Hypoxic pulmonary vasoconstriction

2007 ◽  
Vol 43 ◽  
pp. 61-76 ◽  
Author(s):  
A. Mark Evans
Keyword(s):  
Smooth Muscle ◽  
Cell Activation ◽  
Calcium Release ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Cell Types ◽  
Pulmonary Vasoconstriction ◽  
Alveolar Hypoxia ◽  
Different Cell Types

HPV (hypoxic pulmonary vasoconstriction) is the critical and distinguishing characteristic of the arteries that feed the lung. In marked contrast, systemic arteries dilate in response to hypoxia to meet the metabolic demands of the tissues they supply. Physiologically, HPV contributes to ventilation–perfusion matching in the lung by diverting blood flow to oxygen-rich areas. However, when alveolar hypoxia is global, as in diseases such as emphysema and cystic fibrosis, HPV leads to HPH (hypoxic pulmonary hypertension) and right heart failure. HPV is driven by the intrinsic response to hypoxia of two different cell types, namely the pulmonary arterial smooth muscle and endothelial cells. These are representatives of a group of specialized cells, commonly referred to as oxygen-sensing cells, which are defined by their acute sensitivity to relatively small changes in PO2 and have evolved to monitor oxygen supply and alter respiratory and circulatory function, as well as the capacity of the blood to transport oxygen. Upon exposure to hypoxia, mitochondrial oxidative phosphorylation is inhibited in all such cells and this, in part, mediates cell activation. In the case of pulmonary arteries, constriction is triggered via: (i) calcium release from the smooth muscle sarcoplasmic reticulum and consequent store-depletion-activated calcium entry into the smooth muscle cells and, (ii) the modulation of transmitter release from the pulmonary artery endothelium, which leads to further constriction of the smooth muscle by increasing the sensitivity of the contractile apparatus to calcium.

beta-Adrenergic mechanisms attenuated hypoxic pulmonary vasoconstriction during systemic hypoxia in cats

1994 ◽  
Vol 266 (5) ◽  
pp. H1777-H1785 ◽  
Author(s):  
M. Shirai ◽  
T. Shindo ◽  
I. Ninomiya
Keyword(s):  
Nervous System ◽  
Autonomic Nervous System ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Internal Diameter ◽  
Television System ◽  
Autonomic Nervous ◽  
Pulmonary Vasoconstriction ◽  
Alveolar Hypoxia

In this study, we examined how locally mediated hypoxic pulmonary vasoconstriction is modulated by autonomic nervous system activation during global alveolar hypoxia (GAH) accompanied by systemic hypoxemia. Using an X-ray television system on the in vivo cat lung, we measured changes in the internal diameter (ID) during GAH and regional alveolar hypoxia (RAH) without systemic hypoxemia in identical small pulmonary arteries and veins (100-600 microns ID). We also analyzed the effects of the autonomic nervous system blockade on the hypoxic ID changes. During GAH the ID of the arteries reduced by 5 +/- 1 and 3 +/- 1% with 10 and 5% O2 inhalations, respectively, whereas during RAH the arterial ID reduced by 12 +/- 1 and 18 +/- 1% with 10 and 5% O2 inhalations, respectively. The magnitude of the ID reduction was significantly smaller during GAH than during RAH. After pretreatment with propranolol, however, GAH induced large ID reductions (16 +/- 1 and 23 +/- 1% with 10 and 5% O2 inhalations) with patterns very similar to those seen during RAH. Phentolamine and atropine had no effect on the response during GAH. The ID reductions during RAH, on the other hand, were unaffected by all the blockers. The results indicate that, in the cat, alveolar hypoxia per se acts locally to constrict the small pulmonary vessels and that the hypoxic vasoconstriction is attenuated by a beta-receptor-mediated vasodilator effect during GAH with systemic hypoxemia. In addition, we found that, after adrenalectomy plus ganglion blockade with hexamethonium bromide, the GAH-induced ID reduction with 5% O2 inhalation was enhanced from 3 to 19%.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of the pulmonary vasoconstriction reaction to alveolar hypoxia in systemic high blood pressure

