Compound Danshen Dripping Pill Promotes Adaptation to Acute High-Altitude Exposure

Abstract

Li, Zongbin, Jun Guo, Chunwei Liu, Yajun Shi, Yang Li, Jinli Wang, Dandan Li, Jing Wang, and Yundai Chen. Compound Danshen Dripping Pill promotes adaptation to acute high-altitude exposure. High Alt Med Biol. 21:258–264, 2020.

Background:

In this study, we aimed to investigate whether the traditional Chinese medicine, Compound Danshen Dripping Pill (CDDP), can prevent acute mountain sickness (AMS). We allocated CDDP and matching placebos to 160 volunteers before they ascended to a high altitude. Treadmill exercise tests, echocardiography, blood routine examinations, biochemical analysis, and blood gas analysis were performed upon arrival at high altitude. The primary outcome included incidence of AMS, exercise times, and metabolic equivalents (METs) of treadmill exercise tests. Second endpoints included the heart rates and rate-pressure product (RPP) before and after treadmill exercise tests.

Results:

After high-altitude exposure, the incidence of AMS in the CDDP group was lower than that in the placebo group (48.6% vs. 67.6%, p = 0.022). The exercise time of the treadmill exercise test was significantly longer (507 ± 77.9 seconds vs. 457 ± 90.8 seconds, p = 0.004), the heart rate was lower (pre-exercise: 91.8 ± 11.7 beats/min vs. 97.2 ± 12.7 beats/min, p = 0.016; postexercise: 114 ± 22.2 beats/min vs. 121 ± 22.6 beats/min, p = 0.019), the pre-exercise and postexercise RPP were lower (pre-exercise: 1.13 × 10⁴ ± 1.68 × 10³ mmHg·beats/min vs. 1.23 × 10⁴ ± 1.84 × 10³ mmHg·beats/min, p = 0.027; postexercise: 1.19 × 10⁴ ± 1.75 × 10³ mmHg·beats/min vs. 1.31 × 10⁴ ± 2.00 × 10³ mmHg·beats/min, p = 0.002), and the MET value of the treadmill exercise test was significantly higher (9.93 ± 1.18 METs vs. 9.31 ± 1.52 METs, p = 0.037) in the CDDP group.

Discussion:

CDDP decreases the incidence of AMS and enhances exercise tolerance greater than placebo after high-altitude exposure. CDDP decreases the heart rate and myocardial oxygen consumption, increases the levels of hemoglobin, hematocrit, and antioxidant factors, and decreases the levels of inflammatory factors, which may explain the roles of CDDP in improving the adaptation to high-altitude exposure.

Introduction

When individuals ascend from sea level to high altitudes (≥2500 m) in a short period of time (hours to a few days), or to a higher altitude area from an already high-altitude plateau, most suffer from varying degrees of headache, dizziness, fatigue, nausea, vomiting, palpitation, and other symptoms. This is generally known as acute mountain sickness (AMS). After the expansion of railway and air travel in Qinghai and Tibet, the number of people traveling to high altitudes for work or recreation, such as mining, tourism, trekking, and deployment, is increasing. Therefore, AMS has become a major public health problem. To prevent the occurrence and development of AMS, researchers observed the preventive effects of various drugs on altitude sickness. However, these studies are mainly based on animal experiments, the individual's self-perception of the relief of symptoms, or on measured oxygen saturation and other indicators (Chiu et al., 2013; Berger et al., 2017; Zhou et al., 2017; Burns et al., 2019). There is a marked absence of effective, objective, and repeatable indices, as well as quantitative indices that can be used to evaluate performance capacity in a hypobaric and hypoxic environment at high altitude.

Compound Danshen Dripping Pill (CDDP), a well-established formulation of Salvia miltiorrhiza, is the first compound Chinese medicine successfully completing phase three clinical trials by the US FDA. It has been widely used to treat cardiovascular diseases, diabetic retinopathy, and osteoporosis (Guo et al., 2014; Lian et al., 2015; Luo et al., 2015).

