Mechanism Of Hypoxic Pulmonary Vasoconstriction Research Articles

Pulmonary vascular diseases at high altitude - is it safe to live in the mountains?

This review addresses the concern of the health effects associated with high-altitude living and chronic hypoxia with a focus on pulmonary hypertension. With an increasing global population residing at high altitudes, understanding these effects is crucial for public health interventions and clinical management. Recent literature on the long-term effects of high-altitude residence and chronic hypoxia is comprehensively summarized. Key themes include the mechanisms of hypoxic pulmonary vasoconstriction, the development of pulmonary hypertension, and challenges in distinguishing altitude-related pulmonary hypertension and classical pulmonary vascular diseases, as found at a low altitude. The findings emphasize the need for research in high-altitude communities to unravel the risks of pulmonary hypertension and pulmonary vascular diseases. Clinically, early and tailored management for symptomatic individuals residing at high altitudes are crucial, as well as access to advanced therapies as proposed by guidelines for pulmonary vascular disease. Moreover, identifying gaps in knowledge underscores the necessity for continued research to improve understanding and clinical outcomes in high-altitude pulmonary vascular diseases.

Effects of Iloprost on Oxygenation during One-Lung Ventilation in Patients with Low Diffusing Capacity for Carbon Monoxide: A Randomized Controlled Study.

The protective mechanism of hypoxic pulmonary vasoconstriction during one-lung ventilation (OLV) is impaired in patients with a low diffusing capacity for carbon monoxide (DLCO). We hypothesized that iloprost inhalation would improve oxygenation and lung mechanics in patients with low DLCO who underwent pulmonary resection. Forty patients with a DLCO < 75% were enrolled. Patients were allocated into either an iloprost group (ILO group) or a control group (n = 20 each), in which iloprost and saline were inhaled, respectively. The partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio, pulmonary shunt fraction, alveolar dead space, dynamic compliance, and hemodynamic parameters were assessed 20 min after the initiation of OLV and 20 min after drug administration. Repeated variables were analyzed using a linear mixed model between the groups. Data from 39 patients were analyzed. After iloprost inhalation, the ILO group exhibited a significant increase in the PaO2/FiO2 ratio and a decrease in alveolar dead space compared with the control group (p = 0.025 and p = 0.042, respectively). Pulmonary shunt, dynamic compliance, hemodynamic parameters, and short-term prognosis were comparable between the two groups. Selective iloprost administration during OLV reduced alveolar dead space and improved oxygenation while minimally affecting hemodynamics and short-term prognosis.

Hypoxic pulmonary vasoconstriction as a regulator of alveolar-capillary oxygen flux: A computational model of ventilation-perfusion matching.

The relationship between regional variabilities in airflow (ventilation) and blood flow (perfusion) is a critical determinant of gas exchange efficiency in the lungs. Hypoxic pulmonary vasoconstriction is understood to be the primary active regulator of ventilation-perfusion matching, where upstream arterioles constrict to direct blood flow away from areas that have low oxygen supply. However, it is not understood how the integrated action of hypoxic pulmonary vasoconstriction affects oxygen transport at the system level. In this study we develop, and make functional predictions with a multi-scale multi-physics model of ventilation-perfusion matching governed by the mechanism of hypoxic pulmonary vasoconstriction. Our model consists of (a) morphometrically realistic 2D pulmonary vascular networks to the level of large arterioles and venules; (b) a tileable lumped-parameter model of vascular fluid and wall mechanics that accounts for the influence of alveolar pressure; (c) oxygen transport accounting for oxygen bound to hemoglobin and dissolved in plasma; and (d) a novel empirical model of hypoxic pulmonary vasoconstriction. Our model simulations predict that under the artificial test condition of a uniform ventilation distribution (1) hypoxic pulmonary vasoconstriction matches perfusion to ventilation; (2) hypoxic pulmonary vasoconstriction homogenizes regional alveolar-capillary oxygen flux; and (3) hypoxic pulmonary vasoconstriction increases whole-lobe oxygen uptake by improving ventilation-perfusion matching.