1989 ◽  
Vol 76 (6) ◽  
pp. 589-594 ◽  
Author(s):  
Maurizio D. Guazzi ◽  
Marco Berti ◽  
Elisabetta Doria ◽  
Cesare Fiorentini ◽  
Claudia Galli ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Arterial Pressure ◽  
High Blood Pressure ◽  
Pulmonary Arterial Pressure ◽  
Systemic Hypertension ◽  
Pulmonary Vasoconstriction ◽  
Arteriolar Resistance ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial

1. In systemic hypertension the pulmonary vessels show an excessive tone at rest and hyper-react to adrenoceptor stimulation. Alterations in Ca2+ handling by the vascular smooth muscle cells seem to underlie these disorders. Alveolar hypoxia also constricts pulmonary arteries, increasing the intracellular Ca2+ availability for smooth muscle contraction. This suggests the hypothesis that hypoxic pulmonary vasoconstriction depends on similar biochemical disorders, and that the response to the hypoxic stimulus may be emphasized in high blood pressure. 2. In 21 hypertensive and 10 normotensive men, pulmonary arterial pressure and arteriolar resistance have been evaluated during air respiration and after 15 min of breathing 17, 15 and 12% oxygen in nitrogen. Curves relating changes in pulmonary arterial pressure and arteriolar resistance to the oxygen content of inspired gas had a similar configuration in the two populations, but in hypertension were steeper and significantly shifted to the left of those in normotension, reflecting a lower threshold and an enhanced vasoconstrictor reactivity. 3. This pattern was not related to differences in severity of the hypoxic stimulus, degree of hypocapnia and respiratory alkalosis induced by hypoxia, and plasma catecholamines. 4. The association of high blood pressure with enhanced pulmonary vasoreactivity to alveolar hypoxia could have clinical implications in patients who are chronically hypoxic and have systemic hypertension.

Acute hypoxia increases intracellular [Ca2+] in pulmonary arterial smooth muscle by enhancing capacitative Ca2+ entry

2005 ◽  
Vol 288 (6) ◽  
pp. L1059-L1069 ◽  
Author(s):  
Jian Wang ◽  
Larissa A. Shimoda ◽  
Letitia Weigand ◽  
Wenqian Wang ◽  
Dejun Sun ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Primary Cultures ◽  
Fluorescent Microscopy ◽  
Pulmonary Arteries ◽  
Arterial Smooth Muscle ◽  
Fura 2 ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Hypoxic pulmonary vasoconstriction (HPV) requires influx of extracellular Ca2+ in pulmonary arterial smooth muscle cells (PASMCs). To determine whether capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCCs) contributes to this influx, we used fluorescent microscopy and the Ca2+-sensitive dye fura-2 to measure effects of 4% O2 on intracellular [Ca2+] ([Ca2+]i) and CCE in primary cultures of PASMCs from rat distal pulmonary arteries. In PASMCs perfused with Ca2+-free Krebs Ringer bicarbonate solution (KRBS) containing cyclopiazonic acid to deplete Ca2+ stores in sarcoplasmic reticulum and nifedipine to prevent Ca2+ entry through L-type voltage-operated Ca2+ channels (VOCCs), hypoxia markedly enhanced both the increase in [Ca2+]i caused by restoration of extracellular [Ca2+] and the rate at which extracellular Mn2+ quenched fura-2 fluorescence. These effects, as well as the increased [Ca2+]i caused by hypoxia in PASMCs perfused with normal salt solutions, were blocked by the SOCC antagonists SKF-96365, NiCl2, and LaCl3 at concentrations that inhibited CCE >80% but did not alter [Ca2+]i responses to 60 mM KCl. In contrast, the VOCC antagonist nifedipine inhibited [Ca2+]i responses to hypoxia by only 50% at concentrations that completely blocked responses to KCl. The increased [Ca2+]i caused by hypoxia was completely reversed by perfusion with Ca2+-free KRBS. LaCl3 increased basal [Ca2+]i during normoxia, indicating effects other than inhibition of SOCCs. Our results suggest that acute hypoxia enhances CCE through SOCCs in distal PASMCs, leading to depolarization, secondary activation of VOCCs, and increased [Ca2+]i. SOCCs and CCE may play important roles in HPV.