The principal components of CDDP are S. miltiorrhiza (Danshen), Panax notoginseng (Sanqi), and borneol (Bingpian). S. miltiorrhiza plays roles in improving microcirculation, increasing oxygen saturation (SaO₂), and augmenting the oxygen supply of vital organs. It effectively reduces hypoxia-caused damage to vital organs, especially the heart. It also exerts antioxidative effects, such as reducing malondialdehyde content and increasing superoxide dismutase activities (Cao et al., 2015). P. notoginseng is traditionally used to promote blood flow and hemostasis. It alleviates physical fatigue in mice in a normoxic environment and in high-altitude conditions, which is attributed to its antioxidant and free radical scavenging activities (Ng et al., 2004; Yao et al., 2005; Wang, 2006). Borneol is a therapeutic Chinese medicine that is commonly used to facilitate the delivery of other components and enhance their effects in combination herbal formulas (Zhang et al., 2015).

The development of AMS is associated with multiple factors; yet, no definitive etiology of AMS has been identified. Multiple factors such as age, gender, speed of altitude rise, height of target altitude, acclimatization, and personal susceptibility have been associated with the risk for development of AMS (Basnyat and Murdoch, 2003; Bartsch and Swenson, 2013; Luks et al., 2017). The inflammatory mediators induced by hypoxia were also confirmed to be related to AMS (Hackett and Roach, 2001; Roach and Hackett, 2001; Schoene, 2008). High-altitude hypobaric hypoxia leads to a disturbance of cellular and tissue oxygen metabolism processes, abnormal increase of free radicals, and a decrease of free radical scavenging, all of which results in the occurrence and progression of acute altitude sickness. Previous studies have confirmed that CDDP can prevent and treat acute and chronic high-altitude sickness, but its mechanism remains unclear (Lin et al., 2005; Zhang et al., 2008).

In this study, we introduced the Lake Louise Score Questionnaire, treadmill exercise test, echocardiography, routine blood examination, and biochemical analysis to evaluate the severity of AMS. Our aim was to evaluate the role of CDDP in preventing the occurrence and progression of AMS and to clarify its role in maintaining work capability.

Methods

Ethical approval

The trial protocol was approved by the Institutional Review Board (IRB) of the Chinese PLA General Hospital, Beijing, China. The study is titled Compound Danshen Dripping Pill Decreases the Incidence of Acute Mountain Sickness and Maintains Working Ability (Grant No. S2014-070-01).

Trial design

From July 2014 to June 2016, we conducted a randomized, double-blind, placebo-controlled trial in China. Volunteers were recruited and were randomly assigned to receive either CDDP (at a dose of 405 mg three times daily) or matching placebo for 6 days before their high-altitude Tibetan Plateau experiences.

The primary endpoints included the incidence of AMS, exercise time, and metabolic equivalent (METs) of treadmill exercise tests. Secondary endpoints included the heart rates and rate-pressure product (RPP) before and after the treadmill exercise test, blood cell count examination, biochemical indices, and echocardiography parameters. Participants self-evaluated their state of AMS using the Lake Louise scoring system. There are five self-reported symptoms: headache, gastrointestinal symptoms, fatigue/weakness, dizziness/lightheadedness, and difficulty in sleeping. Each symptom was scored 0–3, with 0 indicating none and 1–3 indicating mild, moderate, and severe, respectively. AMS was defined by a total score of 3 or above (range 0–15, from all symptoms) in the presence of a headache. We considered scores of 3–4 as mild and 5 or higher as severe. Heart rate and SaO₂ were measured by pulse oximeters (NELLCOR OXi MAX N-65; Tyco International Ltd).

Participants

This study included Chinese male adults 18–35 years of age who reside at an altitude of 250 m or lower. Recruitment was also restricted to individuals who had no previous altitude exposure >2500 m. Other exclusion criteria included any issues that may cause vomiting, chronic obstructive pulmonary disease, heart failure, cerebral neoplasm, and any use of medicines aimed at promoting blood circulation, increasing immunity, or antioxidant effects.

