The Journal of Korean Medicine (대한한의학회지)

The Society of Korean Medicine (대한한의학회)
권호 표지
DOI QR코드

DOI QR Code

Effects of Cardiotonic Pills® on Cerebrovascular CO2 Reactivity and Erythrocyte Deformability in Normal Subjects: A Pilot Study

  • Sang-Kwan Moon (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Medical Center) ;
  • Han-Gyul Lee (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Medical Center) ;
  • Seungwon Kwon (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Medical Center) ;
  • Seung-Yeon Cho (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong) ;
  • Seong-Uk Park (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong) ;
  • Woo-Sang Jung (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Medical Center) ;
  • Jung-Mi Park (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong) ;
  • Chang-Nam Ko (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong) ;
  • Ki-Ho Cho (Department of Cardiology and Neurology, Kyung Hee University College of Korean Medicine, Kyung Hee University Medical Center)
  • Received : 2023.10.19
  • Accepted : 2023.11.10
  • Published : 2023.12.01
Download PDF
⟨ Previous Next ⟩

Abstract

Backgrounds and objectives: Cardiotonic Pills® (CP) are used for vascular diseases such as coronary diseases, atherosclerosis, and cerebral infarction. This study aimed to determine the transient effects of CP on cerebrovascular CO2 reactivity (CVR) and erythrocyte deformability in normal subjects. Methods: This study had a crossover design and included 10 participants who were randomly allocated to 2 groups. The experimental group was given CP with water, while the control group was given only water. CVR was measured by hyperventilation-induced CVR of the middle cerebral artery (MCA) using transcranial Doppler (TCD). Erythrocyte deformability was measured using a Rheoscan-D microfluidic ektacytometer. All measurements were performed prior to and 1, 2, and 3 hours after CP or water administration. Blood pressure and heart rate were also measured before and after administration. Results: CP significantly improved CVR 3 hours after administration in the experimental group compared to the control group (p = 0.042). The corrected blood flow velocity at partial pressure of end-tidal carbon dioxide (PETCO2) = 40mmHg (CV40) was also significantly improved 2 and 3 hours after administration in the CP group compared to the control group (p = 0.036 and p = 0.021, respectively). CP significantly improved erythrocyte deformability 3 hours after administration in the experimental group compared to the control group (p = 0.027). Mean heart rate and mean blood pressure showed no change. Conclusions: This study demonstrated that CP increases CVR and erythrocyte deformability. These results suggested that CP improves cerebral microcirculation which provide evidence for the future use of CP for prevention of ischemic stroke and neurodegenerative diseases.

Keywords

Acknowledgement

The authors would like to thank all participants in this study, all the staffs for coordinating the work and all investigators for data collection and analysis.

