EMAN RESEARCH PUBLISHING | <p>Ascorbate blocks acetylcholine- and bradykinin-induced vasodilatation in retinal vascular bed of the bovine isolated perfused eye</p>
Inflammation Cancer Angiogenesis Biology and Therapeutics | Impact 0.4 (CiteScore) | Online ISSN  2207-872X
RESEARCH ARTICLE   (Open Access)

Ascorbate blocks acetylcholine- and bradykinin-induced vasodilatation in retinal vascular bed of the bovine isolated perfused eye

Li-xin XU A, Xiao-bo XIA B, Aman Shah Abdul Majid C, Dan Ji B

+ Author Affiliations

Journal of Angiotherapy 3(1) 123-131 https://doi.org/10.25163/angiotherapy.312067129151519

Submitted: 29 April 2019  Revised: 15 May 2019  Published: 15 May 2019 

Abstract

Background: The regulation of retinal blood flow is largely dependent on alteration of vascular tone of the retinal arterioles in response to local mechanical and chemical stimuli. Such vasomotor activity can be modulated by the release of vasoactive factors from the endothelium. As most blindness-causing disorders are associated with abnormal retinal blood flow, it is critical to determine the abnormality of microcirculation control involved. Methods: The present study developed a model in isolated bovine retinal vascular bed to study agonist-induced vaso-relaxation. Both acetylcholine and bradykinin were used to stimulate vaso-relaxation and the effects of NOS inhibitor and prostacyclin and ascorbate (Vitamin C) were examined. Results: Both acetylcholine and bradykinin efficiently stimulated such a non-traditional vaso-relaxation that neither NO nor prostacyclin is involved. Hence this process was linked to the mediator belonging to endothelium-derived hyperpolarizing factor (EDHF). As a concentrated anti-oxidant in eyes, ascorbate showed capability to block acetylcholine- and bradykinin-induced vasodilatation in bovine retinal arteries. Conclusion: Acetylcholine and bradykinin induces EDHF-mediated vaso-relaxation in bovine retinal blood vessels which is blocked by ascorbate. This study provides insight to EDHF-mediated vasomotor response, as well as various eye disorders caused by dysfunctional retinal arteries, like central retinal artery occlusion.

Keywords: vasodilator, acetylcholine, bradykinin, bovine retinal artery

References

Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Population health metrics. 2010;8:29. Epub 2010/10/26. doi: 10.1186/1478-7954-8-29. PubMed PMID: 20969750; PubMed Central PMCID: PMCPMC2984379.
https://doi.org/10.1186/1478-7954-8-29
PMid:20969750 PMCid:PMC2984379
 
Carr BC, Emigh CE, Bennett LD, Pansick AD, Birch DG, Nguyen C. TOWARDS A TREATMENT FOR DIABETIC RETINOPATHY: Intravitreal Toxicity and Preclinical Safety Evaluation of Inducible Nitric Oxide Synthase Inhibitors. Retina (Philadelphia, Pa). 2017;37(1):22-31. Epub 2016/07/06. doi: 10.1097/iae.0000000000001133. PubMed PMID: 27380429; PubMed Central PMCID: PMCPMC5177480.
https://doi.org/10.1097/IAE.0000000000001133
PMid:27380429 PMCid:PMC5177480
 
Dong Y, Watabe H, Cui J, Abe S, Sato N, Ishikawa H, et al. Reduced effects of endothelium-derived hyperpolarizing factor in ocular ciliary arteries from spontaneous hypertensive rats. Experimental eye research. 2010;90(2):324-9. Epub 2009/11/28. doi: 10.1016/j.exer.2009.11.009. PubMed PMID: 19941853.
https://doi.org/10.1016/j.exer.2009.11.009
PMid:19941853
 
Dudgeon S, Benson DP, MacKenzie A, Paisley-Zyszkiewicz K, Martin W. Recovery by ascorbate of impaired nitric oxide-dependent relaxation resulting from oxidant stress in rat aorta. British journal of pharmacology. 1998;125(4):782-6. Epub 1998/12/01. doi: 10.1038/sj.bjp.0702120. PubMed PMID: 9831915; PubMed Central PMCID: PMCPMC1571043.
https://doi.org/10.1038/sj.bjp.0702120
PMid:9831915 PMCid:PMC1571043
 
