AJP - Lung Journal of Neurophysiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Lung Cell Mol Physiol 287: L1215-L1219, 2004. First published August 20, 2004; doi:10.1152/ajplung.00179.2004
1040-0605/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
287/6/L1215    most recent
00179.2004v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsai, B. M.
Right arrow Articles by Meldrum, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsai, B. M.
Right arrow Articles by Meldrum, D. R.

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Ben M. Tsai,1 Meijing Wang,1,2 Jeffrey M. Pitcher,1 Kirstan K. Meldrum,3 and Daniel R. Meldrum1,2,4

Departments of 1Surgery, 4Cellular and Integrative Physiology, and 3Urology, Indiana University School of Medicine; and 2Indiana Center for Vascular Biology and Medicine, Indianapolis, Indiana 46202

Submitted 18 May 2004 ; accepted in final form 12 August 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-{alpha} and IL-1{beta} via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-{alpha} and IL-1{beta} mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-{alpha} and IL-1{beta} mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application.

hypoxia; pulmonary hypertension; inflammation; tumor necrosis factor

HYPOXIA FREQUENTLY OCCURS in conjunction with inflammatory conditions such as the acute respiratory distress syndrome or severe pulmonary infection. In the absence of infection, an inflammatory response may occur following acute injuries such as ischemia-reperfusion and hypoxia (4, 17). Although much data exist regarding the systemic release of proinflammatory cytokines following acute injury, little is known about the local tissue production of inflammatory cytokines. It is now known that cardiomyocytes generate an intense inflammatory response following acute ischemia-reperfusion injury (14), and these inflammatory mediators contribute to myocardial dysfunction. Therefore, it is possible that hypoxia may stimulate inflammatory cytokine expression from the pulmonary artery (PA) tissue itself.

The signaling pathways involved in generating an acute inflammatory response involve mediators such as protein kinase C (PKC). PKC is a regulatory enzyme activated by numerous effectors, growth factors, hormones, and neurotransmitters (18). PKC isoforms are activated by stimuli such as ischemia-reperfusion (15) and endotoxemia (16). After diacylglycerol release from the cell membrane by phospholipases, PKC is activated and exerts its effects by phosphorylating proteins at serine and threonine residues. In the isolated perfused lung, there is evidence that increased pulmonary vascular resistance is dependent on PKC activation (1, 32). However, the role of PKC in hypoxic contraction of isolated PA is unclear. Furthermore, PKC is known to mediate TNF production in macrophages (16), but its role in tissue cytokine production during hypoxia is unknown.

The purpose of this study was to examine the influence of hypoxia on inflammatory cytokine expression in isolated PA and to determine the role of PKC in these processes. We hypothesized that acute hypoxia results in PA contraction and upregulates proinflammatory cytokine expression in the PA itself and that these effects are mediated by PKC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals [National Institutes of Health (NIH) publication no. 85-23, revised 1985]. All animal protocols were approved by the Institutional Animal Care and Use Committee of the Indiana University School of Medicine. Male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing 250–350 g were allowed ad libitum access to food and water up to the time of experimentation.

Isolated PA ring preparation. Rats were anesthetized with pentobarbital (150 mg/kg ip). Median sternotomy was performed, and heparin sulfate (500 units) was injected into the right ventricular outflow tract. The heart and lungs were removed en bloc and placed in modified Krebs-Henseleit (KH) solution at 4°C. Under a dissecting microscope, extralobar PA branches were dissected out and cleared of surrounding tissue. Right and left main branch PA were cut into 2- to 3-mm-wide rings and suspended on steel hooks connected to force transducers (ADInstruments, Colorado Springs, CO) for measurement of isometric force. Care was taken during this process to avoid endothelial injury. PA rings were immersed in individual water-jacketed organ chambers containing modified Krebs-Henseleit solution bubbled with 95% O2/5% CO2 at 37°C. Force displacement was recorded using a PowerLab (ADInstruments) eight-channel data recorder on an Apple iMac PowerPC G4 Computer (Apple Computer, Cupertino, CA).