References

  1. Kim, J. S. & Yoon, S. S. (1997). Perspectives of stroke in persons living in seoul, south korea: A survey of 1000 subjects. Stroke. 28(6). 1165-1169. https://doi.org/10.1161/01.STR.28.6.1165
  2. Choi H, M. G., Moon SJ (1990). A study of blood stasis on cva and the present state of medical treatment by the remedy of eliminating the stagnant blood and activating the blood. J Korean Med. 11(1). 145-150.
  3. Park, B., You, S., Jung, J., Lee, J. A., Yun, K.-J. & Lee, M. S. (2015). Korean studies on blood stasis: An overview. Evidence-Based Complementary and Alternative Medicine. 2015(doi.org/10.1155/2015/316872
  4. Liao, F. (2000). Herbs of activating blood circulation to remove blood stasis. Clinical Hemorheology and Microcirculation. 23(2, 3, 4). 127-131.
  5. Meifang, G.Faxiang, L. & Shali, D. (2000). An analysis of correlation between blood rheology and thrombosis in vitro on 502 cases with blood stasis syndrome. Jounal of Hubei College of Traditional Chinese Medicine. 1
  6. Horie, Y., Han, J.-Y., Mori, S., Konishi, M., Kajihara, M., Kaneko, T., et al. (2005). Herbal cardiotonic pills prevent gut ischemia/reperfusion-induced hepatic microvascular dysfunction in rats fed ethanol chronically. World Journal of Gastroenterology: WJG. 11(4). 511. 10.3748/wjg.v11.i4.511
  7. Zhao, N., Liu, Y.-Y., Wang, F., Hu, B.-H., Sun, K., Chang, X., et al. (2010). Cardiotonic pills, a compound chinese medicine, protects ischemia-reperfusion-induced microcirculatory disturbance and myocardial damage in rats. American Journal of Physiology-Heart and Circulatory Physiology. 298(4). H1166-H1176. doi.org/10.1152/ajpheart.01186.2009
  8. Han, J.-Y., Fan, J.-Y., Horie, Y., Miura, S., Cui, D.-H., Ishii, H., et al. (2008). Ameliorating effects of compounds derived from salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. Pharmacology & therapeutics. 117(2). 280-295. doi.org/10.1016/j.pharmthera.2007.09.008
  9. Wang, X.-W.Guo, J.Wang, X.-F.Chen, X.-P. & Wen, Z.-Y. (2008). Effects of cardiotonic pill on rbc rheologic abnormalities in hfd-induced mice and lpl deficient mice. Clinical Hemorheology and Microcirculation. 40(4). 281-288. 10.3233/CH-2008-1138
  10. Hyun, S.-H., Im, J.-W., Jung, W.-S., Cho, K.-H., Kim, Y.-S., Ko, C.-N., et al. (2014). Effect of st36 acupuncture on hyperventilation -induced co2 reactivity of the basilar and middle cerebral arteries and heart rate variability in normal subjects. Evidence-Based Complementary and Alternative Medicine. 2014(doi.org/10.1155/2014/574986
  11. Im, J.-W., Moon, S.-K., Jung, W.-S., Cho, K.-H., Kim, Y.-S., Park, T.-H., et al. (2014). Effects of acupuncture at gb20 on co2 reactivity in the basilar and middle cerebral arteries during hypocapnia in healthy participants. The Journal of Alternative and Complementary Medicine. 20(10). 764-770. doi.org/10.1089/acm.2013.0240
  12. Byeon, H.-s., Moon, S.-k., Park, S.-u., Jung, W.-s., Park, J.-m., Ko, C.-n., et al. (2011). Effects of gv20 acupuncture on cerebral blood flow velocity of middle cerebral artery and anterior cerebral artery territories, and co2 reactivity during hypocapnia in normal subjects. The Journal of Alternative and Complementary Medicine. 17(3). 219-224. doi.org/10.1089/acm.2010.0232
  13. Lee, H. K., Moon, S.-K., Jin, C., Cho, S.-Y., Park, S.-U., Jung, W.-S., et al. (2021). Effects of gv14 acupuncture on cerebral blood flow velocity in the basilar and middle cerebral arteries and co2 reactivity during hypercapnia in normal individuals. Evidence-Based Complementary and Alternative Medicine. 2021(doi.org/10.1155/2021/9319413
