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. 2024 Jun 5;12(1):76–84. doi: 10.1159/000539480

The Responses of Arterial Stiffness Parameter Beta-Derived Index of the Aorta and Illiac-Femoral Artery to Acute Hypovolemia in Rabbits

Toshiro Ito a, Shin-ichiro Katsuda a,✉, Yuko Horikoshi b, Toru Funyu a, Akihiro Hazama a, Tsuyoshi Shimizu c, Kohji Shirai d
PMCID: PMC11249569  PMID: 39022558

Abstract

Introduction

Acute hemorrhage decreases blood pressure (BP) and sometimes causes hypovolemic shock. At this time, peripheral arteries are supposed to contract and increase peripheral vascular resistance to raise BP. However, there has not been an adequate index of a degree of arterial stiffness. We assessed changes in arterial stiffness during rapid bleeding using new BP-independent vascular indices, aBeta and ifBeta, determined by applying the cardio-ankle vascular index theory to the elastic (aorta) and muscular (common iliac-femoral) arteries, respectively, in rabbits.

Methods

Eleven Japanese white male rabbits were fixed at the supine position under pentobarbital anesthesia. Fifteen percent of the total blood volume was depleted at a rate of 2 mL/kg/min for 6 min; 15 min later, the withdrawn blood was re-transfused at the same rate. Pressure waves at the origin of the aorta (oA), distal end of the abdominal aorta (dA), distal end of the left common iliac artery (fA), and flow waves at oA were measured simultaneously. Beta was calculated using the following formula: beta = 2ρ/PP × ln(SBP/DBP) × PWV2, where ρ, SBP, DBP, and PP are blood density, systolic, diastolic, and pulse pressures, respectively. aBeta, ifBeta, and aortic-iliac-femoral beta (aifBeta) were calculated using aPWV, ifPWV, and aifPWV, respectively.

Results

BP declined significantly at oA, dA, and fA during the acute bleeding. aBeta and aifBeta increased significantly from 3.7 and 5.0 before the bleeding (control) to 5.0 (about 34%) and 6.3 (about 26%) on average, while ifBeta decreased significantly from 20.5 before the bleeding to 17.1 (about 17%) after the completion of the bleeding. Reverse reactions of those indices were observed by transfusing the removed blood.

Conclusion

Total arterial stiffness (aifBeta) increased; however, the elastic and muscular arteries stiffened and softened during the bleeding, respectively. These results would give useful diagnostic information during fall in BP.

Keywords: Acute bleeding, Beta, Blood pressure, Elastic artery, Muscular artery

Introduction

Rapid hemorrhage can occur during trauma, surgery, aneurysm rupture, labor, or delivery. In humans, a rapid loss of 20% of total blood volume (class II) is generally associated with hemorrhagic shock symptoms, and a loss of 30% is considered life threatening [1, 2]. Decreased blood pressure (BP), associated with decreased blood volume, induces reflex tachycardia, increased cardiac contractility. It is supposed that the systemic arteries contract to raise BP [1, 2]. It is important to investigate how the systemic arteries behave in response to a hemorrhage to ensure high-priority blood supply to the organs. However, the precise mechanism was not clear because there has not been an adequate index reflecting functional arterial stiffness.

Pulse-wave velocity (PWV) has been widely used as an index of arterial stiffness [3, 4]. However, it is difficult to evaluate functional arterial stiffness using PWV because PWV depends on the BP at the time of measurement [5–7]. The cardio-ankle vascular index (CAVI) was developed as a BP-independent index of arterial stiffness based on the stiffness parameter β theory [8] and Bramwell and Hill’s equation [9]. It has been clinically pointed out that the CAVI reflected not only structural stiffness due to aging, atherosclerosis, and diabetes [10–13] but also functional stiffness due to contraction and dilatation of arterial smooth muscle cells [14] such as dialysis [15, 16], septic shock [17], and administration of vasodilating drug [18]. Nagasawa et al. [19] reported in rabbits that the CAVI increased whereas heart-to-ankle PWV decreased in response to a decrease in BP induced by the depletion of 25–30% of total blood volume.

CAVI includes arterial stiffness of the aorta (elastic artery) and common iliac to the anterior and posterior tibial arteries (muscular arteries). Elastic and muscular arteries have been shown to differ in their microstructural and physiological properties [20–22]. Katsuda et al. [23, 24] previously applied the new indices derived from CAVI theory [10–13] to the aorta (aBeta), common iliac and femoral (ifBeta) arteries, and arterial tree from the origin of the aorta (oA) to the distal end of the left femoral artery (fA) (aifBeta), respectively, to assess the response of these arteries to some vasodilating drugs, separately. They found that the elastic and muscular arteries responded differently to the alpha-receptor blocker, phentolamine [23], and the calcium channel blocker, nicardipine [24].