Revisiting the mechanism of hypoxic pulmonary vasoconstriction using isolated perfused/ventilated mouse lung.

Hypoxic Pulmonary Vasoconstriction (HPV) is an important physiological mechanism of the lungs that matches perfusion to ventilation thus maximizing O2 saturation of the venous blood within the lungs. This study emphasizes on principal pathways in the initiation and modulation of hypoxic pulmonary vasoconstriction with a primary focus on the role of Ca2+ signaling and Ca2+ influx pathways in hypoxic pulmonary vasoconstriction. We used an ex vivo model, isolated perfused/ventilated mouse lung to evaluate hypoxic pulmonary vasoconstriction. Alveolar hypoxia (utilizing a mini ventilator) rapidly and reversibly increased pulmonary arterial pressure due to hypoxic pulmonary vasoconstriction in the isolated perfused/ventilated lung. By applying specific inhibitors for different membrane receptors and ion channels through intrapulmonary perfusion solution in isolated lung, we were able to define the targeted receptors and channels that regulate hypoxic pulmonary vasoconstriction. We show that extracellular Ca2+ or Ca2+ influx through various Ca2+-permeable channels in the plasma membrane is required for hypoxic pulmonary vasoconstriction. Removal of extracellular Ca2+ abolished hypoxic pulmonary vasoconstriction, while blockade of L-type voltage-dependent Ca2+ channels (with nifedipine), non-selective cation channels (with 30 µM SKF-96365), and TRPC6/TRPV1 channels (with 1 µM SAR-7334 and 30 µM capsazepine, respectively) significantly and reversibly inhibited hypoxic pulmonary vasoconstriction. Furthermore, blockers of Ca2+-sensing receptors (by 30 µM NPS2143, an allosteric Ca2+-sensing receptors inhibitor) and Notch (by 30 µM DAPT, a γ-secretase inhibitor) also attenuated hypoxic pulmonary vasoconstriction. These data indicate that Ca2+ influx in pulmonary arterial smooth muscle cells through voltage-dependent, receptor-operated, and store-operated Ca2+ entry pathways all contribute to initiation of hypoxic pulmonary vasoconstriction. The extracellular Ca2+-mediated activation of Ca2+-sensing receptors and the cell–cell interaction via Notch ligands and receptors contribute to the regulation of hypoxic pulmonary vasoconstriction.

Dual role of the L-arginine-ADMA-NO pathway in systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction.

In healthy vascular endothelium, nitric oxide acts as a vasodilator paracrine mediator on adjacent smooth muscle cells. By activating soluble guanylyl cyclase, nitric oxide stimulates cyclic guanosine monophosphate (cGMP) which causes relaxation of vascular smooth muscle (vasodilation) and inhibition of platelet aggregation. This mechanism is active in both, the systemic and pulmonary circulation. In the systemic circulation, hypoxia results in local vasodilation, which has been shown to be brought about by stabilization of hypoxia-inducible factor-1α (HIF1α) and concomitant upregulation of endothelial nitric oxide synthase. By contrast, the physiological response to hypoxia in the pulmonary circulation is vasoconstriction. Hypoxia in the lung primarily results from hypoventilation of circumscript areas of the lung, e.g. by bronchial tree obstruction or inflammatory infiltration. Therefore, hypoxic pulmonary vasoconstriction is a mechanism preventing distribution of blood to hypoventilated areas of the lungs, thereby maintaining maximal oxygenation of blood. The exact molecular mechanism of hypoxic pulmonary vasoconstriction is less well understood than hypoxic vasodilation in the systemic circulation. While alveolar epithelial cells may be key in sensing low oxygen concentration, and pulmonary vascular smooth muscle cells obviously are the effectors of vasoconstriction, the pulmonary vascular endothelium plays a crucial role as an intermediate between these cell types. Indeed, dysfunctional endothelial nitric oxide release was observed in humans exposed to acute hypoxia, and animal studies suggest that hypoxic pulmonary vasoconstriction is enhanced by nitric oxide synthase inhibition. This may be caused, in part, by elevation of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthesis. High asymmetric dimethylarginine levels are associated with endothelial dysfunction, vascular disease, and hypertension.