  14. Kim, L.-d., Yun, S.-p., Lee, S.-h., Kim, E.-j., Na, B.-j., Jung, D.-w., et al. (2004). Effects of uwhangchungsim-won (niuhuangqingxin-yuan) on systemic blood pressure, pulse rate, cerebral blood flow, and cerebrovascular reactivity in humans. The Journal of Internal Korean Medicine. 25(3). 440-450.
  15. Jeong, D.-W., Hong, J.-W., Shin, W.-J., Park, Y.-M., Jung, J.-H., Kim, C.-H., et al. (2006). Effects of korean ginseng, korean red ginseng and fermented korean red ginseng on cerebral blood flow, cerebrovascular reactivity, systemic blood pressure and pulse rate in humans. The Journal of Korean Medicine. 27(3). 38-50.
  16. Jin, C., Moon, S.-K., Cho, S.-Y., Park, S.-U., Jung, W.-S., Park, J.-M., et al. (2017). The effect of chunghyul-dan on hyperventilation -induced carbon dioxide reactivity of the middle cerebral artery in normal subjects: A dose-dependent study. Evidence-Based Complementary and Alternative Medicine. 2017(doi.org/10.1155/2017/4567217
  17. Jung, W.-S., Park, J.-Y., Byeon, H.-S., Kim, Y.-J., Park, J.-M., Park, S.-U., et al. (2012). Effects of hyul-bu-chuke-tang on erythrocyte deformability and cerebrovascular co2 reactivity in normal subjects. Evidence-Based Complementary and Alternative Medicine. 2012(doi.org/10.1155/2012/725241
  18. Izumi, Y.Tsuda, Y.Ichihara, S.-I.Takahashi, T. & Matsuo, H. (1996). Effects of defibrination on hemorheology, cerebral blood flow velocity, and co2 reactivity during hypocapnia in normal subjects. Stroke. 27(8). 1328-1332. doi.org/10.1161/01.STR.27.8.1328
  19. Markwalder, T.-M.Grolimund, P.Seiler, R. W.Roth, F. & Aaslid, R. (1984). Dependency of blood flow velocity in the middle cerebral artery on end-tidal carbon dioxide partial pressure-a transcranial ultrasound doppler study. Journal of Cerebral Blood Flow & Metabolism. 4(3). 368-372. https://doi.org/10.1038/jcbfm.1984.54
  20. Shin, S.Ku, Y.Park, M. S. & Suh, J. S. (2005). Slit-flow ektacytometry: Laser diffraction in a slit rheometer. Cytometry Part B: Clinical Cytometry: The Journal of the International Society for Analytical Cytology. 65(1). 6-13. doi.org/10.1002/cyto.b.20048
  21. Silvestrini, M., Vernieri, F., Pasqualetti, P., Matteis, M., Passarelli, F., Troisi, E., et al. (2000). Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. Jama. 283(16). 2122-2127. doi:10.1001/jama.283.16.2122
  22. Maeda, H., Matsumoto, M., Handa, N., Hougaku, H., Ogawa, S., Itoh, T., et al. (1993). Reactivity of cerebral blood flow to carbon dioxide in various types of ischemic cerebrovascular disease: Evaluation by the transcranial doppler method. Stroke. 24(5). 670-675. doi.org/10.1161/01.STR.24.5.670
  23. Markus, H. & Cullinane, M. (2001). Severely impaired cerebrovascular reactivity predicts stroke and tia risk in patients with carotid artery stenosis and occlusion. Brain. 124(3). 457-467. doi.org/10.1093/brain/124.3.457
  24. Kwon, T.-W.Son, Y.-S.Cho, S.-I. & Kim, Y.-K. (2008). Protective effects of cardiotonic pills (cp) on neuroglia cells against oxidative stress and the effects on regional cerebral blood flow in normal rats. The Korea Journal of Herbology. 23(4). 71-79.
  25. Ringelstein, E. B.Sievers, C.Ecker, S.Schneider, P. A. & Otis, S. M. (1988). Noninvasive assessment of co2-induced cerebral vasomotor response in normal individuals and patients with internal carotid artery occlusions. Stroke. 19(8). 963-969. doi.org/10.1161/01.STR.19.8.963