In this study, we evaluated the behavior of the whole arteries (aortic-iliac-femoral arteries), aorta, and iliac-femoral arteries separately using aifBeta, aBeta, and ifBeta to investigate their role in regulating reduced BP and blood flow concomitant with hemodynamic changes such as calculated vascular resistance when 15% of total blood volume was depleted at a rate of 2 mL/kg/min for 6 min and re-transfused at the same rate.

Methods

Animals

Eleven 6-month-old male Japanese white normal rabbits (3.3 ± 0.2 kg) (Kitayama Labes Co., Ltd., Ina City, Nagano, Japan) were used in the experiments. This experiment was conducted in accordance with the Standards for the Care and Housing of Laboratory Animals and the Reduction of Pain [25] of the Ministry of Environment, with the approval of the Animal Experimentation Committee of Fukushima Medical University, approval number 2019033 and 2021007. The rabbits were housed individually in a stainless cage 350 mm in width, 500 mm in depth, and 420 mm in height at a room temperature of 19–25°C and humidity of 50–60%, with a 12-h light/12-h dark cycle. They were fed with commercial rabbit food (Labo R Stock, Nosan Corporation, Yokohama, Japan) at approximately 100 g per animal per day and had free access to water.

Surgical Procedure

Figure 1 shows experimental set-up of the present study. The rabbits were anesthetized by intravenous administration of pentobarbital sodium (Somopentyl; Kyoritsu Seiyaku Corporation, Tokyo, Japan) and restrained at the supine position under pentobarbital anesthesia (30 mg/kg body weight, i.v.), and the trachea was intubated. Butorphanol tartrate (Vetorphal, Meiji Seika Pharma, Co., Ltd., Tokyo, Japan) was administered intramuscularly (0.1 mg/kg) as an analgesic. Procaine hydrochloride was applied to the incision site to relieve the pain. After securing the trachea, two pressure sensor catheters (2.0 Fr, SPS-320, Millar Instruments, Inc., Huston, TX, USA) were inserted from the left common carotid artery and right saphenous artery into the oA and distal end of the abdominal aorta (dA), respectively. A fiber optic pressure sensor (0.9Fr, FPI-LS-10, FIZO Technologies, Inc., Quebec, Canada) was inserted from the left saphenous artery to the distal end of the left femoral artery (fA). A large-bore catheter (1.2 mm, I.D.) was then inserted from the left maxillary vein into the superior vena cava for bleeding and re-transfusion. The chest was carefully opened under spontaneous respiration to avoid pneumothorax, and an ultrasound blood flow probe (6 mm, I.D.) was placed at the oA. Heparin (500 U/kg) was intravenously administered to prevent blood coagulation.

Fig. 1.

Fig. 1.

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Schematic arrangement of the experimental set-up. Pressure waves were measured at the origin of the aorta (oA), the distal end of the abdominal aorta (dA), and the distal end of the left femoral artery (fA). Flow wave was measured at oA. Blood was extracted from the vena cava at a rate of 2 mL per min per body weight. The distances between oA and dA, dA and fA, and oA and fA were measured in situ and used to calculate the aortic PWV (aPWV), iliac-femoral PWV (ifPWV), and aortic-iliac-femoral PWV (aifPWV), respectively. Aortic beta (aBeta), iliac-femoral beta (ifBeta), and aortic-iliac-femoral beta (aifBeta) were determined using the corresponding aPWV, ifPWV, and aifPWV, respectively.

Experimental Protocol

Approximately 15% of total blood volume was depleted from the superior vena cava using a syringe pump (CFV-3200; Nihon Kohden Corporation, Tokyo, Japan) at a rate of 2 mL per kg body weight per minute for 6 min. The withdrawn blood was returned to the superior vena cava at a rate of 2 mL per kg body weight per minute 15 min after the end of bleeding. The pressure waves at oA, dA, and fA and flow waves at oA were simultaneously measured with a catheter tip transducer and an ultrasound flowmeter (T206, Transonic Systems Inc., Ithaca, NY, USA) and recorded on a personal computer (PowerBook G4 M9691J/A, Apple Inc., Cupertino, CA, USA) through an analog-to-digital converter (Powerlab 16/sp, AD Instruments Inc., Sydney, Australia) every 0.1 ms before and after the bleeding and re-transfusion of the blood. At the end of the measurements, the rabbits were euthanized with an overdose of pentobarbital, and the distance between the pressure sensors was accurately measured in situ.