Edwards G, Thollon C, Gardener MJ, Feletou M, Vilaine J, Vanhoutte PM, et al. Role of gap junctions and EETs in endothelium-dependent hyperpolarization of porcine coronary artery. British journal of pharmacology. 2000;129(6):1145-54. Epub 2000/03/22. doi: 10.1038/sj.bjp.0703188. PubMed PMID: 10725263; PubMed Central PMCID: PMCPMC1571957.
https://doi.org/10.1038/sj.bjp.0703188
PMid:10725263 PMCid:PMC1571957
 
Fontana L, McNeill KL, Ritter JM, Chowienczyk PJ. Effects of vitamin C and of a cell permeable superoxide dismutase mimetic on acute lipoprotein induced endothelial dysfunction in rabbit aortic rings. British journal of pharmacology. 1999;126(3):730-4. Epub 1999/04/03. doi: 10.1038/sj.bjp.0702331. PubMed PMID: 10188985; PubMed Central PMCID: PMCPMC1565839.
https://doi.org/10.1038/sj.bjp.0702331
PMid:10188985 PMCid:PMC1565839
 
Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986;320(6061):454-6. Epub 1986/04/03. doi: 10.1038/320454a0. PubMed PMID: 3007998.
https://doi.org/10.1038/320454a0
PMid:3007998
 
Guthrie MJ, Osswald CR, Kang-Mieler JJ. Inverse relationship between the intraretinal concentration of bioavailable nitric oxide and blood glucose in early experimental diabetic retinopathy. Investigative ophthalmology & visual science. 2014;56(1):37-44. Epub 2014/12/17. doi: 10.1167/iovs.14-15777. PubMed PMID: 25503458.
https://doi.org/10.1167/iovs.14-15777
PMid:25503458
 
Haefliger IO, Flammer J, Beny JL, Luscher TF. Endothelium-dependent vasoactive modulation in the ophthalmic circulation. Progress in retinal and eye research. 2001;20(2):209-25. Epub 2001/02/15. PubMed PMID: 11173252.
https://doi.org/10.1016/S1350-9462(00)00020-3
 
Hardy P, Dumont I, Bhattacharya M, Hou X, Lachapelle P, Varma DR, et al. Oxidants, nitric oxide and prostanoids in the developing ocular vasculature: a basis for ischemic retinopathy. Cardiovascular research. 2000;47(3):489-509. Epub 2000/08/30. PubMed PMID: 10963722.
https://doi.org/10.1016/S0008-6363(00)00084-5
 
Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. The Journal of biological chemistry. 2001;276(1):40-7. Epub 2000/10/07. doi: 10.1074/jbc.M004392200. PubMed PMID: 11022034.
https://doi.org/10.1074/jbc.M004392200
PMid:11022034
 
Hou X, Roberts LJ, 2nd, Gobeil F, Jr., Taber D, Kanai K, Abran D, et al. Isomer-specific contractile effects of a series of synthetic f2-isoprostanes on retinal and cerebral microvasculature. Free radical biology & medicine. 2004;36(2):163-72. Epub 2004/01/28. PubMed PMID: 14744628.
https://doi.org/10.1016/j.freeradbiomed.2003.10.024
PMid:14744628
 
Huang A, Vita JA, Venema RC, Keaney JF, Jr. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. The Journal of biological chemistry. 2000;275(23):17399-406. Epub 2000/04/06. doi: 10.1074/jbc.M002248200. PubMed PMID: 10749876.
https://doi.org/10.1074/jbc.M002248200
PMid:10749876
 
Khansari MM, Wanek J, Tan M, Joslin CE, Kresovich JK, Camardo N, et al. Assessment of Conjunctival Microvascular Hemodynamics in Stages of Diabetic Microvasculopathy. Scientific reports. 2017;7:45916. Epub 2017/04/08. doi: 10.1038/srep45916. PubMed PMID: 28387229; PubMed Central PMCID: PMCPMC5384077.
https://doi.org/10.1038/srep45916
PMid:28387229 PMCid:PMC5384077
 