  26. Sorteberg, W., Lindegaard, K.-F., Rootwelt, K., Dahl, A., Russell, D., Nyberg-Hansen, R., et al. (1989). Blood velocity and regional blood flow in defined cerebral artery systems. Acta neurochirurgica. 97(47-52. https://doi.org/10.1007/BF01577739
  27. Lindegaard, K.-F., Lundar, T., Wiberg, J., Sjoberg, D., Aaslid, R. & Nornes, H. (1987). Variations in middle cerebral artery blood flow investigated with noninvasive transcranial blood velocity measurements. Stroke. 18(6). 1025-1030. doi.org/10.1161/01.STR.18.6.1025
  28. Lipowsky, H.Cram, L.Justice, W. & Eppihimer, M. (1993). Effect of erythrocyte deformability on in vivo red cell transit time and hematocrit and their correlation with in vitro filterability. Microvascular research. 46(1). 43-64. doi.org/10.1006/mvre.1993.1034
  29. Simchon, S.Jan, K.-M. & Chien, S. (1987). Influence of reduced red cell deformability on regional blood flow. American Journal of Physiology-Heart and Circulatory Physiology. 253(4). H898-H903. doi.org/10.1152/ajpheart. 1987.253.4.H898
  30. Parthasarathi, K. & Lipowsky, H. H. (1999). Capillary recruitment in response to tissue hypoxia and its dependence on red blood cell deformability. American Journal of Physiology -Heart and Circulatory Physiology. 277(6). H2145-H2157. doi.org/10.1152/ajpheart.1999.277.6.H2145
  31. Hou, W.-C., Tsay, H.-S., Liang, H.-J., Lee, T.-Y., Wang, G.-J. & Liu, D.-Z. (2007). Improving abnormal hemorheological parameters in aging guinea pigs by water-soluble extracts of salvia miltiorrhiza bunge. Journal of ethnopharmacology. 111(3). 483-489. doi.org/10. 1016/j.jep.2006.12.012 https://doi.org/10.1016/j.jep.2006.12.012
  32. Liao, F.Li, W. & Wen, R. (1995). Hemorheological effects of panax notoginseng. Biorheology. 2(32). 335-336. https://doi.org/10.1016/0006-355X(95)92313-Y
  33. Penumathsa, S. V., Koneru, S., Zhan, L., John, S., Menon, V. P., Prasad, K., et al. (2008). Secoisolariciresinol diglucoside induces neovascularization-mediated cardioprotection against ischemia-reperfusion injury in hypercholesterolemic myocardium. Journal of molecular and cellular cardiology. 44(1). 170-179. doi.org/10.1016/j.yjmcc.2007.09.014
  34. Sun, J., Huang, S. H., Tan, B. K.-H., Whiteman, M., Zhu, Y. C., Wu, Y. J., et al. (2005). Effects of purified herbal extract of salvia miltiorrhiza on ischemic rat myocardium after acute myocardial infarction. Life sciences. 76(24). 2849-2860. doi.org/10.1016/j.lfs.2004.11.016
  35. Han, J.-Y., Miura, S., Akiba, Y., Higuchi, H., Kato, S., Suzuki, H., et al. (2001). Chronic ethanol consumption exacerbates microcirculatory damage in rat mesentery after reperfusion. American Journal of Physiology-Gastrointestinal and Liver Physiology. 280(5). G939-G948. doi.org/10.1152/ajpgi.2001.280.5.G939
  36. Son, H. Y.Han, H. S.Jung, H. W. & Park, Y.-K. (2009). Panax notoginseng attenuates the infarct volume in rat ischemic brain and the inflammatory response of microglia. Journal of pharmacological sciences. 109(3). 368-379. doi.org/10.1254/jphs.08197FP
  37. Yang, X.-Y., Zhao, N., Liu, Y.-Y., Hu, B.-H., Sun, K., Chang, X., et al. (2013). Inhibition of nadph oxidase mediates protective effect of cardiotonic pills against rat heart ischemia/reperfusion injury. Evidence-Based Complementary and Alternative Medicine. 2013(doi.org/10.1155/2013/728020)
  38. Wang, F., Liu, Y.-Y., Liu, L.-Y., Guo, J., Sun, K., Wang, C.-S., et al. (2006). Inhibition effect of cardiotonic pills on venous thrombosis induced in rat mesentery by photochemical reaction. Clinical hemorheology and microcirculation. 34(1-2). 131-138.
  39. Moncada, S.Palmer, R. & Higgs, E. (1991). Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacological reviews. 43(2). 109-142.