Oxygen-sensing in the Lung is Regulated by Mitochondrial Complex I Ndufs2: Role of Mitochondria-derived Hydrogen Peroxide in Hypoxic Pulmonary Vasoconstriction

Resistance pulmonary arteries (PA) constrict in response to alveolar hypoxia; conversely the systemic vasculature dilates. Hypoxic pulmonary vasoconstriction (HPV) matches ventilation to perfusion, optimizing systemic oxygen delivery. The core mechanism of HPV is intrinsic to pulmonary artery smooth muscle cells (PASMC) and involves mitochondrial electron transport chain (ETC)-mediated redox regulation of oxygen-sensitive ion channels culminating in increased cytosolic calcium ([Ca2+]i). However, the molecular identity of the mitochondrial O2-sensor and the mechanism by which it regulates vascular tone remains unknown. We hypothesize that the O2-sensor resides in ETC complex I and initiates HPV by varying H2O2 in proportion to PO2. The primary objective was to identify the mitochondrial redox O2-sensor. A secondary goal was identify the ETC-derived reactive oxygen species (ROS) that initiates HPV. Mitochondria were isolated from lungs or kidneys of adult male Sprague-Dawley rats, housed under conditions of normoxia or chronic hypoxia (FiO2 0.1 for 2-3 weeks). Mitochondria-conditioned media (MCM) was then infused into an isolated, perfused lung to examine the effects on HPV. The effects of acute hypoxia on mitochondrial-derived H2O2 and [Ca2+]i was assessed in PASMC using with a dynamic, mitochondria-targeted H2O2 probe and FURA2-AM, respectively. Immunocaptured ETC complex I from pulmonary and renal arterial SMCs was assessed by gel electrophoresis to identify differentially expressed subunits. HPV was attenuated by MCM from normoxic lung (nLM), but not MCM from chronically hypoxic lung or kidney. Catalase attenuated the effects of nLM. Acute hypoxia (~40 mmHg) decreased H2O2 within 112±7 seconds, followed, within 205±34 seconds, by increased [Ca2+]i. The expression of a Complex I subunit, NADH dehydrogenase [ubiquinone] iron-sulfur protein 2 (Ndufs2), was increased in PA versus renal artery SMC. siRNA knockdown of Ndufs2 (siNdufs2) decreased normoxic H2O2 levels and prevented hypoxia-induced increases in [Ca2+]i. Right heart catheterization and intravital microscopy demonstrated that in vivo nebulization of siNdufs2 selectively attenuated HPV in rats and mice. Mitochondrial-derived H2O2 originating from ETC Complex I in PASMC acts as a normoxic vasodilator. Acute hypoxia decreases this vasodilator, leading to HPV. Ndufs2 is a requisite component of the PASMC’s mitochondrial O2-sensor, and acts through its dynamic ability to regulate H2O2 production.

Disappearance of Hypoxic Pulmonary Vasoconstriction and O2-Sensitive Nonselective Cationic Current in Arterial Myocytes of Rats Under Ambient Hypoxia

Acute hypoxia induces contraction of pulmonary artery (PA) to protect ventilation/perfusion mismatch in lungs. As for the cellular mechanism of hypoxic pulmonary vasoconstriction (HPV), hypoxic inhibition of voltage-gated K+ channel (Kv) in PA smooth muscle cell (PASMC) has been suggested. In addition, our recent study showed that thromboxane A2 (TXA2) and hypoxia-activated nonselective cation channel (INSC) is also essential for HPV. However, it is not well understood whether HPV is maintained in the animals exposed to ambient hypoxia for two days (2d-H). Specifically, the associated electrophysiological changes in PASMCs have not been studied. Here we investigate the effects of 2d-H on HPV in isolated ventilated/perfused lungs (V/P lungs) from rats. HPV was almost abolished without structural remodeling of PA in 2d-H rats, and the lost HPV was not recovered by Kv inhibitor, 4-aminopyridine. Patch clamp study showed that the hypoxic inhibition of Kv current in PASMC was similar between 2d-H and control. In contrast, hypoxia and TXA2-activated INSC was not observed in PASMCs of 2d-H. From above results, it is suggested that the decreased INSC might be the primary functional cause of HPV disappearance in the relatively early period (2 d) of hypoxia.

