Acute administration of l-arginine restores nitric oxide-mediated relaxation in isolated pulmonary arteries from pulmonary hypertensive exercise trained rats
Abstract
Hypoxia-induced pulmonary hypertension is associated with an impairment of nitric oxide-mediated vasorelaxation in the pulmonary circulation that is not prevented by exercise training. The present study was designed to test the hypothesis that a decrease in l-arginine bioavailability could be involved in this blunted response to exercise training. Male Wistar rats were randomly assigned to 4 groups: normotensive sedentary, normotensive trained, pulmonary hypertensive sedentary, pulmonary hypertensive trained. Pulmonary hypertension was induced by chronic exposure to hypobaric hypoxia (PIO(2) approximately 90 mmHg). Endothelium-dependent vasorelaxation to acetylcholine (10(-8)-10(-4) M) with or without l-arginine (10(-3) M) and/or nitro-l-arginine methyl ester (5.10(-6) M) was assessed on isolated pulmonary arterial rings. Maximal relaxation to acetylcholine was impaired in both pulmonary hypertensive groups. Acute l-arginine supplementation improved acetylcholine-induced vasorelaxation in the pulmonary hypertensive trained rats (P<0.01), to the level obtained in the normotensive sedentary ones, but not in the pulmonary hypertensive sedentary rats. This improvement was abolished when nitro-l-arginine methyl ester was added to the organ bath and was accounted for by an increase in eNOS protein content. These results confirm that the potential beneficial effect of exercise on nitric oxide-mediated pulmonary artery vasorelaxation is partly blunted by deleterious effects of hypoxia on l-arginine bioavailability. Further studies are needed to evaluate the benefit of the combination of exercise training and l-arginine supplementation for the treatment of pulmonary hypertension.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The hallmark feature of PAH and other forms of PH is reduced bioavailability of NO signaling and poor endothelial responsiveness to triggers of vasodilatation.
“The hallmark feature of PAH and other forms of PH is reduced bioavailability of NO signaling and poor endothelial responsiveness to triggers of vasodilatation[28–34].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [33]
Cites
Nitric oxide: physiology, pathophysiology, and pharmacology.
Moncada, S., Palmer, R. M., & Higgs, E. A. (1991) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06663-3 · Cited by 15,525 · see citing works
Mereles, D., Ehlken, N., Kreuscher, S., Ghofrani, S., Hoeper, M. M., Halank, M., Meyer, F. J., Karger, G., Buss, J., Juenger, J., et al. (2006) · Circulation · doi:10.1161/circulationaha.106.618397 · Cited by 724 · see citing works
Impairment of Endothelium-Dependent Pulmonary-Artery Relaxation in Chronic Obstructive Lung Disease
Dinh‐Xuan, A. T., HIGENBOTTAM, T. W., Clelland, C., Pepke‐Żaba, J., Cremona, G., Butt, A. Y., Large, S., Wells, F. C., & Wallwork, J. L. (1991) · New England Journal of Medicine · doi:10.1056/nejm199105303242203 · Cited by 528 · see citing works
Endothelium-dependent hyperpolarization: a role in the control of vascular tone
Garland, C. J., Plane, F., Kemp‐Harper, B. K., & Cocks, T. M. (1995) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(00)88969-5 · Cited by 447 · see citing works
Primary Pulmonary Hypertension
Archer, S. L., & Rich, S. (2000) · Circulation · doi:10.1161/01.cir.102.22.2781 · Cited by 353 · see citing works
Morris, C. R., Morris, S. M., Hagar, W., van Warmerdam, J., Claster, S., Kepka‐Lenhart, D., Machado, L., Kuypers, F. A., & Vichinsky, E. P. (2003) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200208-967oc · Cited by 328 · see citing works
Pulmonary Hypertension Predicts Mortality and Morbidity in Patients with Dilated Cardiomyopathy