scholarly journals Impaired hypoxic pulmonary vasoconstriction in a mouse model of Leigh syndrome

2019 ◽  
Vol 316 (2) ◽  
pp. L391-L399 ◽  
Author(s):  
Grigorij Schleifer ◽  
Eizo Marutani ◽  
Michele Ferrari ◽  
Rohit Sharma ◽  
Owen Skinner ◽  
...  
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Inflammation ◽  
Leigh Syndrome ◽  
Arterial Oxygen ◽  
Inborn Errors ◽  
Pulmonary Vasoconstriction ◽  
Progressive Encephalopathy ◽  
Alveolar Hypoxia ◽  
The Impact ◽  
Deficient Mice

Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 ( Ndufs4−/−) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4−/− mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen during LMBO was lower in Ndufs4−/− and in piericidin A-treated Ndufs4+/+ mice than in respective controls. Impairment of HPV in Ndufs4−/− mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4-deficient mice, 3 wk of breathing 11% O2 restored HPV in response to LMBO. When compared with Ndufs4−/− mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV.

Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca2+ and nonselective cation channels

2005 ◽  
Vol 289 (1) ◽  
pp. L5-L13 ◽  
Author(s):  
Letitia Weigand ◽  
Joshua Foxson ◽  
Jian Wang ◽  
Larissa A. Shimoda ◽  
J. T. Sylvester
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Cation Channels ◽  
Pulmonary Vasoconstriction ◽  
Nonselective Cation Channels ◽  
Pressor Responses ◽  
Intracellular Ca ◽  
Pulmonary Arterial

Previous studies indicated that acute hypoxia increased intracellular Ca2+ concentration ([Ca2+]i), Ca2+ influx, and capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCC) in smooth muscle cells from distal pulmonary arteries (PASMC), which are thought to be a major locus of hypoxic pulmonary vasoconstriction (HPV). Moreover, these effects were blocked by Ca2+-free conditions and antagonists of SOCC and nonselective cation channels (NSCC). To test the hypothesis that in vivo HPV requires CCE, we measured the effects of SOCC/NSCC antagonists (SKF-96365, NiCl2, and LaCl3) on pulmonary arterial pressor responses to 2% O2 and high-KCl concentrations in isolated rat lungs. At concentrations that blocked CCE and [Ca2+]i responses to hypoxia in PASMC, SKF-96365 and NiCl2 prevented and reversed HPV but did not alter pressor responses to KCl. At 10 μM, LaCl3 had similar effects, but higher concentrations (30 and 100 μM) caused vasoconstriction during normoxia and potentiated HPV, indicating actions other than SOCC blockade. Ca2+-free perfusate and the voltage-operated Ca2+ channel (VOCC) antagonist nifedipine were potent inhibitors of pressor responses to both hypoxia and KCl. We conclude that HPV required influx of Ca2+ through both SOCC and VOCC. This dual requirement and virtual abolition of HPV by either SOCC or VOCC antagonists suggests that neither channel provided enough Ca2+ on its own to trigger PASMC contraction and/or that during hypoxia, SOCC-dependent depolarization caused secondary activation of VOCC.

Abstract 276: Heme Oxygenase-1 Induction Modulates Hypoxic Pulmonary Vasoconstriction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Mansoor Ahmad ◽  
Nader G Abraham ◽  
Michael S Wolin
Keyword(s):  
Organ Culture ◽  
Heme Oxygenase ◽  
Cobalt Chloride ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Heme Oxygenase 1 ◽  
Force Development ◽  
Pulmonary Vasoconstriction ◽  
Copper Chelator ◽  
Relaxing Effect

