Summary
Aims
It is unclear whether the impaired BRS plays a key role in the incidence of cardiovascular diseases. The molecular mechanism of impaired BRS remains to be fully elucidated. We hypothesized that selection of rats based on deficient and normal intrinsic BRS would yield models that reflect cardiovascular diseases risk.
Methods and Results
Twenty generations of selection produced arterial baroreflex low rats and normal rats that differed in BRS by about 2.5‐fold change. Metabolic syndrome (including hypertension, overweight, hyperlipemia, and hyperglycemia) emerged in ABR‐DRs. Although ABR‐DRs consumed less food, they gained significantly more body weight.
Conclusion
Our study demonstrated that intrinsic low BRS induced hypertension and metabolic disorder. Restoration of impaired BRS might be a potent target of therapeutic intervention in metabolic syndrome.
Keywords: ABR‐DRs, ABR‐NRs, baroreflex sensitivity, hypertension, metabolic syndrome
1. INTRODUCTION
Arterial baroreflex regulates cardiovascular function. Baroreflex sensitivity (BRS), commonly assessed as change of heart rate interval in response to change in systolic blood pressure (SBP), is a well‐recognized marker of autonomic activity.1 Large multicenter prospective studies of subjects with or without cardiovascular diseases show that impaired BRS is associated with mortality as well as development of hypertension, arrhythmias, stroke, heart failure, and myocardial infarction.2, 3, 4, 5, 6 A recent study suggests that BRS may help to identify patients with resistant hypertension who are likely to benefit from renal sympathetic denervation.7 Impairment in the baroreflex function also has been demonstrated in diabetic patients and habitual smokers.8, 9 On the other hand, activation of the baroreceptors may be a promising therapy for the treatment of resistant hypertension and heart failure.10, 11, 12 All these observations collectively suggest a strong link between impaired autonomic nervous system and cardiovascular diseases.
However, these data cannot answer whether BRS plays a key role in the occurrence of cardiovascular diseases. Baroreflex feedback signal originates predominantly in the carotid sinus and aortic arch and relays information to nucleus tractus solitarii in the medulla. This information is processed in the nucleus ambiguus and the rostral ventrolateral medulla.13, 14 Baroreflex regulates the balance of vagal outflow and sympathetic firing, which is mainly modulated by nucleus ambiguus and rostral ventrolateral medulla, respectively.13, 14 Activation of baroreflex induced by rise in arterial blood pressure results in increased cardiac vagal activity and decreased sympathetic firing, leading to a decrease in total peripheral resistance, venous return, heart rate, cardiac output, and blood pressure.1, 14
The purpose of this study was to test the hypothesis that rats selected on the basis of abnormal BRS would also involve in the development of cardiovascular diseases.
2. MATERIALS AND METHODS
2.1. Animals and animal care
Sprague Dawley (SD) rats were purchased from Sino‐British SIPPR/BK Lab Animals (Shanghai, China). Rats were housed at controlled temperature (23°C‐25°C) under 12/12‐h light/dark schedule. Standard chow and water were provided ad libitum. All animal procedures were approved by the ethics committee of the Second Military Medical University and performed in compliance with the institutional guide for care and use of laboratory animals.
2.2. Founder population and selective breeding
The founder population was 55 male and 61 female SD rats from genetically heterogeneous stock (Sino‐British SIPPR/BK Lab Animal Ltd, Shanghai, China). To broaden the genetic diversity, each rat was of different parentage.