Koustenis A, Jr., Harris A, Gross J, Januleviciene I, Shah A, Siesky B. Optical coherence tomography angiography: an overview of the technology and an assessment of applications for clinical research. The British journal of ophthalmology. 2017;101(1):16-20. Epub 2016/10/07. doi: 10.1136/bjophthalmol-2016-309389. PubMed PMID: 27707691.
https://doi.org/10.1136/bjophthalmol-2016-309389
PMid:27707691
 
Lee B, Novais EA, Waheed NK, Adhi M, de Carlo TE, Cole ED, et al. En Face Doppler Optical Coherence Tomography Measurement of Total Retinal Blood Flow in Diabetic Retinopathy and Diabetic Macular Edema. JAMA ophthalmology. 2017;135(3):244-51. Epub 2017/02/15. doi: 10.1001/jamaophthalmol.2016.5774. PubMed PMID: 28196198; PubMed Central PMCID: PMCPMC5784830.
https://doi.org/10.1001/jamaophthalmol.2016.5774
PMid:28196198 PMCid:PMC5784830
 
Liao PL, Lin CH, Li CH, Tsai CH, Ho JD, Chiou GC, et al. Anti-inflammatory properties of shikonin contribute to improved early-stage diabetic retinopathy. Scientific reports. 2017;7:44985. Epub 2017/03/23. doi: 10.1038/srep44985. PubMed PMID: 28322323; PubMed Central PMCID: PMCPMC5359562.
https://doi.org/10.1038/srep44985
PMid:28322323 PMCid:PMC5359562
 
Linsenmeier RA, Zhang HF. Retinal oxygen: from animals to humans. Progress in retinal and eye research. 2017;58:115-51. Epub 2017/01/23. doi: 10.1016/j.preteyeres.2017.01.003. PubMed PMID: 28109737; PubMed Central PMCID: PMCPMC5441959.
https://doi.org/10.1016/j.preteyeres.2017.01.003
PMid:28109737 PMCid:PMC5441959
 
Marjanovic I, Marjanovic M, Martinez A, Markovic V, Bozic M, Stojanov V. Relationship between blood pressure and retrobulbar blood flow in dipper and nondipper primary open-angle glaucoma patients. European journal of ophthalmology. 2016;26(6):588-93. Epub 2016/10/30. doi: 10.5301/ejo.5000789. PubMed PMID: 27338118.
https://doi.org/10.5301/ejo.5000789
PMid:27338118
 
McKenna KC, Beatty KM, Scherder RC, Li F, Liu H, Chen AF, et al. Ascorbate in aqueous humor augments nitric oxide production by macrophages. Journal of immunology (Baltimore, Md : 1950). 2013;190(2):556-64. Epub 2012/12/18. doi: 10.4049/jimmunol.1201754. PubMed PMID: 23241881; PubMed Central PMCID: PMCPMC3538947.
https://doi.org/10.4049/jimmunol.1201754
PMid:23241881 PMCid:PMC3538947
 
McNeish AJ, Wilson WS, Martin W, editors. Ascorbic acid attenuates EDHF-mediated vasodilatation in the bovine isolated perfused eye. BPS meeting 2002a; Imperial College London.
 
McNeish AJ, Wilson WS, Martin W. Dominant role of an endothelium-derived hyperpolarizing factor (EDHF)-like vasodilator in the ciliary vascular bed of the bovine isolated perfused eye. British journal of pharmacology. 2001;134(4):912-20. Epub 2001/10/19. doi: 10.1038/sj.bjp.0704332. PubMed PMID: 11606333; PubMed Central PMCID: PMCPMC1573020.
https://doi.org/10.1038/sj.bjp.0704332
PMid:11606333 PMCid:PMC1573020
 
Mori A, Namekawa R, Hasebe M, Saito M, Sakamoto K, Nakahara T, et al. Involvement of prostaglandin I(2) in nitric oxide-induced vasodilation of retinal arterioles in rats. European journal of pharmacology. 2015;764:249-55. Epub 2015/07/08. doi: 10.1016/j.ejphar.2015.07.009. PubMed PMID: 26151307.
https://doi.org/10.1016/j.ejphar.2015.07.009
PMid:26151307
 