Abramson, S. V., Burke, J. F., Kelly, J. J. P., Kitchen, J. G., Dougherty, M. J., Yih, D. F., McGeehin, F. C., Shuck, J. W., & Phiambolis, T. P. (1992) · Annals of Internal Medicine · doi:10.7326/0003-4819-116-11-888 · Cited by 312 · see citing works
Nagaya, N., Uematsu, M., Oya, H., Sato, N., Sakamaki, F., Kyotani, S., Ueno, K., Nakanishi, N., Yamagishi, M., & Miyatake, K. (2001) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.163.4.2007116 · Cited by 200 · see citing works
Time course of enhanced endothelium-mediated dilation in aorta of trained rats
Delp, M. D., & Laughlin, M. H. (1997) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199711000-00011 · Cited by 166 · see citing works
Murata, T., Sato, K., Hori, M., Ozaki, H., & Karaki, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205934200 · Cited by 153 · see citing works
Distribution of NOS in normoxic vs. hypoxic rat lung: upregulation of NOS by chronic hypoxia
Xue, C., Rengasamy, A., Cras, T. D. L., Koberna, P. A., Dailey, G. C., & Johns, R. A. (1994) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1994.267.6.l667 · Cited by 145 · see citing works
Schlaich, M. P., Parnell, M. M., Ahlers, B. A., Finch, S., Marshall, T., Zhang, W., & Kaye, D. M. (2004) · Circulation · doi:10.1161/01.cir.0000149748.79945.52 · Cited by 124 · see citing works
Endothelial Dysfunction in Pulmonary Hypertension
Loscalzo, J. (1992) · New England Journal of Medicine · doi:10.1056/nejm199207093270209 · Cited by 120 · see citing works
Growth of the Heart and Lungs in Hypoxic Rodents: A Model of Human Hypoxic Disease
Hunter, C., Barer, G. R., Shaw, J. W., & Clegg, E. J. (1974) · Clinical Science · doi:10.1042/cs0460375 · Cited by 107 · see citing works
Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension
Fagan, K. A., Morrissey, B., Fouty, B., Sato, K., Harral, J. W., Morris, K. G., Hoedt-Miller, M., Vidmar, S., McMurtry, I. F., & Rodman, D. M. (2001) · Respiratory Research · doi:10.1186/rr74 · Cited by 98 · see citing works
Johnson, L. R., Rush, J. W. E., Turk, J. R., Price, E. M., & Laughlin, M. H. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.90.3.1102 · Cited by 83 · see citing works
Eddahibi, S., Adnot, S., Carville, C., Blouquit, Y., & Raffestin, B. (1992) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1992.263.2.l194 · Cited by 80 · see citing works
Physical conditioning can modulate endothelium-dependent vasorelaxation in rabbits.
Chen, H. I., & Li, H. T. (1993) · Arteriosclerosis and Thrombosis A Journal of Vascular Biology · doi:10.1161/01.atv.13.6.852 · Cited by 74 · see citing works
Chronic hypoxia impairs soluble guanylyl cyclase-mediated pulmonary arterial relaxation in the rat
Crawley, D. E., Zhao, L., Giembycz, M. A., Liu, S., Barnes, P. J., Winter, R. J. D., & Evans, T. W. (1992) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1992.263.3.l325 · Cited by 65 · see citing works
Zharikov, S. I., & Block, E. R. (2000) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2000.278.1.l111 · Cited by 53 · see citing works
Chronic hypoxia attenuates cGMP-dependent pulmonary vasodilation
Jernigan, N. L., & Resta, T. C. (2002) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00273.2001 · Cited by 46 · see citing works
Parnell, M. M., Holst, D. P., & Kaye, D. M. (2005) · Clinical Science · doi:10.1042/cs20050171 · Cited by 39 · see citing works
Alterations in pulmonary vascular function in rats exposed to intermittent hypoxia
Thomas, B. J., & Wanstall, J. C. (2003) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2003.08.015 · Cited by 36 · see citing works
Favret, F., Henderson, K. K., Allen, J., Richalet, J., & González, N. C. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00673.2005 · Cited by 34 · see citing works
Goret, L., Reboul, C., Tanguy, S., Dauzat, M., & Obert, P. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.10.013 · Cited by 30 · see citing works