Procedures

We collected participants' demographic data including age, height, weight, body mass index, habits, and general health conditions at the time of enrollment. Baseline assessments were performed at sea level (Beijing) before departure, including treadmill exercise tests, echocardiography, routine blood tests, and blood biochemical analysis. Subjects received either CDDP or the placebo 5 days before they began a 30-hour journey by train from Beijing to Geermu, Qinghai Province (2800 m). They then took a 3-hour bus from Geermu (2800 m) to the destination at Xidatan (4000 m). They stayed at the destination for 24 hours to complete all the experiments. Treadmill exercises were the first test item followed by echocardiography as the second item. After the echocardiography, venous blood was collected for routine blood testing and blood biochemical analysis. Participants completed the Lake Louise Questionnaire before they departed from the destination. All volunteers completed the tests in this procedure.

Trial oversight

After receiving a verbal explanation of the requirements to participate in the study, each participant signed a written informed consent. The treatment assignments were not disclosed to the participants or the investigators. One investigator, who was not involved in the assessment process, randomly assigned the participants into different groups. Blinding was maintained until all data were analyzed. The funding sources had no roles in the design, data analysis, or interpretation of the results in this trial. Commercial pharmaceutical grade CDDP and placebo were packed by Tasly Pharmaceutical Group (Tianjin, China). CDDP and placebo were both green soft gelatin capsules (405 mg/capsule) in identical containers, and they tasted and smelled the same.

Adverse events

None of the individuals in either group reported any adverse events during the entire process of the trial.

Statistical analyses

Variables were tested for standard normal distribution by the Lilliefors test and for homogeneity of variances by the Bartlett test (Cembrowski et al., 1979; Juhel-Gaugain et al., 2000). Differences between the two groups were analyzed with Student's t-test. When data were not normally distributed or variance was not sufficiently homogeneous, corresponding nonparametric tests were used as indicated when data of such analysis were presented. Data were expressed as mean ± standard deviation unless otherwise stated. The incidences of AMS were compared between the two groups using chi-squared tests. Qualitative variables were reported as a number (percentage). All tests were two tailed. A value of p < 0.05 was considered statistically significant. Statistical analysis was performed with SPSS Statistics (IBM).

Results

Baseline demographic characteristics and compliance to trial regimen

We randomly assigned 160 individuals to either the CDDP group (n = 78) or the placebo group (n = 82). A total of 141 participants were involved in the full analysis (71 in placebo group and 70 in CDDP group). Nineteen individuals were withdrawn from the study. There was no significant difference in the number between the two groups (11 in the placebo group [13.4%] and 8 in the CDDP group [10.3%], p = 0.537).

Analysis of baseline data revealed no statistically significant differences between the CDDP and placebo groups with respect to age, weight, height, smoking, and other health-related conditions (Table 1). The mean age was 24.2 years in the placebo group and 23.3 years in the CDDP group. The mean body weight was 68.2 kg in the placebo group and 66.9 kg in the CDDP group. The mean height was 173 cm in both the placebo group and CDDP group.

Table 1.

Demographic Data of the Subjects in Two Groups

Variable	Placebo group (n = 71)	CDDP group (n = 70)
Age (mean ± SD, years)	24.2 ± 3.5	23.2 ± 2.6
Body weight (mean ± SD, kg)	69.2 ± 9.8	66.9 ± 10.1
Height (mean ± SD, cm)	173 ± 4.7	173 ± 5.7
Body mass index (mean ± SD)	22.9 ± 2.8	22.2 ± 2.6
Smoking	9	11
Hypertension	4	3
Diabetes	2	3

CDDP, Compound Danshen Dripping Pill; SD, standard deviation.

The incidence of AMS

As given in Table 2, fewer participants in the CDDP group (48.1%) developed AMS after high-altitude exposure than in the placebo group (56.4%, p = 0.022). There were 10 individuals in the CDDP group and 19 individuals in the placebo group who had severe AMS (29.4% vs. 39.5%, p = 0.342).