  40. Patel, R. P.Levonen, A.-L.Crawford, J. H. & Darley-Usmar, V. M. (2000). Mechanisms of the pro-and anti-oxidant actions of nitric oxide in atherosclerosis. Cardiovascular Research. 47(3). 465-474. doi.org/10.1016/S0008-6363 (00)00086-9
  41. Ho, F. M., Liu, S. H., Liau, C. S., Huang, P. J., Shiah, S. G. & Lin-Shiau, S. Y. (1999). Nitric oxide prevents apoptosis of human endothelial cells from high glucose exposure during early stage. Journal of cellular biochemistry. 75(2). 258-263. doi.org/10.1002/(SICI)1097-4644(19991101)75:2<258::AID-JCB8>3.0.CO;2-3
  42. White, R. P.Deane, C.Vallance, P. & Markus, H. S. (1998). Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hypercapnia. Stroke. 29(2). 467-472. doi.org/10.1161/01. STR.29.2.467
  43. Okamoto, M.Etani, H.Yagita, Y.Kinoshita, N. & Nukada, T.-a. (2001). Diminished reserve for cerebral vasomotor response to l-arginine in the elderly: Evaluation by transcranial doppler sonography. Gerontology. 47(3). 131-135. doi.org/10.1159/000052786
  44. Bor-Kucukatay, M.Wenby, R. B.Meiselman, H. J. & Baskurt, O. K. (2003). Effects of nitric oxide on red blood cell deformability. American journal of physiology-heart and circulatory physiology. 284(5). H1577-H1584. doi.org/10.1152/ajpheart.00665.2002
  45. Baskurt, O. K.Temiz, A. & Meiselman, H. J. (1998). Effect of superoxide anions on red blood cell rheologic properties. Free Radical Biology and Medicine. 24(1). 102-110. doi.org/10.1016/S0891-5849(97)00169-X
  46. Hebbel, R. P. Leung, A. & Mohandas, N. (1990). Oxidation-induced changes in microrheologic properties of the red blood cell membrane. doi.org/10.1182/blood.V76.5.1015.1015
  47. Meschia, J. F., Bushnell, C., Boden-Albala, B., Braun, L. T., Bravata, D. M., Chaturvedi, S., et al. (2014). Guidelines for the primary prevention of stroke: A statement for healthcare professionals from the american heart association/american stroke association. Stroke. 45(12). 3754-3832. doi.org/10.1161/STR.0000000000000046
  48. Uchiyama, S. (2017). Aspirin for primary stroke prevention in elderly patients with vascular risk factors. Journal of General and Family Medicine. 18(6). 331-335. doi.org/10.1002/jgf2.102
  49. Krishnamurthi, R. V., Feigin, V. L., Forouzanfar, M. H., Mensah, G. A., Connor, M., Bennett, D. A., et al. (2013). Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: Findings from the global burden of disease study 2010. The Lancet Global Health. 1(5). e259-e281. doi.org/10.1016/S2214-109X(13)70089-5
  50. Ueshima, H., Sekikawa, A., Miura, K., Turin, T. C., Takashima, N., Kita, Y., et al. (2008). Cardiovascular disease and risk factors in asia: A selected review. Circulation. 118(25). 2702-2709. doi.org/10.1161/CIRCULATIONA HA.108.790048
  51. Sweeney, M. D.Kisler, K.Montagne, A.Toga, A. W. & Zlokovic, B. V. (2018). The role of brain vasculature in neurodegenerative disorders. Nature neuroscience. 21(10). 1318-1331. 10.1038/s41593-018-0234-x
  52. Vicenzini, E., Ricciardi, M. C., Altieri, M., Puccinelli, F., Bonaffini, N., Di Piero, V., et al. (2007). Cerebrovascular reactivity in degenerative and vascular dementia: A transcranial doppler study. European neurology. 58(2). 84-89. 10.1159/000103642
  53. Pelizzari, L., Lagana, M. M., Rossetto, F., Bergsland, N., Galli, M., Baselli, G., et al. (2019). Cerebral blood flow and cerebrovascular reactivity correlate with severity of motor symptoms in parkinson's disease. Therapeutic Advances in Neurological Disorders. 12(175 6286419838354. 10.1177/17562864198383