Endothelium removed Bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving lowering of superoxide-derived hydrogen peroxide and removing its basal relaxing effect. Induction of heme oxygenase-1 (HO-1) in BPA by 24 hr organ culture with 0.1mM cobalt chloride was accompanied by a decrease in 5μM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to 20mM KCl in BPA was not affected by HO-1, but hypoxic pulmonary vasoconstriction (HPV) was significantly reduced. Organ culture with a HO-1 inhibitor (10μM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Pretreatment of BPA with a copper chelator 10mM diethyldithiocarbamate (DETCA) to inactivate Cu,Zn-SOD, prevented the conversion of superoxide to peroxide, and attenuated HPV. DETCA treatment increased superoxide and decreased peroxide to similar levels in control and HO-1 induced BPA. Peroxide scavenging with 0.1mM ebselen increased force development to 20mM KCl and partially reversed the decrease in HPV seen on induction of HO-1. Thus HO-1 induction in BPA causes an increase in superoxide scavenging by Cu,Zn-SOD resulting in increased levels of peroxide, leading to an attenuation of HPV. The generation of superoxide in BPA is not affected by HO-1 induction as DETCA treated control and HO-1 BPA show similar levels of superoxide. Thus, HO-1 induction appears to attenuate HPV in BPA by increasing the conversion of superoxide to peroxide, leading to peroxide levels which may not be adequately lowered by hypoxia.

Hypoxic induction of Ca2+-dependent action potentials in small pulmonary arteries of the cat

1985 ◽  
Vol 59 (5) ◽  
pp. 1389-1393 ◽  
Author(s):  
D. R. Harder ◽  
J. A. Madden ◽  
C. Dawson
Keyword(s):  
Action Potentials ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Input Resistance ◽  
Potential Generation ◽  
Applied Current ◽  
Pulmonary Vasoconstriction ◽  
Ionic Conductances ◽  
The Relationship ◽  
K Permeability

Small pulmonary arteries (less than 300 micron) from cats were mounted in myographs to record mechanical and electrical responses to hypoxia. When these preparations were exposed to a PO2 of 30–50 Torr after equilibration at 300 Torr they consistently developed active force, which increased or decreased in amplitude as [Ca2+] was raised or lowered, respectively, and was blocked on addition of verapamil. Intracellular electrical recording with glass microelectrodes demonstrated membrane depolarization and action potential generation when PO2 was lowered. Steady-state voltage vs. applied current curves obtained before and during hypoxia showed a significant reduction in input resistance. The relationship between membrane potential and extracellular K+ was not different during hypoxia compared with control, suggesting that there were not marked changes in K+ permeability under this condition. In the presence of verapamil to block Ca2+ inward current the hypoxia-induced action potentials were abolished concomitant with partial membrane repolarization. The results of these studies suggest that in certain isolated pulmonary arteries hypoxia induces contraction by a mechanism involving an increased Ca2+ conductance. These data suggest that the sensor involved in hypoxic pulmonary vasoconstriction may lie within the vessel wall and somehow mediates changes in smooth muscle ionic conductances.

Pulmonary hypoxic vasoconstriction: not affected by chemical sympathectomy

1979 ◽  
Vol 46 (3) ◽  
pp. 529-533 ◽  
Author(s):  
C. A. Hales ◽  
D. M. Westphal
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Systemic Blood Pressure ◽  
Lung Perfusion ◽  
Chemical Sympathectomy ◽  
Test Lung ◽  
Systemic Blood ◽  
Pulmonary Vasoconstriction ◽  
Hypoxic Vasoconstriction ◽  
Alveolar Hypoxia ◽  
6 Hydroxydopamine

The influence of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) on regional alveolar hypoxic vasconstriction and on global hypoxic pulmonary vasoconstriction was investigated. In eight dogs a double-lumened endotracheal tube allowed ventilation of one lung with nitrogen as an alveolar hypoxic challenge while ventilation of the other lung with 100% O2 maintained adequate systemic oxygenation. Distribution of perfusion to the two lungs was determined with 133Xe and external counters. Mean perfusion to the test lung was 50.9 +/- 4.9% of total lung perfusion on room air and decreased by 32.4% (P smaller than 0.01) during alveolar hypoxia. Following 6-OHDA the test lung continued to reduce perfusion during alveolar hypoxia by 27.3%. In five dogs global hypoxia induced a 106% increase in pulmonary vascular resistance (PVR) prior to 6-OHDA and a 90% increase in PVR after 6-OHDA. After 6-OHDA no rise in PRV or systemic blood pressure occurred in response to tyramine, confirming effective sympathectomy by the 6-OHDA. Thus, sympathectomy with 6-OHDA failed to substantially block regional alveolar hypoxic vasoconstriction or global hypoxic pulmonary vasconstriction.