Experimental protocol and groups. Before starting experimental protocols, we stretched PA rings to a predetermined optimal passive tension of 750 mg and allowed them to equilibrate for 60 min, during which time KH solution was changed every 15 min. We then checked viability of each PA ring by measuring contractile response to 80 mmol/l KCl. This dosage of KCl was determined to produce maximal contractile response in previous experiments. After washout of KCl, endothelial integrity of each PA ring was assessed with dilation to acetylcholine (1 µmol/l) after phenylephrine (1 µmol/l) preconstriction. Rings demonstrating <200 mg contraction to phenylephrine were discarded. In endothelium-intact PA, rings demonstrating <50% vasorelaxation to acetylcholine were discarded. After washout of acetylcholine, PA rings were precontracted with phenylephrine, and hypoxia was induced by changing the gas to 95% N2/5% CO2. Experiments were terminated after 60 min of hypoxia, and rings were immediately flash-frozen in liquid nitrogen before mRNA analysis. This protocol was performed in the presence or absence of the PKC inhibitors chelerythrine (1 µmol/l) or calphostin C (1 µmol/l). PKC inhibitors were added 30 min before the onset of hypoxia. In separate experiments, phenylephrine-precontracted PA rings (n = 5) were incubated in the presence of the PKC activator thymeleatoxin (THX, 1 µmol/l) for 60 min. THX has been demonstrated to be an effective activator of multiple PKC isozymes (25, 26).

RT-PCR. Semiquantitative RT-PCR was used to assess TNF-{alpha} and IL-1{beta} gene expression in PA rings. After tissue homogenization of PA rings, total RNA was extracted from each PA segment using RNA STAT-60 (TEL-TEST, Friendswood, TX). Total RNA (0.1 µg) was subjected to cDNA synthesis with a cloned avian myeloblastosis virus first-strand cDNA synthesis kit (Maxim Biotech, South San Francisco, CA). cDNA from each sample was used for PCR of cytokines using message screen rat PCR kits (Maxim Biotech). PCR products were separated by electrophoresis on 1% agarose gel stained with ethidium bromide. Gels were photographed with a Polaroid Gelcam (Polaroid, Waltham, MA) under ultraviolet illumination (Spectronics, Westbury, NY). Gel photographs were scanned with an Epson Perfection 3200 scanner (Epson America, Long Beach, CA) onto an iMac PowerPC G4 computer and analyzed with ImageJ software (NIH).

Chemicals and reagents. All chemical reagents were obtained from Sigma (St. Louis, MO) unless otherwise specified. All drug concentrations are expressed as final molar concentration in the organ bath. All reagents were dissolved in deionized distilled water. KH solution is a physiologically balanced salt solution containing (in mmol/l): 127 NaCl, 4.7 KCl, 17 NaHCO3, 1.17 MgSO4, 1.18 KH2PO4, 2.5 CaCl2, and 5.5 D-glucose. Final pH of all solutions was 7.35–7.45.

Statistical analysis. Force displacement during hypoxia is expressed as percent change from the amount of phenylephrine precontraction. All reported values are means ± SE (n = 7–12/group). Experimental groups were compared by two-way analysis of variance with post hoc Bonferroni test or unpaired Student's t-test (Prism 4; Graphpad Software, San Diego, CA). Differences at an alpha level of 0.05 (P < 0.05) were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Hypoxic pulmonary vasoconstriction. To measure the effect of hypoxia on PA, we gassed phenylephrine-precontracted PA with 95% N2/5% CO2 for 60 min. This produced a PO2 of 30–35 mmHg. Hypoxia caused a biphasic PA vasoconstriction (Fig. 1). The initial contraction occurred ~1–3 min following the onset of hypoxia. This was followed by a vasodilation and then a delayed and sustained vasoconstriction ~15–20 min after the onset of hypoxia. Maximum contractions were measured as the differences between the highest and lowest force displacements during hypoxia (Fig. 1) and expressed as a percentage of the precontractile force (phenylephrine, 1 µmol/l). The maximum early contraction of endothelium-intact control PA (n = 12) was 40.09 ± 8.12%, and the maximum delayed contraction was 94.07 ± 5.94%.