Self-citationTörök, J. (2000) · Physiological Research · doi:10.33549/physiolres.930000.49.107 · Cited by 29 · see citing works
Nitric oxide formation and plasma l-arginine levels in pulmonary hypertensive rats
Sasaki, S., Asano, M., Ukai, T., Nomura, N., Maruyama, K., Manabe, T., & Mishima, A. (2003) · Respiratory Medicine · doi:10.1016/j.rmed.2003.09.013 · Cited by 27 · see citing works
Hypoxic remodeling of the rat pulmonary arterial microcirculation assessed by microdissection
Davies, P. A., & REID, L. M. (1991) · Journal of Applied Physiology · doi:10.1152/jappl.1991.71.5.1886 · Cited by 25 · see citing works
Jeffery, T. K., & Wanstall, J. C. (2001) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-79-3-227 · Cited by 24 · see citing works
Kashimura, O., & Sakai, A. (1991) · International Journal of Biometeorology · doi:10.1007/bf01047288 · Cited by 23 · see citing works
Nitric Oxide and Other Novel Therapies for Pulmonary Hypertension
Claudio Napoli, A., & Loscalzo, J. (2004) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/107424840400900i101 · Cited by 23 · see citing works
Henderson, K. K., Clancy, R. L., & González, N. C. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.90.6.2057 · Cited by 23 · see citing works
Jeffery, T. K., & Wanstall, J. C. (2001) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y00-117 · Cited by 19 · see citing works
Pulmonary Hemodynamics and Physical Training in Patients with Chronic Obstructive Pulmonary Disease
Rogers, T. K., & Howard, P. (1992) · CHEST Journal · doi:10.1378/chest.101.5_supplement.289s · Cited by 16 · see citing works
Sumou, I. K., Du, J., Wei, B., Zhang, C.-Y., Qi, J., & Tang, C. (2006) · Acta Biochimica et Biophysica Sinica · doi:10.1111/j.1745-7270.2006.00131.x · Cited by 10 · see citing works
Decreased exhaled nitric oxide as a marker of postinsult immune paralysis
Attalah, H. L., Honoré, S., Eddahibi, S., Marcos, É., Soussy, C., Adnot, S., & Delclaux, C. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00840.2003 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Laughlin, M. H., Davis, M. J., Secher, N. H., LIESHOUT, J. J. V., Arce‐Esquivel, A. A., Simmons, G. H., Bender, S. B., Padilla, J., Bache, R. J., Merkus, D., et al. (2012) · Comprehensive physiology · doi:10.1002/cphy.c100048 · Cited by 264 · see citing works
Zuckerbraun, B. S., Shiva, S., Ifedigbo, E., Mathier, M. A., Mollen, K. P., Rao, J., Bauer, P. M., Choi, J. J. W., Curtis, E., Choi, A. M. K., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.891077 · Cited by 192 · see citing works
Koch, C. D., Gladwin, M. T., Freeman, B. A., Lundberg, J. O., Weitzberg, E., & Morris, A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.015 · Cited by 186 · see citing works
Efficacy and Safety of Exercise Training in Chronic Pulmonary Hypertension
Pandey, A., Garg, S. K., Khunger, M., Garg, S., Kumbhani, D. J., Chin, K., & Berry, J. D. (2015) · Circulation Heart Failure · doi:10.1161/circheartfailure.115.002130 · Cited by 108 · see citing works
Bueno, M., Wang, J., Mora, A. L., & Gladwin, M. T. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4833 · Cited by 68 · see citing works
Shan, L., Wang, B., Gao, G., Cao, W., & Zhang, Y. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00225.2013 · Cited by 64 · see citing works
Endothelial dysfunction in hypertension: The role of arginase
Danielle, L. M. (2011) · Frontiers in Bioscience-Scholar · doi:10.2741/199 · Cited by 48 · see citing works
Howell, K., Costello, C. M., Sands, M. A., Dooley, I. J., & McLoughlin, P. (2009) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.90327.2008 · Cited by 45 · see citing works
Exercise Training and Rehabilitation in Pulmonary Arterial Hypertension
Zafrir, B. (2013) · Journal of Cardiopulmonary Rehabilitation and Prevention · doi:10.1097/hcr.0b013e3182a0299a · Cited by 38 · see citing works
Mechanisms of the protective effects of nitrate and nitrite in cardiovascular and metabolic diseases
