Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

Regulation of Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease: A Mechanistic Approach

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01398943
• Other study ID #: AHA00115CS
• Status: Completed
• Phase: N/A
• First received: July 19, 2011
• Last updated: November 9, 2017
• Start date: September 2010
• Est. completion date: June 2015

Study information

• Verified date: November 2017
• Source: Augusta University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

More patients with chronic obstructive pulmonary disease (COPD) die from cardiovascular disease than direct pulmonary complications. Inflammation and oxidative stress, characteristic in COPD, are likely contributors to the reduction in nitric oxide (NO) bioavailability and vascular endothelial dysfunction in COPD patients; however, this has yet to be determined. Thus, the overall objective of this proposal is to identify the role of NO bioavailability in contributing to vascular endothelial dysfunction in patients with COPD and to provide insight into the molecular mechanisms involved. Our central hypothesis is that inflammation and oxidative stress, both independently, contribute to the reduction in NO bioavailability and vascular endothelial dysfunction in patients with COPD.

Description:

Flow-Mediated Dilation (FMD) - Subjects will lie in the supine position for 20 minutes to obtain hemodynamic steady state. A blood pressure cuff (Hokanson) will be placed around the forearm (distal to the Doppler transducer) and rapidly inflated to 250 mmHg for 5 minutes (circulatory arrest). Simultaneous ultrasound images of the vessel (B-mode) and Doppler waveforms will be collected 10 seconds prior to and for 2 minutes following deflation of the cuff. All B-mode images will be analyzed using automated edge detection software (Medical Imaging Applications), while intensity weighted velocity spectra segments will be saved to the GE Logiq 7 hard drive for off-line blood velocity waveform analysis. P.I. has utilized the traditional method of brachial artery flow-mediated dilation (FMD) induced by reactive hyperemia to assess vascular endothelial function in populations ranging from young healthy adults to older adults with pathological conditions.

Spygmocor - Pulse Wave Velocity (PWV) - A Spygmocor® device will be used at baseline and following each protocol to assess PWV. PWV analysis provides a non-invasive assessment of arterial stiffness. Increased arterial stiffness is known to be associated with cardiovascular disease. The participant is required to lie in a resting position for approximately 30-45 minutes. The research assistant will place ECG electrode sensors at the carotid, femoral, radial and distal artery locations. A highly sensitive pen-like device, called a tonometer, is then gently applied to record the velocity of the blood flow between each of the points.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with COPD (GOLD stages II-IV) and matched healthy controls

• Caucasian or African American

• Both men and women

• Current and former smokers

Exclusion Criteria:

• GOLD Stage I

• Clinical diagnosis of heart disease, hypertension, or metabolic disease

• Vasoactive medications (i.e. nitrates, beta-blockers, ACE inhibitors, Viagra, etc.)

• Pulmonary hypertension

• Hypothyroidism

• Hyper-homocysteinemia

• Interstitial lung disease

• Phenylketonuria

• Pregnancy

• Sleep apnea

• Anemia

• Raynod's phenomenon

• Gangrene of the digits

• History of low platelets or coagulopathies

• Aspirin sensitivity or allergy

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Tetrahydrobiopterin (BH4)
single dose = 5 mg/kg

Dietary Supplement:
• Antioxidant Cocktail
1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid

Locations

Country	Name	City	State
United States	Augusta University	Augusta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Augusta University	American Heart Association

Country where clinical trial is conducted

United States, 

References & Publications (61)

Anthonisen NR, Connett JE, Enright PL, Manfreda J; Lung Health Study Research Group. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med. 2002 Aug 1;166(3):333-9. — View Citation

Atkinson MH, Ménard HA, Kalish GH. Assessment of salsalate, a nonacetylated salicylate, in the treatment of patients with arthritis. Clin Ther. 1995 Sep-Oct;17(5):827-37. — View Citation