View larger version (11K):
[in this window]
[in a new window]
  		Fig. 1. Actual tracing of hypoxic contraction in isolated pulmonary arteries. Phenylephrine (PE)-precontracted (1 µmol/l) pulmonary arteries were exposed to hypoxia (95% N2/5% CO2, PO2 = 30–35 mmHg) for 60 min. There was an early transient contraction followed by a gradual sustained contraction that occurred 1–3 min and 15–20 min after the onset of hypoxia, respectively. Maximum contractile force displacement was measured as the difference between lowest force preceding contraction and the highest force during contraction.

 
Role of PKC on hypoxic pulmonary vasoconstriction. To measure the effect of PKC inhibition on hypoxic pulmonary vasoconstriction (HPV), selective PKC inhibitors chelerythrine (1 µmol/l) or calphostin C (1 µmol/l) were added to the organ baths 30 min before phenylephrine precontraction. PKC inhibition (n = 7/group) significantly attenuated delayed, but not early, hypoxic contraction (Figs. 2A and 3). The maximum early contraction was 28.13 ± 3.86% with chelerythrine (P = 0.269 vs. hypoxia alone) and 54.85 ± 10.04% with calphostin C (P = 0.274 vs. hypoxia alone), whereas the maximum delayed contraction was 61.55 ± 3.91% with chelerythrine (P < 0.001 vs. hypoxia alone) and 68.04 ± 5.87% with calphostin C (P ≤ 0.05 vs. hypoxia alone).



View larger version (21K):
[in this window]
[in a new window]
  		Fig. 2. Role of PKC in hypoxic pulmonary vasoconstriction. A: in the presence of the PKC inhibitor chelerythrine (1 µmol/l, n = 7), delayed hypoxic contraction was significantly attenuated compared with hypoxia alone (n = 12). {ddagger}P < 0.001 vs. hypoxia alone. B: when the PKC activator thymeleatoxin (THX, 1 µmol/l, n = 5) was added to a PE-precontracted pulmonary artery, a transient relaxation was followed by a gradual sustained contraction over 60 min. This curve was similar in magnitude and timing to the delayed contraction induced by hypoxia alone.

 


View larger version (21K):
[in this window]
[in a new window]
  		Fig. 3. Maximum contractile force with PKC inhibition or activation. In a comparison of maximum contractile force, PKC inhibition (chelerythrine or calphostin C, 1 µmol/l) significantly attenuated delayed hypoxic contraction (61.55 ± 3.91% with chelerythrine and 68.04 ± 5.87% with calphostin C vs. 94.07 ± 5.94% with hypoxia alone). PKC activation (THX, 1 µmol/l) resulted in a maximum contraction (90.70 ± 23.13%), similar to the delayed contraction induced by hypoxia. *P < 0.05 and {ddagger}P < 0.001 vs. hypoxia alone.

 
PKC activation. To investigate the effect of PKC activation on isolated PA, we incubated phenylephrine-precontracted PA with the PKC activator THX (1 µmol/l) for 60 min. THX caused a transient relaxation followed by a gradual sustained vasoconstriction. The force displacement curve of THX is superimposed on the hypoxia alone curve (Fig. 2B) to demonstrate its temporal and quantitative similarities. THX-induced contraction (90.70 ± 23.13%) after 60 min was similar in magnitude (Fig. 3) to the delayed contraction of hypoxia (94.07 ± 5.94%).

Proinflammatory cytokine expression during hypoxia. After 60 min of hypoxia, PA rings were flash frozen in liquid nitrogen and later subjected to mRNA analysis via RT-PCR for the proinflammatory cytokines TNF-{alpha} and IL-1{beta}. Hypoxia increased the expression of TNF-{alpha} (Fig. 4) and IL-1{beta} (Fig. 5) compared with matched normoxic controls. In the presence of chelerythrine, the hypoxic expression of TNF-{alpha} and IL-1{beta} was attenuated. Furthermore, PA rings treated with THX demonstrated increased expression of TNF-{alpha} and IL-1{beta} (Fig. 6).