Effect of hypoxia on responses of respiratory smooth muscle to histamine and LTD4

1988 ◽  
Vol 64 (1) ◽  
pp. 435-440 ◽  
Author(s):  
N. A. Paterson ◽  
J. T. Hamilton ◽  
A. Yaghi ◽  
D. S. Miller
Keyword(s):  
Smooth Muscle ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Smooth Muscle Contraction ◽  
Base Line ◽  
Leukotriene D4 ◽  
Pulmonary Vasoconstriction ◽  
Voltage Dependent ◽  
Vascular Responsiveness ◽  
Porcine Pulmonary Artery ◽  
Parenchymal Lung

The aim of the present study was to compare the effect of reduced oxygenation on the contractions of pulmonary vascular and airway smooth muscle induced by leukotriene D4 (LTD4) with those induced by histamine (an agonist with similar mechanisms of smooth muscle contraction) and KCl (a voltage-dependent stimulus). During hypoxia (PO2: 40 +/- 4 Torr) the responses of isolated porcine pulmonary artery and vein spiral strips to LTD4 increased approximately three- and two-fold, respectively, and the vein also exhibited an augmented response to histamine. The augmentation was blunted (LTD4) or reversed (histamine) during anoxia (PO2: 0 +/- 2 Torr). Responses to KCl were not systematically altered by reduced oxygenation. In contrast, the contractions of the guinea pig parenchymal lung strip by all three agonists were generally suppressed by reduced oxygenation. After reoxygenation, the contractile responses of each of the three smooth muscle preparations were generally increased compared with previous and concurrent base-line observations, particularly the LTD4-induced pulmonary vein contraction that increased approximately sevenfold after reoxygenation after anoxia. The contribution (if any) of leukotrienes to hypoxic pulmonary vasoconstriction may reflect increased vascular responsiveness to leukotrienes during hypoxia as well as (or instead of) increased leukotriene release.

Development of the pulmonary vasculature in newborn lambs: structure-function relationships

1991 ◽  
Vol 70 (3) ◽  
pp. 1255-1264 ◽  
Author(s):  
R. P. Michel ◽  
J. B. Gordon ◽  
K. Chu
Keyword(s):  
Light Microscopy ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Venous Pressure ◽  
Pulmonary Arteries ◽  
Muscle Thickness ◽  
Pulmonary Vasculature ◽  
Pressure Gradients ◽  
Middle Segment ◽  
Pulmonary Vasoconstriction ◽  
Quantitative Light Microscopy

Our objectives were 1) to describe the quantitative light microscopy and ultrastructure of newborn lamb lungs and 2) to correlate hemodynamic changes during normoxia and hypoxia with the morphology. By light microscopy, we measured the percent muscle thickness (%MT) and peripheral muscularization of pulmonary arteries and veins from 25 lambs aged less than 24 h, 2-4 days, 2 wk, and 1 mo. At the same ages, lungs were isolated and perfused in situ and, after cyclooxygenase blockade with indomethacin, total, arterial (delta Pa), middle (delta Pm), and venous pressure gradients at inspired O2 fractions of 0.28 (mild hyperoxia) and 0.04 (hypoxia) were determined with inflow-outflow occlusion. During mild hyperoxia, delta Pa and delta Pm fell significantly between 2-4 days and 2 wk, whereas during hypoxia, only delta Pm fell. The %MT of all arteries (less than 50 to greater than 1,000 microns diam) decreased, and peripheral muscularization of less than 100-microns-diam arteries fell between less than 4 days and greater than 2 wk. Our data suggest that 1) the %MT of arteries determines normoxic pulmonary vascular resistance, because only arterial and middle segment resistance fell, 2) peripheral muscularization is a major determinant of hypoxic pulmonary vasoconstriction, because we observed a fall with age in peripheral muscularization of less than 100-micron-diam arteries and in delta Pm with hypoxia, and 3) the arterial limit of the middle segment defined by inflow-outflow occlusion lies in 100- to 1,000-microns-diam arteries.

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