Data Analysis

Fifty successive pressure and flow waves were analyzed. The peak of the original pressure waves was defined as the peak of the second derivative of the original waveform [26, 27]. PWV was determined as the quotient of the distance between the two pressure sensors to the difference in the rising time of the two pressure waves between oA and dA (aortic PWV, aPWV), between dA and fA (iliac-femoral PWV, ifPWV), and between oA and fA (aortic-iliac-femoral PWV, aifPWV), respectively. Beta was calculated from the following formula: beta = 2ρ/PP × In(SBP/DBP) × PWV2, where ρ, PP, SBP, and DBP indicated density of blood, pulse pressure, systolic and diastolic BPs, respectively. The density of blood (ρ) was assumed to be 1.06 [28]. aBeta, ifBeta, and aifBeta were determined based on the aPWV, ifPWV, and aifPWV, respectively.

On the other hand, CAVI was determined with the following formula: CAVI = a{2ρ/PP × In(SBP/DBP) × PWV2} + b, where “a” and “b” were coefficients. Takahashi et al. [29] calculated the heart-ankle beta as a measure of arterial stiffness from the CAVI value with coefficients a and b and CAVI without coefficients a and b. They found no difference in the significance or power of heart-ankle beta in clinical and epidemiological studies. Therefore, in this study, we used beta without the coefficients as an index of vascular stiffness.

The average SBP and DBP values at oA and dA, dA and fA, and oA and fA were used to calculate aBeta, ifBeta, and aifBeta, respectively. The heart rate (HR) was calculated as the time difference between the rising points of the pressure pulse wave. The mean arterial pressure (MAP) was obtained from the original pressure waves using a low-pass filter with a time constant of 2.5 s. Total peripheral vascular resistance (TPR) was calculated as MAP/CO, where CO was the cardiac output.

One-way analysis of variance was used to test each parameter. Post hoc tests were performed using Scheffé’s multiple comparison test when a significant difference was observed in the analysis of variance. Pearson’s correlation coefficients for each beta and PWV against SBP and DBP were calculated and tested using the F test. The significance level was set at p = 0.05.

Results

Time-Dependent Changes in HR, MAP, CO, and TPR during Bleeding and Re-Transfusion

Figure 2 shows the time-dependent changes in the MAP (a), CO (b), TPR (c), and HR (d) during bleeding and re-transfusion. MAP decreased from 105 mm Hg before the bleeding to 56 mm Hg on average after the completion of the bleeding, increased by only 6 mm Hg approximately just before the re-transfusion, and recovered to the pre-bleeding (control) level after the end of the re-transfusion. Significant differences were observed 3 min after bleeding and 3 min after re-transfusion. CO decreased linearly with hemorrhage from 362 to 105 mL/min on average at the end of the bleeding and increased gradually from approximately 115 mL/min to 330 mL/min on average with re-transfusion of the withdrawn blood. Significant differences were observed between 3 min after the onset of bleeding and 5 min after the onset of re-transfusion. The TPR obtained by calculation increased gradually as the bleeding progressed and reached approximately twice the control value after the end of the bleeding. It decreased gradually with the re-transfusion of blood. Significant differences were observed between 3 min after bleeding and 3 min after re-transfusion. The HR showed a slight increase and decrease during the bleeding and re-transfusion, respectively, which was not statistically significant.

Fig. 2.

Fig. 2.

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Time-dependent changes in MAP (a), CO (b), TPR (c), and HR (d) during bleeding and re-transfusion in rabbits. B.0 indicates before bleeding (control). T.0 indicates before re-transfusion of the withdrawn blood. HR, heart rate; CO, cardiac output; MAP, mean arterial pressure at oA; TPR, total peripheral vascular resistance.

