Hypoxic Pulmonary Vasoconstriction

2012 ◽  
Vol 92 (1) ◽  
pp. 367-520 ◽  
Author(s):  
J. T. Sylvester ◽  
Larissa A. Shimoda ◽  
Philip I. Aaronson ◽  
Jeremy P. T. Ward
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vessels ◽  
Pulmonary Vasoconstriction ◽  
Neonatal Life ◽  
High Altitude Pulmonary Edema ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Isolated Lungs

It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophysiological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.

Hypoxic constriction of porcine distal pulmonary arteries: endothelium and endothelin dependence

2001 ◽  
Vol 280 (5) ◽  
pp. L856-L865 ◽  
Author(s):  
Q. Liu ◽  
J. S. K. Sham ◽  
L. A. Shimoda ◽  
J. T. Sylvester
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Bronchial Arteries ◽  
Pulmonary Vasoconstriction ◽  
Endothelial Denudation ◽  
Basal Release ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

To determine the role of endothelium in hypoxic pulmonary vasoconstriction (HPV), we measured vasomotor responses to hypoxia in isolated seventh-generation porcine pulmonary arteries < 300 μm in diameter with (E+) and without endothelium. In E+ pulmonary arteries, hypoxia decreased the vascular intraluminal diameter measured at a constant transmural pressure. These constrictions were complete in 30–40 min; maximum at Po 2 of 2 mmHg; half-maximal at Po 2 of 40 mmHg; blocked by exposure to Ca2+-free conditions, nifedipine, or ryanodine; and absent in E+ bronchial arteries of similar size. Hypoxic constrictions were unaltered by indomethacin, enhanced by indomethacin plus N G-nitro-l-arginine methyl ester, abolished by BQ-123 or endothelial denudation, and restored in endothelium-denuded pulmonary arteries pretreated with 10−10 M endothelin-1 (ET-1). Given previous demonstrations that hypoxia caused contractions in isolated pulmonary arterial myocytes and that ET-1 receptor antagonists inhibited HPV in intact animals, our results suggest that full in vivo expression of HPV requires basal release of ET-1 from the endothelium to facilitate mechanisms of hypoxic reactivity in pulmonary arterial smooth muscle.

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.

Desflurane Inhibits Hypoxic Pulmonary Vasoconstriction in Isolated Rabbit Lungs

1995 ◽  
Vol 83 (3) ◽  
pp. 552-556. ◽  
Author(s):  
Stephan A. Loer ◽  
Thomas W. L. Scheeren ◽  
Jorg Tarnow
Keyword(s):  
Minimum Alveolar Concentration ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Constant Flow ◽  
Inhibiting Effect ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Inspiratory Oxygen

Background Inhalational anesthetics inhibit hypoxic pulmonary vasoconstriction (HPV) in vivo and in vitro with a half-maximum inhibiting effect (ED50) within concentrations applied for general anesthesia. Because it is unknown whether desflurane acts likewise, we studied its effect on HPV in isolated blood-perfused rabbit lungs and compared its ED50 with that of halothane. Methods Isolated blood-perfused rabbit lungs were randomly allocated to treatment with either desflurane (n = 6) or halothane (n = 6). HPV, defined as an increase in pulmonary arterial pressure (PAP) at constant flow, was elicited by decreasing inspiratory oxygen concentration from 20% to 3% for 4 min. This effect was determined without (control HPV) and with increasing concentrations of the anesthetics (fraction of inspired carbon dioxide kept constant at 4.8 +/- 0.2%, perfusate temperature at 37 degrees C, and blood flow at 100 ml.min-1). Results Before exposure to the anesthetics, PAP increased by 8.6 +/- 1.9 cmH2O for all lungs within 4 min of hypoxia (control PAP for all lungs 19.6 +/- 2.5 cmH2O). Desflurane decreased this effect in a concentration-dependent fashion with an ED50 of 14.5%, compared with that of halothane, with an ED50 of 1.7%. Conclusions Assuming that 1 minimum alveolar concentration (MAC) values of desflurane and halothane for rabbits are 8.9% and 1.39%, respectively, this study yields ED50 values for the inhibition of HPV of approximately 1.6 MAC for desflurane and 1.2 MAC for halothane (P not statistically significant).