View larger version (60K):
[in this window]
[in a new window]
  		Fig. 4. Hypoxia upregulates expression of TNF-{alpha} via a PKC-dependent mechanism. Representative gel photographs (2 lanes per group shown) depicting increased expression of TNF-{alpha} mRNA in pulmonary arteries exposed to 60 min of hypoxia compared with matched controls (60 min of normoxia). In the presence of the PKC inhibitor chelerythrine (1 µmol/l), TNF-{alpha} is not upregulated by hypoxia.

 


View larger version (52K):
[in this window]
[in a new window]
  		Fig. 5. Hypoxia upregulates expression of IL-1{beta} via a PKC-dependent mechanism. Representative gel photographs (2 lanes per group shown) depicting increased expression of IL-1{beta} mRNA in pulmonary arteries exposed to 60 min of hypoxia compared with matched controls (60 min of normoxia). In the presence of the PKC inhibitor chelerythrine (1 µmol/l), IL-1{beta} is not upregulated by hypoxia.

 


View larger version (51K):
[in this window]
[in a new window]
  		Fig. 6. PKC activation upregulates expression of TNF-{alpha} and IL-1{beta}. Representative gel photographs (2 lanes per group shown) depicting increased expression of TNF-{alpha} (top) and IL-1{beta} (bottom) mRNA in pulmonary arteries exposed to 60 min of the PKC activator THX (1 µmol/M) compared with controls (60 min without PKC activator).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
HPV has been extensively studied, yet the exact mechanisms are still unclear. We and others (3, 10, 28) have reported that in isolated rat PA, a biphasic pattern of contraction occurs in response to acute hypoxia. The role of PKC on HPV in isolated perfused lung has been demonstrated in previous studies (1, 32); however, the involvement of PKC in the isolated PA is less clear. Moreover, the role of PKC on local proinflammatory cytokine expression during acute hypoxia has not previously been shown. In this study, we have demonstrated that, in isolated PA 1) PKC mediates delayed hypoxic contraction, 2) hypoxia upregulates PA tissue expression of TNF-{alpha} and IL-1{beta}, and 3) the upregulation of TNF-{alpha} and IL-1{beta} expression during hypoxia is dependent on PKC activation.

We hypothesized that the signaling pathway of HPV involves common intracellular enzymes such as PKC. Indeed, several investigators have demonstrated in isolated lung that delayed contraction is mediated by PKC activation (7, 10, 32). Our results of PKC-dependent delayed hypoxic contraction in isolated PA are consistent with previous studies using isolated perfused lung. Furthermore, we and others (19) demonstrated that PKC activation results in a slow, sustained contraction in isolated arteries. The magnitude and timing of this contraction appear similar to that of the delayed contraction induced by hypoxia (Figs. 2A and 3). Although the exact mechanisms of HPV remain unknown, previous studies (2, 6, 10–12, 21, 23, 27) have hypothesized two signaling processes: 1) inhibition or secretion of an endogenous mediator that results in vasoconstriction and 2) opening or closing of calcium or potassium channels in the pulmonary vascular smooth muscle cell that leads to contraction. There is abundant evidence to support both hypotheses, and the precise mechanism of HPV may actually be multifactorial. Furthermore, each phase of the biphasic hypoxic contractions observed in the isolated PA may have different mechanisms, and there is conflicting evidence regarding the mechanisms responsible for each phase. In the current study, we postulated that the PKC plays a central role in HPV irrespective of extracellular mediators.

PKC activation causes vascular smooth muscle contraction by increasing the influx of calcium, and hypoxic contraction via PKC activation may likewise involve calcium influx. An increase in cytosolic calcium concentration appears to be a key event in HPV (2, 9, 21, 31). Calcium accumulation occurs by release from intracellular stores such as the sarcoplasmic reticulum or influx through voltage-dependent channels. Investigators have shown that blocking calcium channels (2, 10, 22), depletion of intracellular calcium stores (6, 8, 9, 22), and removing extracellular calcium (10, 13) inhibit hypoxic contraction, whereas calcium agonists potentiate HPV (24). Thus we speculate that the downstream events in PKC activation during hypoxia involve calcium influx and subsequent smooth muscle contraction.