Time-Dependent Changes in BP, Beta, and PWV during Bleeding and Re-Transfusion

Figure 3 illustrates the time-dependent changes in SBP and DBP (a), PP (b), beta (c), and PWV (d) during the bleeding and re-transfusion of the withdrawn blood. SBP and DBP decreased gradually by approximately 52 mm Hg and 41 mm Hg on average in the oA and by approximately 82 mm Hg and 48 mm Hg on average in the dA and fA, respectively. The PP at oA decreased by approximately 10 mm Hg on average at the end of the bleeding from the control value, which was statistically significant. The PP at dA and fA decreased significantly by an average of 24 mm Hg. SBP, DBP, and PP slightly increased just before the onset of re-transfusion of the withdrawn blood and thereafter increased gradually with re-transfusion around the control level. Significant differences were observed in SBP and DBP at the oA, dA, and fA and in PP at the oA, dA and fA compared to those before the bleeding, 3, 4 and 5 min after the onset of the bleeding, and 0, 1, 2, and 3 min after re-transfusion of the extracted blood.

Fig. 3.

Fig. 3.

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Time-dependent changes in BP (a), PP (b), beta (c), and PWV (d) during bleeding and re-transfusion in rabbits. B.0 indicates before the bleeding (control). T.0 indicates before re-transfusion of the withdrawn blood. BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; PWV, pulse-wave velocity; oA, origin of the aorta; dA, distal end of the abdominal aorta; fA, distal end of the left femoral artery; aBeta, aortic beta; ifBeta, iliac-femoral beta; aifBeta, aortic-iliac-femoral beta; aPWV, aortic PWV; ifPWV, iliac-femoral PWV; aifPWV, aortic-iliac-femoral PWV.

aBeta and aifBeta increased approximately from 3.7 to 5.0 before the bleeding to 5.0 and 6.3 on average by the end of the bleeding. aBeta and ifBeta showed only a slight increase 15 min after the completion of bleeding and subsequently returned to levels similar to those of the control levels. ifBeta decreased from 20.5 before the bleeding to 17.1 on average after the completion of the bleeding, remained almost unchanged until the onset of re-transfusion, and gradually recovered to the pre-bleeding level following re-transfusion. A significant difference was observed in aBeta and aifBeta between 4 min after bleeding and 2 min after re-transfusion, except for aifBeta at 2 min after re-transfusion. ifBeta showed a significant decrease just before and 1 min after the re-transfusion compared to that before the bleeding. aPWV, ifPWV, and aifPWV decreased from 5.0, 11.9, and 5.8 m/s before the bleeding to 4.3, 8.0, and 4.8 m/s on average at the completion of the bleeding with decreasing BP, respectively. They almost recovered to the control levels owing to the re-transfusion of the extracted blood. There were significant differences in aPWV, ifPWV, and aifPWV between 4 min after the onset of bleeding and 3 min after the initiation of re-transfusion compared to those before the bleeding.

Correlation between Beta, PWV, and BP during the Bleeding

Figure 4 shows the correlations between beta and SBP (a), beta and DBP (b), PWV and SBP (c), and PWV and DBP (d) during bleeding. aifBeta and aBeta negatively correlated with SBP and DBP, whereas ifBeta positively correlated with SBP and DBP. The aifPWV, aPWV, and ifPWV were significantly correlated with SBP and DBP. A similar trend in the correlations of beta and PWV with BP was also observed during the re-transfusion of withdrawn blood.

Fig. 4.

Fig. 4.

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Correlation diagrams between beta and SBP (a), beta and DBP (b), PWV and SBP (c), and PWV and DBP (d) during the bleeding in rabbits. aBeta and aifBeta were significantly negatively correlated with SBP and DBP. ifBeta exhibited a weak positive correlation with SBP and DBP. The aPWV, ifPWV, and aifPWV were significantly correlated with SBP and DBP.

Discussion

Rapid bleeding could occur during accidents, surgery, aortic dissection, and labor and delivery [1, 2]. Bleeding of more than 20% of total blood volume causes symptoms of shock such as cyanosis, hypotension, and tachycardia [1, 2]. It is supposed that a decrease in BP induced by blood loss reflexively causes peripheral vasoconstriction mainly via baroreceptors [1, 2].

In the present study, TPR, calculated as MAP/CO, increased up to approximately 98% of the control level at the end of the bleeding because MAP and CO decreased by a maximum of 46% and 71% caused by the bleeding, respectively. This suggests that the stiffness of the peripheral arteries including large arteries was increased in response to the bleeding. However, vasoconstrictor function of the large artery has little been investigated from the perspective of biological control.