World Health Organization Group III pulmonary hypertension

Pulmonary hypertension in the setting of parenchymal lung disease and conditions associated with chronic hypoxemia is commonly encountered in clinical practice and may adversely affect patients’ function and mortality. Diagnosis of this subgroup of pulmonary hypertension has evolved but still requires right heart catheterization for confirmation. The primary treatment goal is optimization of the underlying parenchymal lung or hypoxemia-associated condition prior to consideration of pharmacologic therapy. Limited published experience with pulmonary hypertension-specific medications for treatment of WHO Group 3 pulmonary hypertension suggests symptomatic and functional benefit in selected individuals. The potential for worsening ventilation–perfusion matching must be considered in these cases, however, since there is a paucity of data regarding the optimal approach to treatment selection. Ongoing medication trials and further investigation of mechanisms of hypoxic pulmonary vasoconstriction provide hope for these patients who in the past often had only lung transplantation as a potential treatment option.

Selective glycolysis blockade in guinea pig pulmonary artery and aorta reverses contractile and electrical responses to acute hypoxia

The goal of this study was to clarify the mechanisms of hypoxic pulmonary vasoconstriction (HPV) reversal following selective glycolysis blockade and to assess possible contribution of endothelial electrogenesis to this phenomenon as a trigger mechanism.We compared smooth muscle (SM) contractility and endothelial cell (EC) membrane potential (MP) during acute hypoxia before and after glycolysis blockade. MPs were recorded from the endothelium of guinea pig pulmonary artery (GPPA) and thoracic aorta (GPTA) using the patch-clamp technique. Acute hypoxia caused hyperpolarization in GPTA EC, while EC from GPPA were depolarized. Also, acute hypoxia elicited constriction in isolated GPPA and dilatation in GPTA. Selective glycolysis inhibition always reversed both electrical and contractile responses in GPPA to hypoxia, but in GPTA this only occurred in 30% of experiments. It is likely that an unknown glycolysis-driven mechanism in EC mediates vascular tone regulation under hypoxia and underlies the paradoxical difference in the response of pulmonary and systemic arterial SM to hypoxia. Our data suggest that HPV development in GPPA might, at least partially, be driven by EC depolarization spreading to the underlying SM cells.

Activation of Glucose-6-phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction

Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to a decrease in airway O(2) tension, but the underlying mechanism is incompletely understood. We studied the contribution of glucose-6-phosphate dehydrogenase (Glc-6-PD), an important regulator of NADPH redox and production of reactive oxygen species, to the development of HPV. We found that hypoxia (95% N(2), 5% CO(2)) increased contraction of bovine pulmonary artery (PA) precontracted with KCl or serotonin. Depletion of extracellular glucose reduced NADPH, NADH, and HPV, substantiating the idea that glucose metabolism and Glc-6-PD play roles in the response of PA to hypoxia. Our data also show that inhibition of glycolysis and mitochondrial respiration (indicated by an increase in NAD(+) and decrease in the ATP-to-ADP ratio) by hypoxia, or by inhibitors of pyruvate dehydrogenase or electron transport chain complexes I or III, increased generation of reactive oxygen species, which in turn activated Glc-6-PD. Inhibition of Glc-6-PD decreased Ca(2+) sensitivity to the myofilaments and diminished Ca(2+)-independent and -dependent myosin light chain phosphorylation otherwise increased by hypoxia. Silencing Glc-6-PD expression in PA using a targeted small interfering RNA abolished HPV and decreased extracellular Ca(2+)-dependent PA contraction increased by hypoxia. Similarly, Glc-6-PD expression and activity were significantly reduced in lungs from Glc-6-PD(mut(-/-)) mice, and there was a corresponding reduction in HPV. Finally, regression analysis relating Glc-6-PD activity and the NADPH-to-NADP(+) ratio to the HPV response clearly indicated a positive linear relationship between Glc-6-PD activity and HPV. Based on these findings, we propose that Glc-6-PD and NADPH redox are crucially involved in the mechanism of HPV and, in turn, may play a key role in increasing pulmonary arterial pressure, which is involved in the development of pulmonary hypertension.