There is evidence that hypoxemia alone, in the absence of blood loss or tissue injury, has been shown to induce the systemic release of proinflammatory cytokines by macrophages (5). In this study, hypoxia upregulated the expression of TNF-{alpha} and IL-1{beta} from the PA itself, and this response was inhibited by chelerythrine. Pharmacological activation of PKC also upregulated PA expression of TNF-{alpha} and IL-1{beta}. PKC isoforms have previously been shown to mediate TNF-{alpha} and IL-1{beta} production from macrophages (16), but this is the first demonstration of PKC-mediated cytokine expression in PA. Although it is not clear what role proinflammatory cytokine production from the PA plays, or the magnitude of cytokine production from the PA, these findings suggest that the local production of cytokines may effect direct changes in vascular reactivity. Indeed, previous studies have shown that inflammatory cytokines potentiate HPV (33). This could be compared with the relatively recent recognition that production of inflammatory mediators from cardiomyocytes may contribute to myocardial dysfunction following ischemia-reperfusion or other acute insults (14).

The upregulation of cytokine expression from PA may occur at the pretranscriptional level. In this regard, nuclear factor (NF)-{kappa}B, a transcription factor involved in the transcription of proinflammatory molecules, may be involved in the signaling pathway of HPV. This was suggested by a study showing that NF-{kappa}B inhibitors blocked HPV (29). PKC may also be involved in the expression of NF-{kappa}B-dependent genes because Page et al. (20) demonstrated that activation of PKC-{Delta} in airway epithelial cells induces NF-{kappa}B nuclear translocation and binding to DNA. Thus the activation of inflammation as well as the physiological response of the vasculature to acute hypoxia may be dependent on PKC activation.

In summary, we have demonstrated for the first time that acute hypoxia upregulates the PA tissue expression of proinflammatory cytokines. This was correlated with the well-recognized physiological observation that hypoxia causes PA contraction, and both processes were attenuated by PKC inhibition. These findings suggest a putative therapeutic role for PKC inhibition in the treatment of HPV.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by NIH Grants GM-070628 (D. R. Meldrum) and DK-065892 (K. K. Meldrum). Support was also received from The Cryptic Masons Medical Research Foundation (D. R. Meldrum, M. Wang), The Clarian Values Fund (D. R. Meldrum, K. K. Meldrum) and The Showalter Trust (D. R. Meldrum).