The CAVI, a stiffness index from the aorta to the tibial artery, reflects not only structural stiffness [11–13] but also functional changes in stiffness owing to contraction and dilation of the arterial wall [14]. The CAVI was significantly higher in dialysis patients than in normal subjects [15] and increased after dialysis with water removal greater than 5% [16] and during septic shock [17]. Shimizu et al. [18] demonstrated using CAVI that the arterial wall responded to nitroglycerine in normal subjects and patients with coronary arterial disease. Nagasawa et al. [19] clarified in rabbits that CAVI increased significantly despite the fall in BP owing to the depletion of 25–30% of the total blood volume, whereas the heart-to-ankle PWV decreased significantly, accompanied by a decrease in BP.

aifBeta is a total stiffness of the aorta (elastic arteries) and the common iliac to the femoral arteries (muscular arteries), which is almost corresponding to CAVI. The time-dependent change in aifBeta during the bleeding and re-transfusion (Fig. 3c) reflected that of the TPR (Fig. 2c) even if there was difference in percentage in increase. aifBeta increased significantly by up to approximately 25% of the pre-bleeding (control) level during the bleeding, although aBeta, the stiffness of the aorta, increased by a maximum of approximately 35% of the control level despite the decline in BP during the bleeding while ifBeta, the stiffness of the iliac to femoral artery, decreased at most by approximately 17% of the control value. The responses of aBeta and ifBeta were reciprocal.

One possible reason for the increased aifBeta (approximately 25%) owing to the bleeding is the ratio of the lengths of the aorta and the common iliac to femoral arteries. The length of the aorta (from oA to dA) is approximately 76% of the total length from oA to fA, whereas the length of the muscular artery (from dA to fA) accounted for approximately 24% of the total length. The increase in aifBeta, calculated based on the maximum increase and decrease in aBeta (35%) and ifBeta (17%), and the percentages of the elastic and muscular artery, was estimated to be 22.3%, although this was somewhat less than the actual increase in aifBeta (25%).

The increased aBeta would involve in the rheological properties of the aorta. The aorta has a high percentage of elastic fibers and functions as conduit arteries with auxiliary pumps [20, 21]. The elastic properties are prominent in the proximal region [20, 21]. The diameter of the aorta may be passively reduced by a decrease in blood flow and BP, resulting in a diminished pulsatile change in diameter. This is supported by the decreased PP. The significant increase in aBeta during bleeding is thought to be a result of the functional stiffening of the aortic wall, probably to maintain cerebral blood flow in response to reduced blood flow and BP. Increased aBeta was also observed following the administration of phentolamine [23] and nicardipine [24]. The detailed mechanism of the increased aBeta during the bleeding should be investigated in the future.

On the other hand, ifBeta decreased approximately by 17% during the acute bleeding, which was approximately half of that of ifPWV (approximately 33%). This means that the iliac-femoral artery is less stiffened and actively involves little contraction to maintain blood flow and pressure in response to the bleeding. Muscular arteries are located between the aorta and the arterioles. Blood is thought to have difficulty flowing through the muscular arteries and being stored there to a certain degree because the arterioles are strongly constricted due to the bleeding.

Change in intravascular pressure usually exerts directly on the wall from the media (elastin fibers and smooth muscles cells) to the adventitia (collagen fibers). Wall response to the change in intravascular pressure is mainly determined by content and arrangement of the smooth muscle cells, and the elastin and collagen fibers, resulting in change in diameter. Muscular arteries have a higher percentage of smooth muscle than elastic arteries [20–22] and play an important role in regulating blood flow to organs [30]. Azuma and Hasegawa [20, 21] demonstrated that stress relaxation was greater in muscular arteries than in elastic arteries. The wall of the muscular artery is thought to remain somewhat stretched despite decreased CO and BP, which is associated with a larger decrease in PP (24 mm Hg) in the dA and fA than in the oA (10 mm Hg). ifBeta also did not increase until 2 min after the onset of re-transfusion. A larger stress relaxation in the muscular artery is convenient to store blood in the iliac to femoral artery to supply blood to the lower abdominal organs during the rapid bleeding. Similar phenomena may also occur in the splanchnic muscular arteries such as celiac and mesenteric arteries. Further investigation is required to elucidate the detailed mechanism of the vascular response between the elastic and muscular arteries to the bleeding.

aifBeta, aBeta, and ifBeta tended to recover immediately before the re-transfusion of the extracted blood without bleeding treatment. The neural BP control system and renin-angiotensin system are activated within 30 s and 2 min of the sudden fluctuation of BP, respectively, to restore BP levels [31]. Neural regulation of BP is thought to operate during the bleeding because the TPR increases up to approximately twice of the control value. However, Nagasawa et al. [19] showed that the sympathetic nervous system was not involved in the increase in the CAVI. Further studies are required to investigate participation of sympathetic nervous system and renin-angiotensin system to BP control during acute hypovolemic conditions.