Bailey DM, Davies B, Young IS, Jackson MJ, Davison GW, Isaacson R, Richardson RS. EPR spectroscopic detection of free radical outflow from an isolated muscle bed in exercising humans. J Appl Physiol (1985). 2003 May;94(5):1714-8. Epub 2003 Mar 7. — View Citation

Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997 Apr 10;336(15):1066-71. Review. — View Citation

Barr RG, Mesia-Vela S, Austin JH, Basner RC, Keller BM, Reeves AP, Shimbo D, Stevenson L. Impaired flow-mediated dilation is associated with low pulmonary function and emphysema in ex-smokers: the Emphysema and Cancer Action Project (EMCAP) Study. Am J Respir Crit Care Med. 2007 Dec 15;176(12):1200-7. Epub 2007 Aug 29. — View Citation

Bleeker MW, Kooijman M, Rongen GA, Hopman MT, Smits P. Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle. J Physiol. 2005 Jun 1;565(Pt 2):685-94. Epub 2005 Mar 31. — View Citation

Bombardier C, Peloso PM, Goldsmith CH. Salsalate, a nonacetylated salicylate, is as efficacious as diclofenac in patients with rheumatoid arthritis. Salsalate-Diclofenac Study Group. J Rheumatol. 1995 Apr;22(4):617-24. — View Citation

Casaburi R. Skeletal muscle function in COPD. Chest. 2000 May;117(5 Suppl 1):267S-71S. Review. — View Citation

Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med. 1996 Jan 18;334(3):150-4. — View Citation

Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993 Nov;88(5 Pt 1):2149-55. — View Citation

Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992 Nov 7;340(8828):1111-5. — View Citation

Channon KM. Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med. 2004 Nov;14(8):323-7. Review. — View Citation

De Boer WI. Cytokines and therapy in COPD: a promising combination? Chest. 2002 May;121(5 Suppl):209S-218S. Review. — View Citation

Edwards DG, Schofield RS, Lennon SL, Pierce GL, Nichols WW, Braith RW. Effect of exercise training on endothelial function in men with coronary artery disease. Am J Cardiol. 2004 Mar 1;93(5):617-20. — View Citation

Eickhoff P, Valipour A, Kiss D, Schreder M, Cekici L, Geyer K, Kohansal R, Burghuber OC. Determinants of systemic vascular function in patients with stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008 Dec 15;178(12):1211-8. doi: 10.1164/rccm.200709-1412OC. Epub 2008 Oct 3. — View Citation

Eskurza I, Myerburgh LA, Kahn ZD, Seals DR. Tetrahydrobiopterin augments endothelium-dependent dilatation in sedentary but not in habitually exercising older adults. J Physiol. 2005 Nov 1;568(Pt 3):1057-65. Epub 2005 Sep 1. — View Citation

Fukai T. Endothelial GTPCH in eNOS uncoupling and atherosclerosis. Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1493-5. — View Citation

Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J, Shoelson SE. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci. 2008 May;1(1):36-43. doi: 10.1111/j.1752-8062.2008.00026.x. — View Citation

Green D. Point: Flow-mediated dilation does reflect nitric oxide-mediated endothelial function. J Appl Physiol (1985). 2005 Sep;99(3):1233-4; discussion 1237-8. — View Citation

Guerci B, Kearney-Schwartz A, Böhme P, Zannad F, Drouin P. Endothelial dysfunction and type 2 diabetes. Part 1: physiology and methods for exploring the endothelial function. Diabetes Metab. 2001 Sep;27(4 Pt 1):425-34. Review. — View Citation

Halliwell B. Free radicals and antioxidants: a personal view. Nutr Rev. 1994 Aug;52(8 Pt 1):253-65. Review. — View Citation

Harris RA, Nishiyama SK, Wray DW, Tedjasaputra V, Bailey DM, Richardson RS. The effect of oral antioxidants on brachial artery flow-mediated dilation following 5 and 10 min of ischemia. Eur J Appl Physiol. 2009 Nov;107(4):445-53. doi: 10.1007/s00421-009-1147-x. Epub 2009 Aug 11. — View Citation