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. R. Meldrum, 545 Barnhill Dr., Emerson Hall 215, Indianapolis, IN 46202 (E-mail: dmeldrum{at}iupui.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Barman SA. Effect of protein kinase C inhibition on hypoxic pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol 280: L888–L895, 2001.[Abstract/Free Full Text]
  2. Barman SA. Potassium channels modulate hypoxic pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol 275: L64–L70, 1998.[Abstract/Free Full Text]
  3. Bennie RE, Packer CS, Powell DR, Jin N, and Rhoades RA. Biphasic contractile response of pulmonary artery to hypoxia. Am J Physiol Lung Cell Mol Physiol 261: L156–L163, 1991.[Abstract/Free Full Text]
  4. Chandel NS, Trzyna WC, McClintock DS, and Schumacker PT. Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. J Immunol 165: 1013–1021, 2000.[Abstract/Free Full Text]
  5. Ertel W, Morrison MH, Ayala A, and Chaudry IH. Hypoxemia in the absence of blood loss or significant hypotension causes inflammatory cytokine release. Am J Physiol Regul Integr Comp Physiol 269: R160–R166, 1995.[Abstract/Free Full Text]
  6. Gelband CH and Gelband H. Ca2+ release from intracellular stores is an initial step in hypoxic pulmonary vasoconstriction of rat pulmonary artery resistance vessels. Circulation 96: 3647–3654, 1997.[Abstract/Free Full Text]
  7. Goirand F, Bardou M, Guerard P, Dumas JP, Rochette L, and Dumas M. ETA, mixed ETA/ETB receptor antagonists, and protein kinase C inhibitor prevent acute hypoxic pulmonary vasoconstriction: influence of potassium channels. J Cardiovasc Pharmacol 41: 117–125, 2003.[CrossRef][ISI][Medline]
  8. Hampl V, Cornfield DN, Cowan NJ, and Archer SL. Hypoxia potentiates nitric oxide synthesis and transiently increases cytosolic calcium levels in pulmonary artery endothelial cells. Eur Respir J 8: 515–522, 1995.[Abstract]
  9. Jabr RI, Toland H, Gelband CH, Wang XX, and Hume JR. Prominent role of intracellular Ca2+ release in hypoxic vasoconstriction of canine pulmonary artery. Br J Pharmacol 122: 21–30, 1997.[CrossRef][ISI][Medline]
  10. Jin N, Packer CS, and Rhoades RA. Pulmonary arterial hypoxic contraction: signal transduction. Am J Physiol Lung Cell Mol Physiol 263: L73–L78, 1992.[Abstract/Free Full Text]
  11. Johns RA, Linden JM, and Peach MJ. Endothelium-dependent relaxation and cyclic GMP accumulation in rabbit pulmonary artery are selectively impaired by moderate hypoxia. Circ Res 65: 1508–1515, 1989.[Abstract/Free Full Text]
  12. Kourembanas S, Marsden PA, McQuillan LP, and Faller DV. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest 88: 1054–1057, 1991.[ISI][Medline]
  13. Mathew R, Burke-Wolin T, Gewitz MH, and Wolin MS. O2 and rat pulmonary artery tone: effects of endothelium, Ca2+, cyanide, and monocrotaline. J Appl Physiol 71: 30–36, 1991.[Abstract/Free Full Text]
  14. Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol Regul Integr Comp Physiol 274: R577–R595, 1998.[Abstract/Free Full Text]
  15. Meldrum DR, Cleveland JC Jr, Mitchell MB, Sheridan BC, Gamboni-Robertson F, Harken AH, and Banerjee A. Protein kinase C mediates Ca2+-induced cardioadaptation to ischemia-reperfusion injury. Am J Physiol Regul Integr Comp Physiol 271: R718–R726, 1996.[Abstract/Free Full Text]
  16. Meldrum DR, Meng X, Sheridan BC, McIntyre RC Jr, Harken AH, and Banerjee A. Tissue-specific protein kinase C isoforms differentially mediate macrophage TNFalpha and IL-1beta production. Shock 9: 256–260, 1998.[ISI][Medline]
  17. Meldrum DR, Shames BD, Meng X, Fullerton DA, McIntyre RC Jr, Grover FL, and Harken AH. Nitric oxide downregulates lung macrophage inflammatory cytokine production. Ann Thorac Surg 66: 313–317, 1998.[Abstract/Free Full Text]
  18. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258: 607–614, 1992.[Abstract/Free Full Text]
  19. Orton EC, Raffestin B, and McMurtry IF. Protein kinase C influences rat pulmonary vascular reactivity. Am Rev Respir Dis 141: 654–658, 1990.[ISI][Medline]
  20. Page K, Li J, Zhou L, Iasvovskaia S, Corbit KC, Soh JW, Weinstein IB, Brasier AR, Lin A, and Hershenson MB. Regulation of airway epithelial cell NF-kappa B-dependent gene expression by protein kinase C delta. J Immunol 170: 5681–5689, 2003.[Abstract/Free Full Text]
  21. Post JM, Hume JR, Archer SL, and Weir EK. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol Cell Physiol 262: C882–C890, 1992.[Abstract/Free Full Text]