Mori A, Saito M, Sakamoto K, Narita M, Nakahara T, Ishii K. Stimulation of prostanoid IP and EP(2) receptors dilates retinal arterioles and increases retinal and choroidal blood flow in rats. European journal of pharmacology. 2007;570(1-3):135-41. Epub 2007/07/14. doi: 10.1016/j.ejphar.2007.05.052. PubMed PMID: 17628525.
https://doi.org/10.1016/j.ejphar.2007.05.052
PMid:17628525
 
Nelli S, Wilson WS, Laidlaw H, Llano A, Middleton S, Price AG, et al. Evaluation of potassium ion as the endothelium-derived hyperpolarizing factor (EDHF) in the bovine coronary artery. British journal of pharmacology. 2003;139(5):982-8. Epub 2003/07/04. doi: 10.1038/sj.bjp.0705329. PubMed PMID: 12839872; PubMed Central PMCID: PMCPMC1573923.
https://doi.org/10.1038/sj.bjp.0705329
PMid:12839872 PMCid:PMC1573923
 
Ono S, Nagaoka T, Omae T, Tanano I, Kamiya T, Otani S, et al. Beraprost sodium, a stable prostacyclin analogue, elicits dilation of isolated porcine retinal arterioles: roles of eNOS and potassium channels. Investigative ophthalmology & visual science. 2014;55(9):5752-9. Epub 2014/08/02. doi: 10.1167/iovs.14-14902. PubMed PMID: 25082887.
https://doi.org/10.1167/iovs.14-14902
PMid:25082887
 
Opatrilova R, Kubatka P, Caprnda M, Busselberg D, Krasnik V, Vesely P, et al. Nitric oxide in the pathophysiology of retinopathy: evidences from preclinical and clinical researches. Acta ophthalmologica. 2018;96(3):222-31. Epub 2017/04/10. doi: 10.1111/aos.13384. PubMed PMID: 28391624.
https://doi.org/10.1111/aos.13384
PMid:28391624
 
Otani S, Nagaoka T, Omae T, Tanano I, Kamiya T, Ono S, et al. Histamine-Induced Dilation of Isolated Porcine Retinal Arterioles: Role of Endothelium-Derived Hyperpolarizing Factor. Investigative ophthalmology & visual science. 2016;57(11):4791-8. Epub 2016/09/13. doi: 10.1167/iovs.15-19038. PubMed PMID: 27618417.
https://doi.org/10.1167/iovs.15-19038
PMid:27618417
 
Pechauer AD, Hwang TS, Hagag AM, Liu L, Tan O, Zhang X, et al. Assessing total retinal blood flow in diabetic retinopathy using multiplane en face Doppler optical coherence tomography. The British journal of ophthalmology. 2018;102(1):126-30. Epub 2017/05/13. doi: 10.1136/bjophthalmol-2016-310042. PubMed PMID: 28495904; PubMed Central PMCID: PMCPMC5800769.
https://doi.org/10.1136/bjophthalmol-2016-310042
PMid:28495904 PMCid:PMC5800769
 
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. The British journal of ophthalmology. 2006;90(3):262-7. Epub 2006/02/21. doi: 10.1136/bjo.2005.081224. PubMed PMID: 16488940; PubMed Central PMCID: PMCPMC1856963.
https://doi.org/10.1136/bjo.2005.081224
PMid:16488940 PMCid:PMC1856963
 
Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. The American journal of physiology. 1986;250(5 Pt 2):H822-7. Epub 1986/05/01. doi: 10.1152/ajpheart.1986.250.5.H822. PubMed PMID: 3010744.
https://doi.org/10.1152/ajpheart.1986.250.5.H822
PMid:3010744
 
Sharma S, Saxena S, Srivastav K, Shukla RK, Mishra N, Meyer CH, et al. Nitric oxide and oxidative stress is associated with severity of diabetic retinopathy and retinal structural alterations. Clinical & experimental ophthalmology. 2015;43(5):429-36. Epub 2015/02/14. doi: 10.1111/ceo.12506. PubMed PMID: 25675974.
https://doi.org/10.1111/ceo.12506
PMid:25675974
 