Effect of dehydroepiandrosterone on hypoxic pulmonary vasoconstriction: a Ca2+-activated K+-channel opener

1998 ◽  
Vol 274 (2) ◽  
pp. L186-L195 ◽  
Author(s):  
Imad S. Farrukh ◽  
Wei Peng ◽  
Urszula Orlinska ◽  
John R. Hoidal
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Mean Shift ◽  
Pulmonary Vasculature ◽  
K Channel ◽  
Initial Increase ◽  
Cyclic Monophosphate ◽  
Pulmonary Vasoconstriction ◽  
Channel Opener ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial

In the present study, we investigated the effects of the naturally occurring hormone dehydroepiandrosterone (DHEA) on hypoxic pulmonary vasoconstriction (HPVC) in isolated ferret lungs and on K+ currents in isolated and cultured ferret pulmonary arterial smooth muscle cells (FPSMCs). Severe alveolar hypoxia (3% O2-5% CO2-92% N2) caused an initial increase in pulmonary arterial pressure (Ppa) that was followed by a reversal in pulmonary hypertension. Maintaining alveolar hypoxia caused a sustained secondary increase in Ppa. Pretreating the lungs with the K+-channel inhibitor tetraethylammonium (TEA) caused a small increase in baseline Ppa, potentiated HPVC, and prevented the reversal of HPVC during the sustained alveolar hypoxia. Treating the lungs with DHEA caused a near-complete reversal of HPVC in control lungs and in lungs that were pretreated with TEA. DHEA also reversed the KCl-induced increase in Ppa. In FPSMCs, DHEA caused an adenosine 3′,5′-cyclic monophosphate- and guanosine 3′,5′-cyclic monophosphate-independent increase in activity of the Ca2+-activated K+(KCa) current. In a cell-attached configuration, DHEA caused a mean shift of −22 mV in the voltage-dependent activation of the KCa channel. We conclude that DHEA is a novel KCa-channel opener of the pulmonary vasculature.

scholarly journals Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs

2014 ◽  
Vol 116 (7) ◽  
pp. 715-723 ◽  
Author(s):  
Philipp A. Pickerodt ◽  
Roland C. Francis ◽  
Claudia Höhne ◽  
Friederike Neubert ◽  
Stella Telalbasic ◽  
...  
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Administration Routes ◽  
Pulmonary Vasodilation ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasoconstriction ◽  
Thiadiazole Ring ◽  
Pulmonary Arterial ◽  
Isolated Lungs ◽  
Spontaneously Breathing

Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg·kg−1·h−1); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg·kg−1·h−1); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg·kg−1·h−1). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn·s·cm−5 with hypoxia ( P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn·s·cm−5 during hypoxia. With MTZ and NMA, the MPAP rise (4 ± 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 ± 77 and 68 ± 82 dyn·s·cm−5 with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV.

Effects of indomethacin on estradiol-induced attenuation of hypoxic vasoconstriction in lamb lungs

1986 ◽  
Vol 61 (6) ◽  
pp. 2116-2121 ◽  
Author(s):  
J. B. Gordon ◽  
R. C. Wetzel ◽  
M. L. McGeady ◽  
N. F. Adkinson ◽  
J. T. Sylvester
Keyword(s):  
Steady State ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Response Relationship ◽  
Stimulus Response ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Vasodilator ◽  
Hypoxic Vasoconstriction ◽  
Pulmonary Arterial ◽  
Isolated Lungs

To determine whether cyclooxygenase products mediated the attenuation of hypoxic pulmonary vasoconstriction induced by estradiol, we measured pulmonary arterial pressure at a flow of 50 ml X min-1 X kg-1 (Ppa50) during steady-state exposures to inspired O2 tensions (PIO2) between 0 and 200 Torr in isolated lungs of juvenile ewes. Intramuscular estradiol (10 mg) 44–60 h before study significantly decreased perfusate concentrations of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of the pulmonary vasodilator, prostacyclin, but did not significantly affect the stimulus-response relationship between PIO2 and Ppa50. Estradiol (20 mg) 3–5 days before study increased 6-keto-PGF1 alpha concentrations and decreased Ppa50 at PIO2 of 10, 30, and 50 Torr. Indomethacin added to the perfusate of these lungs reduced 6-keto-PGF1 alpha to undetectable levels and altered the estradiol-induced attenuation, increasing Ppa50 at PIO2 of 10 and 30 Torr, but decreasing Ppa50 at PIO2 of 200 Torr. Despite these effects, Ppa50 remained lower than the values measured in lungs not treated with estradiol. These results suggest that the estradiol-induced attenuation of the hypoxic stimulus-response relationship was mediated only in part by cyclooxygenase products, the net effects of which were vasodilation at PIO2 of 10 and 30 Torr, but vasoconstriction at PIO2 of 200 Torr.