Activation of Glucose‐6‐Phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction

Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to a decrease in airway O2 tension, but the underlying mechanism is incompletely understood. We studied the contribution of glucose‐6‐phosphate dehydrogenase (G6PD), an important regulator of NADPH redox and production of reactive oxygen species, to the development of HPV. We found that hypoxia (95%N2‐5%CO2) increased contraction of bovine pulmonary artery (PA) precontracted with KCl or serotonin. Depletion of extracellular glucose reduced NADPH, NADH and HPV, substantiating the idea that glucose metabolism and G6PD play roles in the response of PA to hypoxia. Our data also show that inhibition of glycolysis and mitochondrial respiration (indicated by an increase in NAD+ and decrease in the ATP‐to‐ADP ratio) by hypoxia, or by inhibitors of pyruvate dehydrogenase or electron transport chain complexes I or III, increased generation of reactive oxygen species, which in turn activated G6PD. Silencing G6PD expression in PA using a targeted siRNA abolished HPV and diminished Ca2+‐independent and Ca2+‐dependent myosin light chain phosphorylation otherwise increased by hypoxia. Similarly, G6PD expression and activity were significantly reduced in lungs from G6PDmut(−/−) mice, and there was a corresponding reduction in HPV. Finally, regression analysis relating G6PD activity and the NADPH‐to‐NADP+ ratio to the HPV response clearly indicated a positive linear relationship between G6PD activity and HPV. Based on these findings, we propose that G6PD and NADPH redox are crucially involved in the mechanism of HPV and, in turn, may play a key role in increasing pulmonary arterial pressure, which is involved in the development of pulmonary hypertension. (Supported by NIH grant RO1HL085352)

Oxidant-Redox Regulation of Pulmonary Vascular Responses to Hypoxia and Nitric Oxide-cGMP Signaling

Most current theories for the mechanism of hypoxic pulmonary vasoconstriction (HPV) include a role for reactive oxygen species and/or changes in redox regulation, but extreme controversy exists regarding which systems and redox changes mediate the HPV response. Nitric oxide (NO) appears to help to maintain low pulmonary arterial pressure, suppress HPV, and prevent the development of pulmonary hypertension. Our studies have found a key role for glucose-6-phosphate dehydrogenase in bovine pulmonary arterial smooth muscle functioning to maintain elevated levels of cytosolic NADPH which fuels the generation of vasodilator levels of hydrogen peroxide. HPV results from hypoxia removing vasodilation by peroxide. Decreased superoxide generation by Nox4 oxidase and its conversion to peroxide by Cu,Zn-SOD appear to be potential factors in sensing hypoxia, and decreased cGMP-associated vasodilation and removal of redox controlled vasodilator mechanisms by increased cytosolic NADPH may be key coordinators of the HPV response. Oxidant generation associated with vascular disease processes, including the removal of NO by superoxide, and attenuation of its ability to stimulate cGMP production by oxidation of the heme and thiols of soluble guanylate cyclase attenuate potential beneficial actions of NO on pulmonary arterial function. While pulmonary hypertension appears to have multiple poorly understood effects on redox-associated processes, potentially influencing responses to hypoxia and NO-cGMP signaling, much remains to be elucidated regarding how these processes may be important factors in the progression, expression and therapeutic treatment of pulmonary hypertension.

Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem

Hypoxic pulmonary vasoconstriction (HPV) normally optimises ventilation-perfusion matching in the lung, but leads to pulmonary hypertension (PH) under conditions of global hypoxia. The past few years have provided some major advances in our understanding of this complex phenomenon, but significant controversy remains concerning many of the key underlying mechanisms. On balance, recent evidence is most consistent with an elevation in mitochondria-derived reactive oxygen species as a key event for initiation of HPV, with consequent Ca2+ release from intracellular ryanodine-sensitive stores, although the activation pathways and molecular identity of the associated Ca2+ entry pathways remain unclear. Recent studies have also raised our perception of the critical role played by Rho kinase (ROCK) in both sustained HPV and the development of PH, further promoting ROCK and the pathways regulating its activity and expression as important therapeutic targets.

