Effects of NADPH oxidase inhibitors on hypoxic vasoconstriction in buffer-perfused rabbit lungs

1995 ◽  
Vol 268 (5) ◽  
pp. L747-L752 ◽  
Author(s):  
F. Grimminger ◽  
N. Weissmann ◽  
R. Spriestersbach ◽  
E. Becker ◽  
S. Rosseau ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Selective Inhibition ◽  
Ang Ii ◽  
Selective Blockade ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
On Line ◽  
Test Specificity

The involvement of NADPH oxidase in hypoxic pulmonary vasoconstriction (HPV) was investigated in buffer-perfused rabbit lungs, employing the inhibitors diphenyleneiodonium (DPI) and apocynin. Responses to the vasoconstrictors U-46619 and angiotensin II (ANG II) were used to test specificity. Lung nitric oxide (NO) generation was assessed by on-line monitoring of NO exhalation (chemiluminescence), and the efficacy of DPI and apocynin on the NADPH oxidase-dependent O2- generation was quantified in alveolar macrophages by fluorescent-activated cell sorter technique. In a concentration range between 1 and 5 mM, apocynin inhibited macrophage respiratory burst and HPV but similarly suppressed U-46619-induced vasoconstrictor responses. DPI inhibited macrophage O2- generation in concentrations > or = 0.5 microM. At doses between 0.5 and 1.5 microM, DPI blocked lung NO generation, thereby increasing HPV. At higher doses (4 microM), in contrast, DPI fully blocked the hypoxia-induced pressor responses, whereas the vasoconstrictor responses to U-46619 and [Asn1, Val5] ANG II were not diminished. In the presence of NG-monomethyl-L-arginine, used to block lung NO generation throughout, DPI exhibited only the monophasic selective inhibition of HPV. We conclude that apocynin lacks specificity for HPV, but DPI, in addition to inhibiting lung NO generation, causes selective blockade of the hypoxia-induced vasoconstriction. This finding supports the hypothesis that an NADPH oxidase is involved in hypoxia sensing or specific signal transduction events underlying HPV.

scholarly journals Evidence for a role of protein kinase C in hypoxic pulmonary vasoconstriction

1999 ◽  
Vol 276 (1) ◽  
pp. L90-L95 ◽  
Author(s):  
Norbert Weissmann ◽  
Robert Voswinckel ◽  
Thorsten Hardebusch ◽  
Simone Rosseau ◽  
Hossein Ardeschir Ghofrani ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Ang Ii ◽  
Pkc Inhibitor ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation, thus optimizing gas exchange. NADPH oxidase-related superoxide anion generation has been suggested as part of the signaling response to hypoxia. Because protein kinase (PK) C activation can occur during hypoxia and PKC activation is known to be critical for NADPH oxidase stimulation in different cell types, we probed the role of PKC in hypoxic vasoconstriction in intact rabbit lungs. Control vasoconstrictor responses were elicited by angiotensin II (ANG II) and the stable thromboxane analog U-46619. Portions of the experiments were performed while NO synthesis and prostanoid generation were blocked with N G-monomethyl-l-arginine and acetylsalicylic acid to avoid confounding effects due to interference with these vasoactive mediators. The PKC inhibitor H-7 (10–50 μM) caused dose-dependent inhibition of HPV, but this agent lacked specificity because ANG II- and U-46619-induced vasoconstrictions were correspondingly suppressed. In contrast, low concentrations of the specific PKC inhibitor bisindolylmaleimide I (BIM; 1–15 μM) strongly inhibited the hypoxic vasoconstriction without any interference with the responses to the pharmacological agents. Superimposable dose-inhibition curves were also obtained for BIM when lung NO synthesis and prostanoid generation were blocked throughout the experiments. Under either condition, BIM did not affect normoxic vascular tone. The PKC activator farnesylthiotriazole (FTT), ascertained to stimulate rabbit NADPH oxidase by provocation of alveolar macrophage superoxide anion generation in vitro, caused rapid-onset, transient pressor responses in normoxic lungs. After FTT, the hypoxic vasoconstrictor response was totally suppressed, in contrast to the largely maintained pressor responses to ANG II and U-46619. The lungs became refractory even to delayed hypoxic challenges after FTT application. In conclusion, these data support the concept that activation of PKC is involved in the transduction pathway forwarding pulmonary vasoconstriction in response to alveolar hypoxia.