Liu, Y., Croft, K. D., Hodgson, J. M., Mori, T., & Ward, N. C. (2020) · Nitric Oxide · doi:10.1016/j.niox.2020.01.006 · Cited by 41 · see citing works
Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension
Pankey, E. A., Badejo, A. M., Casey, D. B., Lasker, G. F., Riehl, R. A., Murthy, S. N., Nossaman, B. D., & Kadowitz, P. J. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.02.004 · Cited by 35 · see citing works
Brown, M. B., Kempf, A., Collins, C. M., Long, G., Owens, M., Gupta, S., Hellman, Y., Wong, V., Farber, M. O., & Lahm, T. (2017) · Pulmonary Circulation · doi:10.1177/2045893217743966 · Cited by 34 · see citing works
Laughlin, M. H., Davis, M. J., Secher, N. H., LIESHOUT, J. J. V., Arce‐Esquivel, A. A., Simmons, G. H., Bender, S. B., Padilla, J., Bache, R. J., Merkus, D., et al. (2012) · Comprehensive physiology · doi:10.1002/j.2040-4603.2012.tb00398.x · Cited by 28 · see citing works
Speer, H., D'Cunha, N. M., Davies, M. J., McKune, A. J., & Naumovski, N. (2020) · Beverages · doi:10.3390/beverages6010011 · Cited by 18 · see citing works
Novel therapeutic strategies targeting vascular endothelium in essential hypertension
Tousoulis, D., Παπαγεωργίου, Ν., Androulakis, E. S., Paroutoglou, K., & Stefanadis, C. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2010.522989 · Cited by 13 · see citing works
Öztürk, E. İ., & Uma, S. (2010) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e3181f4838b · Cited by 12 · see citing works
Yan, T., Zhang, G., Li, B.-L., Zhong, K., Xu, Z., & Han, L. (2012) · Heart Lung and Circulation · doi:10.1016/j.hlc.2012.07.008 · Cited by 12 · see citing works
Extrapulmonary manifestations of pulmonary arterial hypertension
Singh, N., Al‐Naamani, N., Brown, M. B., Long, G., Thenappan, T., Umar, S., Ventetuolo, C. E., & Lahm, T. (2024) · Expert Review of Respiratory Medicine · doi:10.1080/17476348.2024.2361037 · Cited by 11 · see citing works
HEINONEN, I. H. A., Savolainen, A., Han, C., Kemppainen, J., Oikonen, V., Luotolahti, M., Duncker, D. J., Merkus, D., Knuuti, J. M., & Kalliokoski, K. K. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00710.2012 · Cited by 11 · see citing works
Allergic activation of mast cells.
Parker, C. W. (1986) · PubMed · Cited by 5 · see citing works
Exercise improves systemic metabolism in a monocrotaline model of pulmonary hypertension
Poojary, G., Vasishta, S., Thomas, H., Satyamoorthy, K., Ramachandran, P., Joshi, M. B., & Babu, A. S. (2024) · Sports Medicine and Health Science · doi:10.1016/j.smhs.2024.03.001 · Cited by 3 · see citing works
Nitric Oxide in Pathophysiology and Treatment of Pulmonary Hypertension
Maruyama, J., Yokochi, A., Zhang, E., Sawada, H., & Maruyam, K. (2013) · InTech eBooks · doi:10.5772/55680 · Cited by 1 · see citing works
Maron, B. A. (2014) · Pulmonary Circulation · doi:10.1086/678544 · Cited by 1 · see citing works
Tavasoli, F. (2014) · TSpace (University of Toronto)
- Authors
- Goret, L., Tanguy, S., Guiraud, I., Dauzat, M., & Obert, P.
- Affiliations
- Université d'Avignon et des Pays de Vaucluse (FR)
- Université Montpellier 1 (FR)
- Corresponding author
- Goret, Lucie
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 581
- Issue
- 1-2
- Pages
- 148-156
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W2022666582
- Cited by
- 24
- References
- 35
- Citations by year
- 2024: 2 · 2020: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 6
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- L-arginine, nitric oxide, pulmonary hypertension, exercise training, hypobaric hypoxia, pulmonary vasodilation, endothelium-dependent relaxation, nitric oxide synthase, L-NAME, acetylcholine
- MeSH terms
- Animals, Arginine, Hypertension, Pulmonary, Male, Nitric Oxide, Nitroprusside, Physical Conditioning, Animal, Pulmonary Artery, Vasodilation, Rats, Wistar, Rats, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