  22. Robertson TP, Hague D, Aaronson PI, and Ward JP. Voltage-independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat. J Physiol 525: 669–680, 2000.[Abstract/Free Full Text]
  23. Rodman DM, Yamaguchi T, Hasunuma K, O'Brien RF, and McMurtry IF. Effects of hypoxia on endothelium-dependent relaxation of rat pulmonary artery. Am J Physiol Lung Cell Mol Physiol 258: L207–L214, 1990.[Abstract/Free Full Text]
  24. Rodman DM, Yamaguchi T, O'Brien RF, and McMurtry IF. Hypoxic contraction of isolated rat pulmonary artery. J Pharmacol Exp Ther 248: 952–959, 1989.[Abstract/Free Full Text]
  25. Roivainen R and Messing RO. The phorbol derivatives thymeleatoxin and 12-deoxyphorbol-13-O-phenylacetate-10-acetate cause translocation and down-regulation of multiple protein kinase C isozymes. FEBS Lett 319: 31–34, 1993.[CrossRef][ISI][Medline]
  26. Ryves WJ, Evans AT, Olivier AR, Parker PJ, and Evans FJ. Activation of the PKC-isotypes alpha, beta 1, gamma, delta and epsilon by phorbol esters of different biological activities. FEBS Lett 288: 5–9, 1991.[CrossRef][ISI][Medline]
  27. Sato K, Morio Y, Morris KG, Rodman DM, and McMurtry IF. Mechanism of hypoxic pulmonary vasoconstriction involves ETA receptor-mediated inhibition of KATP channel. Am J Physiol Lung Cell Mol Physiol 278: L434–L442, 2000.[Abstract/Free Full Text]
  28. Tsai BM, Wang M, Turrentine MW, Mahomed Y, Brown JW, and Meldrum DR. Hypoxic pulmonary vasoconstriction in cardiothoracic surgery: basic mechanisms to potential therapies. Ann Thorac Surg 78: 360–368, 2004.[Abstract/Free Full Text]
  29. Uzun O and Demiryurek AT. Nuclear factor-kappaB inhibitors abolish hypoxic vasoconstriction in sheep-isolated pulmonary arteries. Eur J Pharmacol 458: 171–174, 2003.[CrossRef][ISI][Medline]
  30. Von Euler US and Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 12: 301–320, 1946.
  31. Weir EK and Archer SL. The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels. FASEB J 9: 183–189, 1995.[Abstract]
  32. Weissmann N, Voswinckel R, Hardebusch T, Rosseau S, Ghofrani HA, Schermuly R, Seeger W, and Grimminger F. Evidence for a role of protein kinase C in hypoxic pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol 276: L90–L95, 1999.[Abstract/Free Full Text]
  33. Ziesche R, Petkov V, Williams J, Zakeri SM, Mosgoller W, Knofler M, and Block LH. Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue. Proc Natl Acad Sci USA 93: 12478–12483, 1996.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
T. Lahm, K. M. Patel, P. R. Crisostomo, T. A. Markel, M. Wang, C. Herring, and D. R. Meldrum
Endogenous estrogen attenuates pulmonary artery vasoreactivity and acute hypoxic pulmonary vasoconstriction: the effects of sex and menstrual cycle
Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E865 - E871.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
S. Earley, S. V. Straub, and J. E. Brayden
Protein kinase C regulates vascular myogenic tone through activation of TRPM4
Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2613 - H2622.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. A. Madden, R. M. Wadsworth, T. Lahm, D. R. Meldrum, J. X-J. Yuan, C. S. Packer, and N. J. Pelaez
Point:Counterpoint Comments
J Appl Physiol, May 1, 2007; 102(5): 2077 - 2079.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
T. A. John, B. O. Ibe, and J. Usha Raj
Oxygen alters caveolin-1 and nitric oxide synthase-3 functions in ovine fetal and neonatal lung microvascular endothelial cells
Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1079 - L1093.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
S. Y. Cheranov and J. H. Jaggar
TNF-{alpha} dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2+ spark activation
Am J Physiol Cell Physiol, April 1, 2006; 290(4): C964 - C971.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
B. M. Tsai, M. W. Turrentine, B. C. Sheridan, M. Wang, A. C. Fiore, J. W. Brown, and D. R. Meldrum
Differential Effects of Phosphodiesterase-5 Inhibitors on Hypoxic Pulmonary Vasoconstriction and Pulmonary Artery Cytokine Expression
Ann. Thorac. Surg., January 1, 2006; 81(1): 272 - 278.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
287/6/L1215    most recent
00179.2004v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsai, B. M.
Right arrow Articles by Meldrum, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsai, B. M.
Right arrow Articles by Meldrum, D. R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.