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is a physiological response to alveolar hypoxia which distributes pulmonary capillary blood flow to alveolar areas of high oxygen partial pressure. Impairment of this mechanism may result in hypoxaemia. Under conditions of chronic hypoxia generalised vasoconstriction of the pulmonary vasculature in concert with hypoxia-induced vascular remodelling leads to pulmonary hypertension. Although the principle of HPV was recognised decades ago, its exact pathway still remains elusive. Neither the oxygen sensing process nor the exact pathway underlying HPV is fully deciphered yet. The effector pathway is suggested to include L-type calcium channels, nonspecific cation channels and voltage-dependent potassium channels, whereas mitochondria and nicotinamide adenine dinucleotide phosphate oxidases are discussed as oxygen sensors. Reactive oxygen species, redox couples and adenosine monophosphate-activated kinases are under investigation as mediators of hypoxic pulmonary vasoconstriction. Moreover, the role of calcium sensitisation, intracellular calcium stores and direction of change of reactive oxygen species is still under debate. In this context the present article focuses on the basic mechanisms of hypoxic pulmonary vasoconstriction and also outlines differences in current concepts that have been suggested for the regulation of hypoxic pulmonary vasoconstriction.

Mechanisms of oxygen sensing: a key to therapy of pulmonary hypertension and patent ductus arteriosus.

Specialized tissues that sense acute changes in the local oxygen tension include type 1 cells of the carotid body, neuroepithelial bodies in the lungs, and smooth muscle cells of the resistance pulmonary arteries and the ductus arteriosus (DA). Hypoxia inhibits outward potassium current in carotid body type 1 cells, leading to depolarization and calcium entry through L-type calcium channels. Increased intracellular calcium concentration ([Ca+ +]i) leads to exocytosis of neurotransmitters, thus stimulating the carotid sinus nerve and respiration. The same K+ channel inhibition occurs with hypoxia in pulmonary artery smooth muscle cells (PASMCs), causing contraction and providing part of the mechanism of hypoxic pulmonary vasoconstriction (HPV). In the SMCs of the DA, the mechanism works in reverse. It is the shift from hypoxia to normoxia that inhibits K+ channels and causes normoxic ductal contraction. In both PA and DA, the contraction is augmented by release of Ca+ + from the sarcoplasmic reticulum, entry of Ca+ + through store-operated channels (SOC) and by Ca+ + sensitization. The same three 'executive' mechanisms are partly responsible for idiopathic pulmonary arterial hypertension (IPAH). While vasoconstrictor mediators constrict both PA and DA and vasodilators dilate both vessels, only redox changes mimic oxygen by having directly opposite effects on the K+ channels, membrane potential, [Ca(++)]i and tone in the PA and DA. There are several different hypotheses as to how redox might alter tone, which remain to be resolved. However, understanding the mechanism will facilitate drug development for pulmonary hypertension and patent DA.

Oxygen sensors in hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism adapting lung perfusion to regional ventilation. Perturbations to HPV, such as those occurring in pneumonia, acute respiratory distress syndrome and liver failure, can result in arterial hypoxemia. Under conditions of general hypoxia, HPV increases pulmonary vascular resistance and thus causes acute pulmonary hypertension. Despite intensive research, the underlying mechanisms of HPV have not been fully elucidated. Deciphering signalling pathways that result in HPV could suggest novel approaches to address a failure of HPV, as well as for the treatment of pulmonary hypertension associated with HPV. Within this context, this review focuses on current concepts in the oxygen sensing mechanisms that underlie HPV.