Table 2.

Incidence of Acute Mountain Sickness at High Altitude in Two Groups

Group	Cases	No AMS	AMS	χ²	p
Placebo	71	23	48	5.25	0.022
CDDP	70	36	34
Total	141	59	82

AMS, acute mountain sickness.

Treadmill exercise test

CDDP significantly improved the length of exercise time and MET value of the treadmill exercise test, reduced the heart rate and RPP at high altitude. As given in Table 3, the exercise time of the treadmill test was significantly longer in the CDDP group than in the placebo group (507 ± 77.9 seconds vs. 457 ± 90.8 seconds, p = 0.004). The MET value of the treadmill exercise test was significantly higher in the CDDP group than in the placebo group (9.93 ± 1.18 METs vs. 9.31 ± 1.52 METs, p = 0.037). The pre-exercise and postexercise heart rate were lower in the CDDP group than in the placebo group (pre-exercise: 91.8 ± 11.7 beats/min vs. 97.2 ± 12.7 beats/min, p = 0.016; postexercise: 114 ± 22.2 beats/min vs. 121 ± 22.6 beats/min, p = 0.019). The pre-exercise and postexercise RPP were lower in the CDDP group than in the placebo group (pre-exercise: 1.13 × 10⁴ ± 1.68 × 10³ mmHg·beats/min vs. 1.23 × 10⁴ ± 1.84 × 10³ mmHg·beats/min, p = 0.027; postexercise: 1.19 × 10⁴ ± 1.75 × 10³ mmHg·beats/min vs. 1.31 × 10⁴ ± 2.00 × 10³ mmHg·beats/min, p = 0.002). No differences were detected in pulse oxygen saturation or blood pressure (p > 0.05).

Table 3.

Effect of Compound Danshen Dripping Pill on Treadmill Exercise Test at High Altitude (Mean ± Standard Deviation)

Variable	Placebo group (n = 71)	CDDP group (n = 70)	p
Pre-exercise SaO₂ (%)	85.3 ± 5.9	85.7 ± 5.8	0.587
Postexercise SaO₂ (%)	75.8 ± 6.6	75.0 ± 6.7	0.955
Exercise time (seconds)	457 ± 90.8	507 ± 77.9	0.004^a
METs	9.31 ± 1.52	9.93 ± 1.18	0.037^a
Pre-exercise heart rate (beats/min)	97.2 ± 12.7	91.8 ± 11.7	0.016^a
Postexercise heart rate (beats/min)	121 ± 22.6	114 ± 22.2	0.019^a
Pre-exercise SBP (mmHg)	139 ± 22.1	134 ± 24.1	0.356
Pre-exercise DBP (mmHg)	69.6 ± 12.7	70.4 ± 8.9	0.873
Postexercise SBP (mmHg)	140 ± 23.7	135 ± 29.4	0.409
Postexercise DBP(mmHg)	70.2 ± 12.0	72.6 ± 15.4	0.362
Pre-exercise RPP (mmHg·beats/min)	1.23 × 10⁴ ± 1.84 × 10³	1.13 × 10⁴ ± 1.68 × 10³	0.027^a
Postexercise RPP (mmHg·beats/min)	1.31 × 10⁴ ± 2.00 × 10³	1.19 × 10⁴ ± 1.75 × 10³	0.002^a

DBP, diastolic blood pressure; METs, metabolic equivalents; RPP, rate-pressure product; SBP, systolic blood pressure.

Statistically significant comparison between the placebo group and the CDDP group.

