A Third Gas in the Respiratory Cycle

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