Harris RA, Padilla J, Hanlon KP, Rink LD, Wallace JP. Reproducibility of the flow-mediated dilation response to acute exercise in overweight men. Ultrasound Med Biol. 2007 Oct;33(10):1579-85. Epub 2007 Jun 27. — View Citation

Harris RA, Padilla J, Rink LD, Wallace JP. Variability of flow-mediated dilation measurements with repetitive reactive hyperemia. Vasc Med. 2006 Feb;11(1):1-6. — View Citation

Heitzer T, Brockhoff C, Mayer B, Warnholtz A, Mollnau H, Henne S, Meinertz T, Münzel T. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase. Circ Res. 2000 Feb 4;86(2):E36-41. — View Citation

Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med. 1996 Feb;153(2):530-4. — View Citation

Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, Wilkins MR, Channon KM. Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation. 2005 Apr 26;111(16):2126-33. Epub 2005 Apr 11. — View Citation

Kingwell BA, Formosa M, Muhlmann M, Bradley SJ, McConell GK. Nitric oxide synthase inhibition reduces glucose uptake during exercise in individuals with type 2 diabetes more than in control subjects. Diabetes. 2002 Aug;51(8):2572-80. — View Citation

Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J. 1994 Mar 1;298 ( Pt 2):249-58. Review. — View Citation

Lieberman EH, Gerhard MD, Uehata A, Selwyn AP, Ganz P, Yeung AC, Creager MA. Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol. 1996 Dec 1;78(11):1210-4. — View Citation

Macnee W. Pathogenesis of chronic obstructive pulmonary disease. Clin Chest Med. 2007 Sep;28(3):479-513, v. Review. — View Citation

Maiorana A, O'Driscoll G, Taylor R, Green D. Exercise and the nitric oxide vasodilator system. Sports Med. 2003;33(14):1013-35. Review. — View Citation

Mercier JG, Hokanson JF, Brooks GA. Effects of cyclosporine A on skeletal muscle mitochondrial respiration and endurance time in rats. Am J Respir Crit Care Med. 1995 May;151(5):1532-6. — View Citation

Moro L, Pedone C, Scarlata S, Malafarina V, Fimognari F, Antonelli-Incalzi R. Endothelial dysfunction in chronic obstructive pulmonary disease. Angiology. 2008 Jun-Jul;59(3):357-64. doi: 10.1177/0003319707306141. Epub 2008 Apr 2. — View Citation

Mullen MJ, Kharbanda RK, Cross J, Donald AE, Taylor M, Vallance P, Deanfield JE, MacAllister RJ. Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia. Circ Res. 2001 Feb 2;88(2):145-51. — View Citation

Nandi M, Miller A, Stidwill R, Jacques TS, Lam AA, Haworth S, Heales S, Vallance P. Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse. Circulation. 2005 Apr 26;111(16):2086-90. Epub 2005 Apr 11. — View Citation

Neunteufl T, Kostner K, Katzenschlager R, Zehetgruber M, Maurer G, Weidinger F. Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol. 1998 Sep;32(3):711-6. — View Citation

Padilla J, Harris RA, Fly AD, Rink LD, Wallace JP. A comparison between active- and reactive-hyperaemia-induced brachial artery vasodilation. Clin Sci (Lond). 2006 Mar;110(3):387-92. — View Citation

Padilla J, Harris RA, Fly AD, Rink LD, Wallace JP. The effect of acute exercise on endothelial function following a high-fat meal. Eur J Appl Physiol. 2006 Oct;98(3):256-62. Epub 2006 Aug 3. — View Citation

Pierce GL, Lesniewski LA, Lawson BR, Beske SD, Seals DR. Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation. 2009 Mar 10;119(9):1284-92. doi: 10.1161/CIRCULATIONAHA.108.804294. Epub 2009 Feb 23. — View Citation

Plantinga Y, Ghiadoni L, Magagna A, Giannarelli C, Franzoni F, Taddei S, Salvetti A. Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients. Am J Hypertens. 2007 Apr;20(4):392-7. — View Citation