Echocardiography parameters

As given in Table 4, the pulmonary systolic blood pressure was higher in the CDDP group than in the placebo group (29.8 ± 13.5 mmHg vs. 23.4 ± 11.9 mmHg, p = 0.008). The maximum regurgitation velocity of the tricuspid valve was higher in the CDDP group than in the placebo group (2.58 ± 0.45 cm/s vs. 2.29 ± 0.56 cm/s, p = 0.002). The internal diameter of the right ventricle was smaller in the CDDP group than in the placebo group (57.4 ± 6.27 mm vs. 60.1 ± 7.87 mm, p = 0.028); the right ventricular outflow tract velocity-time integral was lower in the CDDP group than in the placebo group (18.6 ± 3.8 cm vs. 20.2 ± 3.9 cm, p = 0.020).

Table 4.

Effect of Compound Danshen Dripping Pill on Echocardiography Parameters When Rest at High Altitude (Mean ± Standard Deviation)

Variable	Placebo group (n = 71)	CDDP group (n = 70)	p
Pulmonary systolic blood pressure (mmHg)	23.4 ± 11.9	29.8 ± 13.5	0.008^a
Mean pulmonary arterial pressure (mmHg)	15.5 ± 5.8	17.7 ± 4.9	0.022^a
RVOT VTI (cm)	20.2 ± 3.9	18.6 ± 3.8	0.020
RVOTprox (mm)	25.4 ± 4.2	24.8 ± 3.3	0.720
TRVmax (cm/s)	2.29 ± 0.56	2.58 ± 0.45	0.002
TAPSE (mm)	19.8 ± 4.31	20.3 ± 3.48	0.476
RV (mm)	60.1 ± 7.87	57.4 ± 6.27	0.028
CI (L/min/m²)	2.96 ± 0.80	2.98 ± 0.66	0.902
SV (ml)	58.1 ± 10.5	56.2 ± 9.5	0.374
EF (%)	61.4 ± 3.7	61.9 ± 4.5	0.534
FS (%)	32.1 ± 2.9	32.3 ± 3.4	0.565

Statistically significant comparison between the placebo group and the CDDP group.

CI, cardiac index; EF, ejection fraction; FS, shortening fraction; RV, right ventricle; RVOT, right ventricular outflow tract; SV, stroke volume; TAPSE, tricuspid annular plane systolic excursion; TRV, three tricuspid regurgitation velocity; VTI, velocity-time integral.

Comparison of main routine blood test indicators

As given in Table 5, the hemoglobin level was higher in the CDDP group than in the placebo group (167 ± 9.4 g/L vs. 163 ± 9.7 g/L, p = 0.036); the hematocrit level was higher in the CDDP group than in the placebo group (49.4% ± 2.75% vs. 48.3% ± 3.39%, p = 0.043); the platelet count was higher in the CDDP group than in the placebo group (192 ± 43.3 × 10⁹/L vs. 209 ± 46.5 × 10⁹/L, p = 0.041); the white blood count was lower in the CDDP group than in the placebo group (6.32 ± 2.09 × 10⁹/L vs. 6.92 ± 2.17 × 10⁹/L, p = 0.046), in which the percentage of monocytes was lower in the CDDP group than in the placebo group (3.23% ± 1.60% vs. 3.83% ± 1.99%, p = 0.046).

Table 5.

Effect of Compound Danshen Dripping Pill on Blood Cells at High Altitude (Mean ± Standard Deviation)

Variable	Placebo group (n = 71)	CDDP group (n = 70)	p
RBC ( × 10¹²/L)	5.41 ± 0.46	5.44 ± 0.41	0.304
Hb (g/L)	163 ± 9.7	167 ± 9.4	0.036^a
Plt ( × 10⁹/L)	209 ± 46.5	192 ± 43.3	0.041^a
WBC ( × 10⁹/L)	6.92 ± 2.17	6.32 ± 2.09	0.046
Neutrophil (%)	67.4 ± 12.3	69.6 ± 11.1	0.412
Monocyte (%)	3.83 ± 1.99	3.23 ± 1.60	0.036^a
Basophil (%)	0.96 ± 0.94	1.19 ± 0.98	0.257
Lymphocyte (%)	24.9 ± 11.7	23.4 ± 11.3	0.483
Eosinophil (%)	2.52 ± 1.88	2.56 ± 1.82	0.731
Plateletcrit (%)	21.4 ± 4.96	20.2 ± 4.16	0.064
Hematocrit (%)	48.3 ± 3.39	49.4 ± 2.75	0.043^a

Statistically significant comparison between the placebo group and the CDDP group.