An anesthesiologist's guide to hypoxic pulmonary vasoconstriction: implications for managing single-lung anesthesia and atelectasis

Hypoxic pulmonary vasoconstriction is the pulmonary circulation's homeostatic mechanism for matching regional perfusion to ventilation and optimizing systemic PaO2. The role of hypoxic pulmonary vasoconstriction in anesthesiology is reviewed. In hypoxic pulmonary vasoconstriction, airway hypoxia causes resistance pulmonary arteries to constrict, diverting blood to better-oxygenated alveoli. Hypoxic pulmonary vasoconstriction optimizes O2 uptake in atelectasis, pneumonia, asthma, and adult respiratory distress syndrome. During single-lung anesthesia, hypoxic pulmonary vasoconstriction helps maintain systemic oxygenation. When hypoxic pulmonary vasoconstriction is weak, systemic hypoxemia is exacerbated. Although not widely used, the peripheral chemoreceptor agonist almitrine enhances hypoxic pulmonary vasoconstriction and improves PaO2 during single-lung anesthesia. The mechanism of hypoxic pulmonary vasoconstriction involves a redox-based O2 sensor within pulmonary artery smooth muscle cells. Pulmonary artery smooth muscle cells mitochondria vary production of reactive O2 species in proportion to PaO2. Hypoxic withdrawal of these redox second messengers inhibits voltage-gated potassium channels, depolarizing the pulmonary artery smooth muscle cells. Depolarization activates L-type calcium channels, increasing cytosolic calcium and triggering hypoxic pulmonary vasoconstriction. An understanding of hypoxic pulmonary vasoconstriction is clinically relevant for anesthesiologists. Randomized clinical trials with robust endpoints are required to assess strategies for enhancing hypoxic pulmonary vasoconstriction in thoracic surgery patients.

Role of pentose phosphate pathway-derived NADPH in hypoxic pulmonary vasoconstriction

We have previously shown that pentose phosphate pathway (PPP) inhibitors, 6-aminonicotimade (6-AN) and epiandrosterone (EPI), markedly reduce hypoxic pulmonary vasoconstriction (HPV). Although it has been suggested that changes in the NADPH/NADP + ratio and redox status are involved in the mechanism of HPV, the role of PPP-derived NADPH in this phenomenon is not known. The aim of this study, therefore, was to investigate the role of PPP-derived NADPH in HPV using isolated rat pulmonary arteries (PA) and perfused rat lungs. The NADPH/NADP + ratio and NADPH levels in PA and lungs exposed to hypoxia increased 2-fold and 7-fold, respectively, compared to time-matched normoxic controls. Both hypoxia-induced increases in lung NADPH levels and lung perfusion pressure were inhibited by 6-AN (500 μM) or EPI (300 μM). The chemical inhibitors of PPP and hypoxia similarly decreased lung tissue NOx levels by approximately 50%. In contrast, hypoxia increased the lung soluble guanylate cyclase (sGC) activity (from 22.9±6.3 to 57.1±7.6 pmol/min/g), which was prevented by PPP inhibitors. ODQ, a sGC inhibitor, potentiated HPV. These results suggest that while PPP-derived NADPH may play a significant role in HPV, it may also moderate the magnitude of HPV through activation of the NO-sGC-cGMP vasodilation pathway.

HIGHLIGHTED TOPIC: Pulmonary Circulation and Hypoxia

In 1946, Ulf von Euler and Goran Liljestrand published revolutionary findings on the impact of hypoxia as a stimulant for vasoconstriction in the pulmonary circulation. More than 50 years later, exploring the mechanistic basis for this relationship is still a vital area of research. Among the many

Role of GS Proteins in Hypoxic Constriction of Sheep Pulmonary Artery Rings

The introduction of hypoxia is well known to cause contraction of pulmonary artery rings in vitro. Despite intensive studies, the cellular mechanisms of hypoxic pulmonary vasoconstriction are still not well defined. In this study, we aimed to determine the contribution of G_S proteins in hypoxia-induced vasoconstriction in large-diameter sheep pulmonary arteries using cholera toxin (CT). Hypoxia caused further contractions in serotonin but not in NaF-precontracted pulmonary artery rings. However, hypoxic vasoconstriction due to lowering of pO₂ from 97 to 5 mm Hg was totally abolished by preincubation with CT in serotonin-precontracted arteries. These preliminary results indicate that signal transduction mediated by G_s proteins may be an important mechanism in the hypoxic vasoconstriction of isolated pulmonary arteries of sheep.