Prostaglandin synthetase inhibitors do not decrease hypoxic pulmonary vasoconstriction

1976 ◽  
Vol 41 (5) ◽  
pp. 714-718 ◽  
Author(s):  
E. K. Weir ◽  
I. F. McMurtry ◽  
A. Tucker ◽  
J. T. Reeves ◽  
R. F. Grover
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Prostaglandin Synthesis ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
Before And After ◽  
Anesthetized Dogs ◽  
Prostaglandin Antagonists ◽  
The Stability

Prostaglandins are naturally occurring substances with powerful vasoactive effects that are released from tissues during hypoxia or ischemia. Several workers have suggested that a prostaglandin may help to mediate the pulmonary vascular pressor response to alveolar hypoxia. To investigate this possibility, we have measured the pressor responses to hypoxia before and after prostaglandin synthesis antagonism with meclofenamate in eight anesthetized dogs, two groups of awake calves (n=10 and =5), and nine isolated, perfused rat lungs. In addition, synthesis was inhibited by the use of indomethacin in nine additional dogs. The stability of the pulmonary vascular response to repeated hypoxic challenges was demonstrated in nine other dogs. In each species and with both prostaglandin antagonists, the pulmonary pressorresponses to hypoxia were significantly increased rather than reduced. We conclude that prostaglandins do not mediate the pulmonary vasoconstriction caused by hypoxia. The consistent increase observed suggests that hypoxic vasoconstriction stimulates prostaglandin synthesis, the net effect of which is pulmonary vasodilatation which opposes the constriction.

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs

1995 ◽  
Vol 78 (4) ◽  
pp. 1509-1515 ◽  
Author(s):  
F. Grimminger ◽  
R. Spriestersbach ◽  
N. Weissmann ◽  
D. Walmrath ◽  
W. Seeger
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Sharp Drop ◽  
Pulmonary Vasoconstriction ◽  
Exhaled No ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
Alveolar Hypoxia

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs. J. Appl. Physiol. 78(4): 1509–1515, 1995.--We investigated the role of nitric oxide (NO) generation in hypoxic pulmonary vasoconstriction in buffer-perfused rabbit lungs. Exhaled NO was detected by chemiluminescence, and intravascular NO release was quantified as perfusate accumulation of nitrite, peroxynitrite, and nitrate (NOx). Under baseline conditions, exhaled NO was 45.3 +/- 4.1 parts per billion (1.8 +/- 0.2 nmol/min), and lung NOx release into the perfusate was 4.1 +/- 0.4 nmol/min. Alveolar hypoxia (alveolar PO2 of approximately 23 Torr) induced readily reproducible pressor responses preceded by a sharp drop in exhaled NO concentration. In contrast, perfusate NOx accumulation was not affected. Vasoconstrictor responses to U-46619 and angiotensin II were not accompanied by a decrease in NO exhalation. NG-monomethyl-L-arginine dose-dependently suppressed NO exhalation and amplified pressor responses to hypoxia > U-46619 and angiotensin II. In conclusion, portions of baseline NO generation originating from sites with ready access to the gaseous space sharply decrease in response to alveolar hypoxia, whereas the intravascular release of NO is unchanged. Such differential regulation of lung NO synthesis in response to hypoxia may suggest a complex role in the regulation or modulation of hypoxic pulmonary vasoconstriction.

Effects of cyclo- and lipoxygenase inhibitors on hypoxic vasoconstriction in isolated ferret lungs

1988 ◽  
Vol 64 (3) ◽  
pp. 936-943 ◽  
Author(s):  
J. E. Gottlieb ◽  
M. McGeady ◽  
N. F. Adkinson ◽  
J. T. Sylvester
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Autologous Blood ◽  
Nordihydroguaiaretic Acid ◽  
Lipoxygenase Inhibitors ◽  
Prostaglandin F2 Alpha ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction

To evaluate the role of leukotrienes in hypoxic pulmonary vasoconstriction, we measured steady-state pressor responses to graded hypoxia in isolated ferret lungs perfused with autologous blood containing 0.001, 0.03, 1, or 3 mM nordihydroguaiaretic acid (NDGA), 1 mM BW 755C, or 0.02-0.05 mM indomethacin. Untreated lungs served as controls. Perfusate concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha, measured by radioimmunoassay, were markedly reduced in all treated lungs, indicating inhibition of cyclooxygenase. The maximum pressor response to hypoxia measured at a blood flow of 50 ml.min-1. kg-1 averaged 26.6 ± 2.4 Torr in untreated lungs and was not affected by BW 755C or 0.001-0.03 mM NDGA. Because BW 755C and NDGA inhibited cyclooxygenase at concentrations that did not affect hypoxic vasoconstriction and because both agents are thought to inhibit lipoxygenase with a potency greater than or equal to that with which they inhibit cyclooxygenase, these results do not support the possibility that hypoxic pulmonary vasoconstriction was mediated by leukotrienes. At concentrations of 1 and 3 mM, NDGA inhibited the maximum hypoxic pressor response by 57 and 95%, respectively. The mechanism of this attenuation is unknown; however, it was apparently not due to cyclooxygenase inhibition, since indomethacin enhanced the maximum hypoxic pressor response by 45%. Nor was it due to blockade of calcium entry or interference with the contractile process in pulmonary vascular smooth muscle, since 1 mM NDGA did not inhibit vasoconstrictor responses to KCl or prostaglandin F2 alpha.

Calcitonin gene-related peptide modulates pulmonary vascular reactivity in isolated rat lungs

1994 ◽  
Vol 77 (1) ◽  
pp. 142-146 ◽  
Author(s):  
P. L. Janssen ◽  
A. Tucker
Keyword(s):  
Vascular Reactivity ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Calcitonin Gene Related Peptide ◽  
Ang Ii ◽  
Related Peptide ◽  
Pulmonary Vasoconstriction ◽  
Rat Lungs ◽  
Pressor Responses ◽  
Calcitonin Gene

The role of calcitonin gene-related peptide (CGRP) in modulating hypoxic pulmonary vasoconstriction was assessed. The effects of CGRP and its antagonist [CGRP-(8–37)] on responses to acute hypoxia (3% O2) and angiotensin II (ANG II; 0.4 microgram) were studied in isolated lungs of male Sprague-Dawley rats perfused with a salt solution. Rats with pulmonary hypertension, induced by simulated altitude exposure, were also used to determine the actions of CGRP in a remodeled pulmonary vascular bed. In normotensive (NT) and altitude-exposed (AE) lungs, CGRP injections (10 nM), given after stable pressor responses were attained, attenuated (P < 0.05) subsequent hypoxic pressor responses. Pretreatment with CGRP-(8–37) (10 nM) enhanced (P < or = 0.05) initial ANG II-induced pressor responses in both AE and NT lungs. CGRP-(8–37) pretreatment (10 nM) had little influence on the hypoxic pressor responses in either NT or AE lungs. Results indicate that CGRP modulates hypoxic pulmonary vasoconstriction and that CGRP-(8–37) enhances pressor responses to ANG II in NT and AE rat lungs.

Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity

1991 ◽  
Vol 261 (2) ◽  
pp. H487-H492 ◽  
Author(s):  
J. Haynes ◽  
P. A. Kithas ◽  
A. E. Taylor ◽  
S. J. Strada
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Muscle Relaxation ◽  
Selective Inhibition ◽  
Smooth Muscle Relaxation ◽  
Ang Ii ◽  
Camp Phosphodiesterase ◽  
Cyclic Monophosphate ◽  
Pressor Responses ◽  
Camp Hydrolysis

Guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) are mediators of smooth muscle relaxation. In this study, selective inhibitors of phosphodiesterase (PDE) isozymes were used to assess the role of cyclic nucleotide hydrolysis in angiotensin II (ANG II) and hypoxic pulmonary vasoconstriction. In isolated rat lungs, the hypoxic pressor response (HPR) was induced with a 95% N2-5% CO2 gas mixture. When administered during the plateau of the HPR, trequinsin (nonselective PDE inhibitor) and indolidan (cGMP-inhibitable cAMP PDE inhibitor) significantly (P = 0.01) decreased the pulmonary arterial pressure (Ppa) by 60 +/- 7 and 53 +/- 3%, respectively, compared with zaprinast (cGMP PDE inhibitor), rolipram (cGMP-insensitive cAMP PDE inhibitor), and the 0.1% dimethyl sulfoxide (DMSO) vehicle control, which decreased the Ppa by 6 +/- 3, 4 +/- 3, and 0%, respectively. In the trequinsin and indolidan groups, the subsequent ANG II pressor responses and HPRs were significantly (P = 0.01) decreased when compared with the zaprinast, rolipram, and DMSO groups. During normoxia, none of the PDE inhibitor (0.3-30 microM) had an effect on the baseline Ppa. These results suggest that cAMP hydrolysis by the cGMP-inhibitable cAMP PDE play a significant role in pulmonary vascular tone regulation.

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.

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.

Does leukotriene C4 mediate hypoxic vasoconstriction in isolated ferret lungs?

1990 ◽  
Vol 68 (1) ◽  
pp. 253-259 ◽  
Author(s):  
C. M. Tseng ◽  
M. McGeady ◽  
T. Privett ◽  
A. Dunn ◽  
J. T. Sylvester
Keyword(s):  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Physiological Salt Solution ◽  
Leukotriene C4 ◽  
Prostaglandin F2 Alpha ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Pulmonary Arterial

To evaluate leukotriene (LT) C4 as a mediator of hypoxic pulmonary vasoconstriction, we examined the effects of FPL55712, a putative LT antagonist, and indomethacin, a cyclooxygenase inhibitor, on vasopressor responses to LTC4 and hypoxia (inspired O2 tension = 25 Torr) in isolated ferret lungs perfused with a constant flow (50 ml.kg-1.min-1). Pulmonary arterial injections of LTC4 caused dose-related increases in pulmonary arterial pressure during perfusion with physiological salt solution containing Ficoll (4 g/dl). FPL55712 caused concentration-related inhibition of the pressor response to LTC4 (0.6 micrograms). Although 10 micrograms/ml FPL55712 inhibited the LTC4 pressor response by 61%, it did not alter the response to hypoxia. At 100 microgram/ml, FPL55712 inhibited the responses to LTC4 and hypoxia by 73 and 71%, respectively, but also attenuated the vasoconstrictor responses to prostaglandin F2 alpha (78% at 8 micrograms), phenylephrine (68% at 100 micrograms), and KCl (51% at 40 mM). At 0.5 microgram/ml, indomethacin significantly attenuated the pressor response to arachidonic acid but did not alter responses to LTC4 or hypoxia. These results suggest that in isolated ferret lungs 1) the vasoconstrictor response to LTC4 did not depend on release of cyclooxygenase products and 2) LTC4 did not mediate hypoxic vasoconstriction.

Metabolic and respiratory hydrogen ion effects on hypoxic pulmonary vasoconstriction

1984 ◽  
Vol 57 (2) ◽  
pp. 545-550 ◽  
Author(s):  
C. Marshall ◽  
L. Lindgren ◽  
B. E. Marshall
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Respiratory Acidosis ◽  
Hydrogen Ion ◽  
Regression Equations ◽  
Rat Lung ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Ion Effects

Hypoxic pulmonary vasoconstriction (HPV) was studied in the ventilated-perfused rat lung in vitro. Respiratory acidosis and alkalosis were obtained by ventilating with 2, 7, or 10% CO2 (21% O2-balance N2). Metabolic acidosis and alkalosis were produced by the addition of 0.9 N NaHCO3 or 1 N lactic acid to the perfusate at constant PCO2. At each pH the pressor responses to 2 and 4% O2 were compared with the maximum pressor response (R%max) obtained with zero O2 and 5% CO2 at a normal pH (approximately 7.35). HPV was maximal when the [H+] was between 38 and 50 nM and was attenuated by changes of pH in either direction. Both respiratory and metabolic pH changes had similar effects. The combined linear regression equations were as follows: with 2% O2 the response to acidosis was R%max = 101.37 – 0.52 [H+] and to alkalosis was R%max = 2.03 [H+] - 3.85; with 4% O2 the response to acidosis was R%max = 56.88 – 0.3 [H+] and to alkalosis was R%max = 1.16 [H+] - 4.95. These effects were not due to changes of ionized calcium.

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