Hb, hemoglobin; Plt, platelet; RBC, red blood cell; WBC, white blood cell.

Blood biochemical analysis

As given in Table 6, the total bilirubin and the direct bilirubin levels were higher in the CDDP group than in the placebo group (total bilirubin: 8.79 ± 4.11 μmol/L vs. 7.41 ± 3.59 μmol/L, p = 0.015; direct bilirubin: 5.11 ± 2.74 μmol/L vs. 4.22 ± 2.38 μmol/L, p = 0.019).

Table 6.

Effect of Compound Danshen Dripping Pill on Blood Biochemistry at High Altitude (Mean ± Standard Deviation)

Variable	Placebo (n = 71)	Compound Danshen (n = 70)	p
UA (mmol/L)	377.4 ± 89.2	386.3 ± 87.2	0.565
Na (mmol/L)	142.9 ± 3.5	143.4 ± 4.0	0.272
K (mmol/L)	4.28 ± 0.46	4.29 ± 0.41	0.709
Cl (mmol/L)	100.1 ± 3.2	99.4 ± 3.2	0.266
Alanine aminotransferase (U/L)	20.6 ± 9.6	20.5 ± 13.1	0.405
Aspartate aminotransferase (U/L)	19.4 ± 5.6	20.6 ± 5.7	0.277
Glucose (mmol/L)	5.13 ± 0.95	5.15 ± 1.14	0.913
Total bilirubin (μmol/L)	7.41 ± 3.59	8.79 ± 4.11	0.015^a
Cr (mmol/L)	75.1 ± 12.5	75.5 ± 13.9	0.853
Direct bilirubin (μmol/L)	4.22 ± 2.38	5.11 ± 2.74	0.019^a
CK-MB (U/L)	14.2 ± 3.9	16.6 ± 12.6	0.682

Statistically significant comparison between the placebo group and the CDDP group.

CK-MB, creatine kinase, MB isoenzyme; Cr, creatinine; UA, uric acid.

Discussion

This study evaluated the effectiveness of the traditional Chinese medicine, CDDP, in preventing AMS and maintaining working ability, using a treadmill exercise test, echocardiography, and physiological indices. The incidence of AMS was significantly lower in the CDDP group, indicating that CDDP is effective in reducing the occurrence and development of AMS.

The treadmill exercise test is an important clinical tool to evaluate exercise capacity. It is frequently used to assess the cardiovascular function in a wide range of individuals from patients with heart disease to professional athletes. It is noninvasive and provides a wealth of clinically relevant diagnostic and prognostic information. In a clinical situation, we frequently use this test for the evaluation of exercise intolerance, the effects of specific interventions such as physical training and medication, and changes or alterations in exercise capacity. In this study, we used the treadmill exercise test to evaluate the effectiveness of drugs in maintaining working abilities and protecting the functions of vital organs. However, as for all its above usage, the treadmill exercise test lacks parameter values for individuals in high-altitude areas. We successfully performed the treadmill exercise test at high altitude and none of the participants reported any complications, indicating that the treadmill exercise test is feasible and safe in assessing working ability at high altitude.

This study showed that CDDP significantly improved the MET value of treadmill exercise tests. MET is a physiological measure expressing the energy cost of physical activities and is defined as the ratio of metabolic rate (and therefore the rate of energy consumption) during a specific physical activity to a reference metabolic rate. One MET is considered equivalent to the consumption of 3.5 mL of oxygen per kilogram of body mass per minute and roughly equivalent to the energy cost of sitting quietly. In the treadmill exercise test, MET is commonly used as a measurement unit of exercise tolerance (Ainsworth et al., 2011). CDDP improved both the MET value and exercise time of individuals who had performed the treadmill exercise test, indicating that CDDP could improve the performance and tolerance of individuals experiencing altitude sickness as a result of changing to a higher altitude in a short period of time.