CAVI reflects vascular smooth muscle contraction [14–19] and relaxation as well as structural stiffness of the arterial wall such as atherosclerosis [10–13]. CAVI is not only a surrogate marker of arterial stiffness but also that of peripheral resistance or compliance. In this study, aBeta and aifBeta significantly increased, whereas ifBeta significantly decreased in response to the rapid bleeding. aBeta and aifBeta also showed strong negative correlation with SBP and DBP, while ifBeta did weak positive correlation with SBP and DBP as shown in Figure 4. The change in beta was opposing between the elastic and muscular arteries. These results suggest that the elastic artery (aorta) becomes stiffer functionally with decreasing BP and CO during the rapid bleeding to ensure blood flow to the brain and that the muscular artery (iliac to femoral artery) becomes softer functionally to store blood there to supply the lower abdominal organs. Similar results have been observed in rabbits administered alpha-adrenergic receptor blocker, phentolamine [23], and calcium channel blocker, nicardipine [24]. Detailed mechanism should be clarified in the future.

On the other hand, aPWV, ifPWV, and aifPWV changed in BP-dependent manner during the acute bleeding and re-transfusion. PWV is not useful for accurate evaluation of change in arterial stiffness induced by bleeding.

It is important to understand the changes in hemodynamic conditions of patients induced by hemorrhage or water removal during hemodialysis [16] in a clinical setting. The CAVI could be a useful indicator for differentiating between the types of shock in emergency cases in the future. An increasing trend in the CAVI indicates sympathetic vasoconstriction in cases of hypovolemic shock. Decreasing or unchanging trends in CAVI would reflect severe peripheral vasodilation in cases of distributive shock, such as anaphylactic and/or septic shock [17]. The difference in response between the elastic and muscular arteries to the acute bleeding at 15% of the total blood volume and the functional recovery of two arteries from hypovolemic and hypotensive conditions due to the re-transfusion of the extracted blood could give more useful information to devise a treatment strategy such as blood transfusion and fluid administration.

Limitations

The present data were obtained experimentally in anesthetized rabbits. Acute hemorrhage is often observed in the operating or emergency rooms in general clinical settings. The CAVI includes the stiffness of the elastic (aorta) and muscular arteries (iliac to tibial arteries). Therefore, it is necessary to establish a system to measure segmental CAVI in the elastic and muscular arteries of patients with significant hemorrhage. This investigation will be useful in the management of hypovolemic shock and dialysis. Furthermore, the vascular response to hemorrhage should be elucidated in future studies in patients with hypertension.

Conclusion

The total stiffness of the elastic (aorta) and muscular (common iliac to femoral) arteries increased significantly in response to the rapid bleeding at 15% of the total blood volume for 6 min. The elastic and muscular arteries stiffened and softened functionally, respectively. The functional change in stiffness of two arteries recovered approximately to the control level due to the re-transfusion. Future studies should investigate whether elastic and muscular arteries interact with each other during bleeding.

Acknowledgment

The authors would like to express our gratitude to Mr. Haruyuki Wago for his kind assistance in the present study.

Statement of Ethics

This experiment was conducted in accordance with the Standards for the Care and Housing of Laboratory Animals and the Reduction of Pain of the Ministry of Environment, with the approval of the Animal Experimentation Committee of Fukushima Medical University (approval No.: 2019033 and 2021007).

Conflict of Interest Statement

The authors declare there is no conflict of interest in this study.

Funding Sources

The authors received no external funding.

Author Contributions

Toshiro Ito and Shin-ichiro Katsuda designed this study, conducted the experiment, and analyzed the data. Toru Funyu conducted the experiment. Yuko Horikoshi, Akihiro Hazama, and Tsuyoshi Shimizu discussed the results and checked the manuscript. Kohji Shirai discussed the results and revised the manuscript. All authors have read and agreed to submit the manuscript to Pulse.

Funding Statement

The authors received no external funding.

Data Availability Statement

The data that support the findings of this study are not publicly available due to the experimental data from animals. The corresponding author (S.K.) can release the data, if the lead or corresponding author deems it necessary to disclose the data in response to a reasonable request from a reader.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are not publicly available due to the experimental data from animals. The corresponding author (S.K.) can release the data, if the lead or corresponding author deems it necessary to disclose the data in response to a reasonable request from a reader.

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