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)

TRPC6, a Therapeutic Target for Pulmonary Hypertension

2021 ◽  
Author(s):  
Pritesh P. Jain ◽  
Ning Lai ◽  
Mingmei Xiong ◽  
Jiyuan Chen ◽  
Aleksandra Babicheva ◽  
...  
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Vasoconstriction ◽  
Good Target ◽  
Trpc6 Channel ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Orally Bioavailable ◽  
Selective Blocker

Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Pulmonary vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and pulmonary arterial remodeling due to PASMC proliferation are causes for increased pulmonary vascular resistance in patients with PAH. We and others observed upregulation of TRPC6 channels in PASMC from patients with PAH. An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC triggers PASMC contraction and vasoconstriction, while Ca2+-dependent activation of PI3K/AKT/mTOR pathway is pivotal for cell proliferation and gene expression. Despite evidence supporting a pathological role of TRPC6, no selective and orally bioavailable TRPC6 blocker has yet been developed and tested for treatment of PAH. We sought to investigate whether block of receptor-operated Ca2+ channels or TRPC6 can reverse established PH in mice via inhibiting Ca2+-dependent activation of AKT/mTOR signaling. Here we report that intrapulmonary application of 2-aminoethyl diphenyl borniate (2-APB), a non-selective blocker of cation channels or BI-749237, a selective blocker of TRPC6, significantly and reversibly inhibited acute hypoxic pulmonary vasoconstriction. Intraperitoneal injection of 2-APB significantly attenuated the development of PH and partially reversed established PH. Oral gavage of the selective TRPC6 blocker BI-749237 reversed established PH by 50% via regression of pulmonary vascular remodeling. Furthermore, 2-APB and BI-749237 both inhibited PDGF- and serum-mediated phosphorylation of AKT and mTOR in PASMC. These results indicates that the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH. BI-749237, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH.

Garlic prevents hypoxic pulmonary hypertension in rats

1998 ◽  
Vol 275 (2) ◽  
pp. L283-L287 ◽  
Author(s):  
Michael B. Fallon ◽  
Gary A. Abrams ◽  
Tarek T. Abdel-Razek ◽  
Jun Dai ◽  
Shi-Juan Chen ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Control Group ◽  
Nitric Oxide Synthase Inhibitor ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor

Hypoxic pulmonary vasoconstriction underlies the development of high-altitude pulmonary edema. Anecdotal observations suggest a beneficial effect of garlic in preventing high-altitude symptoms. To determine whether garlic influences pulmonary vasoconstriction, we assessed the effect of garlic on pulmonary pressures in rats subjected to alveolar hypoxia and on vasoconstriction in isolated pulmonary arterial rings. Garlic gavage (100 mg/kg body wt) for 5 days resulted in complete inhibition of acute hypoxic pulmonary vasoconstriction compared with the control group. No difference in mean arterial pressure or heart rate response to hypoxia was seen between the groups. Garlic solution resulted in a significant dose-dependent vasorelaxation in both endothelium-intact and mechanically endothelium-disrupted pulmonary arterial rings. The administration of N G-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor) inhibited the vasodilatory effect of garlic by 80%. These studies document that garlic blocks hypoxic pulmonary hypertension in vivo and demonstrate a combination of endothelium-dependent and -independent mechanisms for the effect in pulmonary arterial rings.

A distensible vessel model applied to hypoxic pulmonary vasoconstriction in the neonatal pig

1993 ◽  
Vol 74 (5) ◽  
pp. 2049-2056 ◽  
Author(s):  
L. D. Nelin ◽  
G. S. Krenz ◽  
D. A. Rickaby ◽  
J. H. Linehan ◽  
C. A. Dawson
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Autologous Blood ◽  
Vessel Diameter ◽  
Flow Data ◽  
Neonatal Pigs ◽  
Pulmonary Vasoconstriction ◽  
Resistance Vessels ◽  
Torr Pressure ◽  
Pulmonary Arterial ◽  
Isolated Lungs

Recently, we presented a simple two-parameter distensible vessel model as a potential tool for characterizing pulmonary vascular pressure vs. flow curves under zone 3 conditions (Linehan et al. J. Appl. Physiol. 73: 987–994, 1992). One parameter, alpha, represents the distensibility of the resistance vessels as the fractional change in vessel diameter per Torr change in pressure, and the other parameter, R0, represents the vascular resistance that would exist if the resistance vessels were at their respective diameters obtained if the vascular pressure were zero. The objective of the present study was to determine whether this distensible vessel model was capable of describing the pressure vs. flow data obtained during hypoxia vasoconstriction and under control conditions in isolated lungs from neonatal pigs. The piglet lungs were perfused with autologous blood, and the pulmonary arterial pressure was measured over a range of flow rates from 15 to 250 ml.min-1 x kg-1 at constant left atrial (3 Torr) pressure. The model provided a reasonable fit to the data under both conditions. Hypoxia resulted in a significant increase in R0, from 0.39 +/- 0.10 Torr.ml-1 x min.kg during control conditions to 1.41 +/- 0.46 Torr.ml-1 x min.kg during hypoxia. alpha was 2.4 +/- 0.4%/Torr under control conditions and 2.0 +/- 0.4%/Torr during hypoxia, but this difference was not statistically significant. The results suggest that the distensible vessel model may be useful for interpreting pressure-flow data in terms of changes in geometry and distensibility of the resistance vessels in response to a vasoconstrictor stimulus such as hypoxia.

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