We also found that CDDP significantly decreased the RPP after the treadmill exercise test. RPP is used in cardiology and exercise physiology to determine the myocardial workload. It is a measure of the stress put on the cardiac muscle based on the number of times it needs to beat per minute (heart rate) and the arterial blood pressure. It was a direct indication of the energy demand of the heart and thus a good measure of the energy consumption of the heart (Gobel et al., 1978). CDDP significantly decreased RPP before and after the treadmill exercise test, which might contribute to the improvement of exercise tolerance by CDDP.

CDDP significantly decreased the mean heart rate compared with placebo before and after the treadmill exercise test at high altitude. Several previous studies showed that a higher heart rate was associated with the incidence of AMS and a decrease of cardiovascular function (O'Connor et al., 2004; Naeije, 2010; Wu et al., 2010; Hooper and Mellor, 2011). We hypothesized that the reduced heart rate from using CDDP may also contribute to the improvement of high-altitude adaption.

The partial pressure of atmospheric oxygen falls progressively as barometric pressure decreases with increasing altitude. Exposure to high altitudes places considerable challenges on individuals including the development of AMS and diminished working ability. In this study, we confirmed that CDDP significantly reduced the incidence of AMS and increased a person's working ability. We further corroborated that CDDP provided these benefits without improving oxygenation. Therefore, we explored the possible underlying mechanisms by electrocardiography, blood cell tests, and blood biochemical examination.

CDDP increased the pulmonary artery systolic pressure and TRVmax compared with the placebo but the values remained within the normal range values. Previous research demonstrated that marked reduction of the arterial oxygen content increased pulmonary vasoconstriction. Exposure to high altitudes in lowlanders caused an increase in mean pulmonary arterial pressure in order for the heart to cope with the vasoconstriction of the pulmonary arteries (Penaloza and Arias-Stella, 2007; Huez et al., 2009; Naeije, 2008). The importance of increased pulmonary arterial pressure and TRVmax by CDDP after acute high-altitude exposure remains to be established. We also discovered that CDDP significantly decreased the diameter of right ventricular dilation compared with the placebo.

High-altitude environments induce various cellular effects that are strictly related to changes in oxidative balance. Compared with the placebo, CDDP reduced the count of white blood cells and the percentage of monocytes. Whether the decrease of white blood cells, especially the decrease of monocytes induced by the CDDP was related to the improvement of adaptation to high altitude remained unclear.

Blood biochemical indicators are usually analyzed to evaluate the function of vital organs. We detected increased levels of bilirubin with CDDP use after exposing the participants to the high-altitude environment. We also noticed that the increased level of bilirubin induced by the CDDP was fall in normal test range. It is therefore difficult to describe its physiologic role.

The limitation of this study is that the increase of pulmonary artery pressure caused by CDDP is contradictory to its improvement effective in preventing AMS and improving working ability after high-altitude exposure. Previous study has shown that CDDP effectively reduces the pulmonary artery pressure and improves pulmonary arteriole remodeling in rats with pulmonary arterial hypertension induced by monocrotaline (Li et al., 2013). In this study, echocardiography was performed after treadmill exercise test and we found that CDDP prolonged the exercise time compared with the placebo. Whether the difference of pulmonary artery pressure caused by the prolonged exercise time remains unclear; it needs further verification.

In summary, CDDP is found to be effective in preventing AMS and improving working ability after high-altitude exposure. CDDP decreases the heart rate and myocardial oxygen consumption, ameliorates cardiac structure and function, increases the hemoglobin, hematocrit, and antioxidant factors, and decreases inflammatory factors. The above mechanisms may explain the roles of CDDP in improving adaptation to high altitudes.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the National Science and Technology Major Projects Fund for Major New Drug Innovation and Development with the specific project funding under Grant Agreement No. 2014ZX09J14102-02A. The funders had no role in the decision to publish or the preparation of the article.

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