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.

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.

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.

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.

Role of protein kinase C in 15-HETE-induced hypoxic pulmonary vasoconstriction

2009 ◽  
Vol 80 (2-3) ◽  
pp. 115-123 ◽  
Author(s):  
Lei Guo ◽  
Xiaobo Tang ◽  
Xiaojie Chu ◽  
Lihua Sun ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasoconstriction ◽  
Kinase C

Abstract 422: Role of Brain Salt-inducible Kinase 1 in Responses to Central Sodium in Salt-induced Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Bing S Huang ◽  
Roselyn A White ◽  
Frans H Leenen
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Specific Protein ◽  
Feedback Mechanism ◽  
Ang Ii ◽  
High Salt Diet ◽  
Pressor Responses ◽  
Induced Hypertension ◽  
Protein Kinase C Inhibitor

In Dahl salt sensitive (S) rats, sympatho-excitatory and pressor responses to CSF Na + are enhanced. Salt-inducible kinase 1 (SIK1) increases Na + /K + -ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of sympatho-excitatory and pressor responses to Na + in the brain. Icv injection of the protein kinase inhibitor staurosporine (staur, 5ng) to inhibit SIK1 similarly enhanced renal sympathetic nerve activity (RSNA), BP and HR responses to icv infusion of Na + -rich aCSF in Wistar and salt-resistant Dahl SS.BN13. The enhancement in Dahl S rats was only 1/3 of that in other strains. Staur had no effect on BP responses to icv Ang II or carbachol, whereas the specific protein kinase C inhibitor GF109203X attenuated pressor responses to icv Na + -rich aCSF or Ang II. Hypothalamic SIK1 protein and activity, measured by Western blot and phosphocellulose binding technique, were lower in Dahl S vs SS.BN13 rats after high salt diet for 2 weeks. Staur at 5-50 nM inhibited SIK1 activity in a dose-related manner. These data suggest that the SIK1 -Na + /K + -ATPase network in neurons acts as a feedback mechanism to attenuate sympatho-excitatory and pressor responses to increases in brain [Na + ]. Lower neuronal SIK1 protein expression and activity in Dahl S rats may contribute to enhanced responses to CSF Na + and thereby to their salt-induced hypertension. Data= means±SE (n=4-7). * p<0.05, vs. SS.BN13 or Wistar rats.

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.

scholarly journals Possible role of brain salt-inducible kinase 1 in responses to central sodium in Dahl rats

2012 ◽  
Vol 303 (2) ◽  
pp. R236-R245 ◽  
Author(s):  
Bing S. Huang ◽  
Roselyn A. White ◽  
Frans H. H. Leenen
Keyword(s):  
Protein Kinase ◽  
Wistar Rats ◽  
Kinase Inhibitor ◽  
Specific Protein ◽  
Ang Ii ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
Pressor Responses ◽  
Protein Kinase C Inhibitor

In Dahl salt-sensitive (S) rats, Na+ entry into the cerebrospinal fluid (CSF) and sympathoexcitatory and pressor responses to CSF Na+ are enhanced. Salt-inducible kinase 1 (SIK1) increases Na+/K+-ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of CSF [Na+] and responses to Na+ in the brain. SIK1 protein and activity were lower in hypothalamic tissue of Dahl S (SS/Mcw) compared with salt-resistant SS.BN13 rats. Intracerebroventricular infusion of the protein kinase inhibitor staurosporine at 25 ng/day, to inhibit SIK1 further increased mean arterial pressure (MAP) and HR but did not affect the increase in CSF [Na+] or hypothalamic aldosterone in Dahl S on a high-salt diet. Intracerebroventricular infusion of Na+-rich artificial CSF caused significantly larger increases in renal sympathetic nerve activity, MAP, and HR in Dahl S vs. SS.BN13 or Wistar rats on a normal-salt diet. Intracerebroventricular injection of 5 ng staurosporine enhanced these responses, but the enhancement in Dahl S rats was only one-third that in SS.BN13 and Wistar rats. Staurosporine had no effect on MAP and HR responses to intracerebroventricular ANG II or carbachol, whereas the specific protein kinase C inhibitor GF109203X inhibited pressor responses to intracerebroventricular Na+-rich artificial CSF or ANG II. These results suggest that the SIK1-Na+/K+-ATPase network in neurons acts to attenuate sympathoexcitatory and pressor responses to increases in brain [Na+]. The lower hypothalamic SIK1 activity and smaller effect of staurosporine in Dahl S rats suggest that impaired activation of neuronal SIK1 by Na+ may contribute to their enhanced central responses to sodium.

scholarly journals Hypoxic Pulmonary Vasoconstriction in Humans: Tale or Myth

2017 ◽  
Vol 11 (1) ◽  
pp. 1-13 ◽  
Author(s):  
A. Hussain ◽  
M.S. Suleiman ◽  
S.J. George ◽  
M. Loubani ◽  
A. Morice
Keyword(s):  
Reactive Oxygen Species ◽  
Rho Gtpases ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Underlying Mechanism ◽  
Clinical Implications ◽  
Oxygen Species ◽  
Adaptive Process ◽  
Pulmonary Vasoconstriction ◽  
Hypoxic Vasoconstriction

Hypoxic Pulmonary vasoconstriction (HPV) describes the physiological adaptive process of lungs to preserves systemic oxygenation. It has clinical implications in the development of pulmonary hypertension which impacts on outcomes of patients undergoing cardiothoracic surgery. This review examines both acute and chronic hypoxic vasoconstriction focusing on the distinct clinical implications and highlights the role of calcium and mitochondria in acute versus the role of reactive oxygen species and Rho GTPases in chronic HPV. Furthermore it identifies gaps of knowledge and need for further research in humans to clearly define this phenomenon and the underlying mechanism.

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