Shima N, Kimoto M, Yamaguchi M, Yamagami S. Increased proliferation and replicative lifespan of isolated human corneal endothelial cells with L-ascorbic acid 2-phosphate. Investigative ophthalmology & visual science. 2011;52(12):8711-7. Epub 2011/10/08. doi: 10.1167/iovs.11-7592. PubMed PMID: 21980003.
https://doi.org/10.1167/iovs.11-7592
PMid:21980003
 
Shin YU, Lee SE, Cho H, Kang MH, Seong M. Analysis of Peripapillary Retinal Vessel Diameter in Unilateral Normal-Tension Glaucoma. Journal of ophthalmology. 2017;2017:8519878. Epub 2017/07/01. doi: 10.1155/2017/8519878. PubMed PMID: 28660081; PubMed Central PMCID: PMCPMC5474240.
https://doi.org/10.1155/2017/8519878
PMid:28660081 PMCid:PMC5474240
 
Srinivas S, Tan O, Nittala MG, Wu JL, Fawzi AA, Huang D, et al. ASSESSMENT OF RETINAL BLOOD FLOW IN DIABETIC RETINOPATHY USING DOPPLER FOURIER-DOMAIN OPTICAL COHERENCE TOMOGRAPHY. Retina (Philadelphia, Pa). 2017;37(11):2001-7. Epub 2017/01/19. doi: 10.1097/iae.0000000000001479. PubMed PMID: 28098726.
https://doi.org/10.1097/IAE.0000000000001479
PMid:28098726
 
Takusagawa HL, Liu L, Ma KN, Jia Y, Gao SS, Zhang M, et al. Projection-Resolved Optical Coherence Tomography Angiography of Macular Retinal Circulation in Glaucoma. Ophthalmology. 2017;124(11):1589-99. Epub 2017/07/06. doi: 10.1016/j.ophtha.2017.06.002. PubMed PMID: 28676279; PubMed Central PMCID: PMCPMC5651191.
https://doi.org/10.1016/j.ophtha.2017.06.002
PMid:28676279 PMCid:PMC5651191
 
Tarr JM, Kaul K, Chopra M, Kohner EM, Chibber R. Pathophysiology of diabetic retinopathy. ISRN ophthalmology. 2013;2013:343560. Epub 2014/02/25. doi: 10.1155/2013/343560. PubMed PMID: 24563789; PubMed Central PMCID: PMCPMC3914226.
https://doi.org/10.1155/2013/343560
PMid:24563789 PMCid:PMC3914226
 
Wilson WS, Shahidullah M, Millar C. The bovine arterially-perfused eye: an in vitro method for the study of drug mechanisms on IOP, aqueous humour formation and uveal vasculature. Current eye research. 1993;12(7):609-20. Epub 1993/07/01. PubMed PMID: 7693396.
https://doi.org/10.3109/02713689309001840
PMid:7693396
 
Yan H, Wang D, Ding TB, Zhou HY, Yan WJ, Wang XC. Comparison of lens oxidative damage induced by vitrectomy and/or hyperoxia in rabbits. International journal of ophthalmology. 2017;10(1):6-14. Epub 2017/02/06. doi: 10.18240/ijo.2017.01.02. PubMed PMID: 28149770; PubMed Central PMCID: PMCPMC5225342.
 
Yoshioka T, Nagaoka T, Song Y, Yokota H, Tani T, Yoshida A. Role of neuronal nitric oxide synthase in regulating retinal blood flow during flicker-induced hyperemia in cats. Investigative ophthalmology & visual science. 2015;56(5):3113-20. Epub 2015/03/19. doi: 10.1167/iovs.14-15854. PubMed PMID: 25783603.
https://doi.org/10.1167/iovs.14-15854
PMid:25783603

Committee on Publication Ethics

PDF
Full Text
Export Citation

View Dimensions


View Plumx



View Altmetric



4
Save
0
Citation
979
View
2
Share