A novel system for transcutaneous application of carbon dioxide causing an "artificial Bohr effect" in the human body

Yoshitada Sakai, Masahiko Miwa, Keisuke Oe, Takeshi Ueha, Akihiro Koh, Takahiro Niikura, Takashi Iwakura, Sang Yang Lee, Masaya Tanaka, Masahiro Kurosaka, Yoshitada Sakai, Masahiko Miwa, Keisuke Oe, Takeshi Ueha, Akihiro Koh, Takahiro Niikura, Takashi Iwakura, Sang Yang Lee, Masaya Tanaka, Masahiro Kurosaka

Abstract

Background: Carbon dioxide (CO(2)) therapy refers to the transcutaneous administration of CO(2) for therapeutic purposes. This effect has been explained by an increase in the pressure of O(2) in tissues known as the Bohr effect. However, there have been no reports investigating the oxygen dissociation of haemoglobin (Hb) during transcutaneous application of CO(2)in vivo. In this study, we investigate whether the Bohr effect is caused by transcutaneous application of CO2 in human living body.

Methods: We used a novel system for transcutaneous application of CO(2) using pure CO(2) gas, hydrogel, and a plastic adaptor. The validity of the CO(2) hydrogel was confirmed in vitro using a measuring device for transcutaneous CO(2) absorption using rat skin. Next, we measured the pH change in the human triceps surae muscle during transcutaneous application of CO(2) using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) in vivo. In addition, oxy- and deoxy-Hb concentrations were measured with near-infrared spectroscopy in the human arm with occulted blood flow to investigate O2 dissociation from Hb caused by transcutaneous application of CO(2).

Results: The rat skin experiment showed that CO(2) hydrogel enhanced CO(2) gas permeation through the rat skin. The intracellular pH of the triceps surae muscle decreased significantly 10 min. after transcutaneous application of CO(2). The NIRS data show the oxy-Hb concentration decreased significantly 4 min. after CO(2) application, and deoxy-Hb concentration increased significantly 2 min. after CO(2) application in the CO(2)-applied group compared to the control group. Oxy-Hb concentration significantly decreased while deoxy-Hb concentration significantly increased after transcutaneous CO(2) application.

Conclusions: Our novel transcutaneous CO(2) application facilitated an O(2) dissociation from Hb in the human body, thus providing evidence of the Bohr effect in vivo.

Conflict of interest statement

Competing Interests: The hydro-gel was received as a gift from NeoChemir Inc. Takeshi Uhea is a full-time employee of NeoChemir Inc. Masaya Tanaka is Chief Executive Officer of NeoChemir Inc. and has patent licensing arrangements with the hydro-gel and CO2 application. The international patent publication number is WO2004/002393; the publication date is January 8, 2004. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Rationale of the experimental outline.
Figure 1. Rationale of the experimental outline.
(A) The application of our novel system for transcutaneous application of CO2 (For the upper limb). (B) The application of our novel system for transcutaneous application of CO2 (For the lower limb).
Figure 2. Measuring device to validate CO…
Figure 2. Measuring device to validate CO2 hydrogel in vitro using rat skin.
Figure 3. Novel system for transcutaneous CO…
Figure 3. Novel system for transcutaneous CO2 application in the forearm with NIRS probe.
Figure 4. pH changes in CO 2…
Figure 4. pH changes in CO2-absorbing solution during transcutaneous CO2 application through the rat skin with or without the CO2 hydrogel.
The graph shows pH changes during CO2 application with or without the CO2 hydrogel. (n = 6). Graph data are expressed as means ± S.E.M.
Figure 5. Intramuscular pH changes in the…
Figure 5. Intramuscular pH changes in the triceps surae muscle during transcutaneous application of CO2 using 31P-MRS.
The graph shows that pH decreases during the accumulation of CO2. (n = 5) Graph data are expressed as means ± S.E.M.
Figure 6. Measurement of oxygenated and deoxygenated…
Figure 6. Measurement of oxygenated and deoxygenated Hb concentration during transcutaneous application of CO2 using NIRS.
(A) Continuous measurement of oxy and deoxy-Hb concentrations using NIRS with pooling blood by a pneumatic tourniquet. The bold lines demonstrate the CO2 group data. All data show the changes in Hb concentrations from the starting point to the end point of measurement (n = 7). Data show the decrease in oxy-Hb and the increase in deoxy-Hb after pooling blood, followed by the greater decrease in oxy-Hb and greater increase in deoxy-Hb in CO2 group after transcutaneous CO2 application. (B) Relative changes in amounts of oxy/deoxy-Hb (the values 8 min. after blood pooling started were set as standards). Graph data are expressed as mean ± S.E.M. The averages and significance checks were calculated based on measurements of the 7 subjects. Statistical significance at P<0.05 is denoted by *, and P<0.01 is denoted by **. The graph shows a significant decrease in oxy-Hb and increase in deoxy-Hb in the CO2 group.

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