Plotnick GD, Corretti MC, Vogel RA. Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal. JAMA. 1997 Nov 26;278(20):1682-6. — View Citation

Raitakari OT, Adams MR, McCredie RJ, Griffiths KA, Celermajer DS. Arterial endothelial dysfunction related to passive smoking is potentially reversible in healthy young adults. Ann Intern Med. 1999 Apr 6;130(7):578-81. — View Citation

Read MA, Whitley MZ, Williams AJ, Collins T. NF-kappa B and I kappa B alpha: an inducible regulatory system in endothelial activation. J Exp Med. 1994 Feb 1;179(2):503-12. — View Citation

Richardson RS, Secher NH, Tschakovsky ME, Proctor DN, Wray DW. Metabolic and vascular limb differences affected by exercise, gender, age, and disease. Med Sci Sports Exerc. 2006 Oct;38(10):1792-6. — View Citation

Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol. 1986 May;250(5 Pt 2):H822-7. — View Citation

Sander M, Chavoshan B, Victor RG. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. 1999 Apr;33(4):937-42. — View Citation

Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000 Apr 25;101(16):1899-906. — View Citation

Selvaraj CL, Gurm HS, Gupta R, Ellis SG, Bhatt DL. Chronic obstructive pulmonary disease as a predictor of mortality in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2005 Sep 15;96(6):756-9. — View Citation

Shapiro SD, Senior RM. Matrix metalloproteinases. Matrix degradation and more. Am J Respir Cell Mol Biol. 1999 Jun;20(6):1100-2. Review. — View Citation

Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000 Mar 7;101(9):948-54. — View Citation

Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol. 2000 Sep;36(3):758-65. — View Citation

Tsai WC, Li YH, Lin CC, Chao TH, Chen JH. Effects of oxidative stress on endothelial function after a high-fat meal. Clin Sci (Lond). 2004 Mar;106(3):315-9. — View Citation

Ueda S, Matsuoka H, Miyazaki H, Usui M, Okuda S, Imaizumi T. Tetrahydrobiopterin restores endothelial function in long-term smokers. J Am Coll Cardiol. 2000 Jan;35(1):71-5. — View Citation

Uehata A, Lieberman EH, Gerhard MD, Anderson TJ, Ganz P, Polak JF, Creager MA, Yeung AC. Noninvasive assessment of endothelium-dependent flow-mediated dilation of the brachial artery. Vasc Med. 1997;2(2):87-92. — View Citation

Verma S, Buchanan MR, Anderson TJ. Endothelial function testing as a biomarker of vascular disease. Circulation. 2003 Oct 28;108(17):2054-9. Review. — View Citation

Vogel RA, Corretti MC, Plotnick GD. Effect of a single high-fat meal on endothelial function in healthy subjects. Am J Cardiol. 1997 Feb 1;79(3):350-4. — View Citation

Wheatcroft SB, Williams IL, Shah AM, Kearney MT. Pathophysiological implications of insulin resistance on vascular endothelial function. Diabet Med. 2003 Apr;20(4):255-68. Review. — View Citation

Williams TJ, Howard M, Roget J, Esmore DS. Exercise capacity after combined heart-lung transplantation. Transplant Proc. 1992 Oct;24(5):2018. — View Citation

Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998 Nov 5;396(6706):77-80. — View Citation

Zarubina EG, Mishina EA, Osadchuk MA. [The role of endothelial dysfunction in the pathogenesis of combined cardiopulmonary diseases]. Klin Med (Mosk). 2006;84(5):31-4. Russian. — View Citation

* Note: There are 61 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Flow-Mediated Dilation (FMD)	Brachial artery FMD induced by reactive hyperemia will be used to assess vascular endothelial function at baseline and several hours after each experimental intervention.	Post FMD was taken approximately 110 min after baseline
Secondary	Pulse Wave Velocity	A measure of vascular stiffness at baseline and several hours after each experimental intervention.	Post PWV was taken approximately 90 min after baseline