2.3. Blood pressure continuous recording and BRS measurement in conscious rats
The recording and measurement were conducted as described previously in detail.15, 16 Rats were intraperitoneally administered ketamine (50 mg/kg) and diazepam (5 mg/kg) for anesthesia. The lower abdominal aorta was catheterized via the left femoral artery with a polyethylene catheter full of heparin (100 U/mL) for measuring blood pressure and heart rate. The left femoral vein was cannulated with another catheter filled with normal saline for phenylephrine administration. The catheters were tunneled subcutaneously, exposed through the interscapular skin and fixed. Two days later, rats were placed individually in cylindrical cages for blood pressure recording and BRS measurement. The aortic catheter was connected to a pressure transducer via a swivel allowing rats to move freely. Beat‐to‐beat blood pressure signals and heart period were digitized by the MPA‐HBBS system (Alcott Biotech Co. Ltd, Shanghai, China) mounted in computer. After approximately 3‐h habituation, the blood pressure and heart period signals were determined online. The mean values of these parameters during 1‐h period were calculated and served as SBP, DBP, and heart period. Heart rate was calculated from the heart period values.
2.4. Noninvasive measurement of blood pressure17
Blood pressure and heart rate by the tail‐cuff method was measured with ALC‐NIBP noninvasive measuring and analyzing system for blood pressure (Alcott Biotech Co. Ltd, Shanghai, China).
2.5. Body weight, weekly food intake, and metabolic analyses
Body weight and weekly food intake were recorded at the indicated time points. Rats (fasted 12 hours) were intraperitoneally injected with glucose (2 g/kg) for glucose tolerance test (GTT) and intraperitoneally injected with human recombinant insulin (0.75 units/kg, Novo Nordisk, Bagsvaerd, Denmark) for insulin tolerance test (ITT).18 Blood glucose concentration was measured at the indicated time points with LifeScan glucometer (Johnson & Johnson Medical, Shanghai, China). Plasma insulin levels during GTT were measured with insulin ELISA kit (Shibayagi Co. Ltd, Shibukawa, Japan).
2.6. Biochemical assays
Fasting (12 hours) serum samples were used for measuring biochemical factors involved in glucose and lipid metabolism, including glucose, triglyceride, cholesterol, and low‐density lipoprotein. All the above indexes were measured with HITAHI 7600 automatic biochemical analyzer (Hitachi High‐Technologies, Tokyo, Japan). Plasma leptin was measured with ELISA kit (R&D Systems, Minneapolis, MN, USA). Plasma insulin was analyzed with ELISA kit (Shibayagi Co. Ltd).
2.7. Echocardiography
Rats were anesthetized with ketamine (50 mg/kg) and diazepam (5 mg/kg). The chest was shaved with chemical depilatory cream and applied with warmed ultrasound gel to optimize the visibility of the cardiac chambers. Echocardiography was performed using the Vevo 770 high‐resolution in vivo micro‐imaging system (FUJIFILM Visualsonics Inc., Toronto, Ontario, Canada). Echocardiography and data processing were conducted by the same technician, and animal grouping was unknown to him.
2.8. Recording of renal sympathetic nerve activity (RSNA)
The surgical procedures and recording of renal sympathetic nerve activity were conducted as described previously.19 Briefly, rats were intraperitoneally administered with urethane and α‐chloralose (800 mg/kg and 40 mg/kg, respectively) for anesthesia. The right femoral artery and femoral vein were catheterized for blood pressure measurement and drug administration, respectively. The renal sympathetic nerve was exposed retroperitoneally and isolated from surrounding connective tissue, and placed on a pair of platinum‐iridium recording electrodes (Beijing Xuyue Sci. & Tech. Co. Ltd, Beijing, China). The nerve‐electrodes junction was covered with Wacker Sil‐Gel (Wacker Chemie AG, Munich, Bavaria, Germany) for insulating electrically from surrounding tissues. The renal sympathetic nerve activity signal was amplified and recorded with the PowerLab system (ADInstruments Pty Ltd, Bella Vista, NSW, Australia). After recording the baseline of renal sympathetic nerve activity, phenylephrine was administered to activate baroreflex by increasing SBP (~50 mm Hg) and renal sympathetic nerve activity was recorded.
The maximum nerve activity (Max) and background noise level of renal sympathetic nerve activity were also obtained. Briefly, Max occurred 1‐2 minutes after the rat was euthanized. Background noise level was recorded 15‐20 minutes after the rat was euthanized. Baseline of renal sympathetic nerve activity, subtracting the noise level from the absolute value, was expressed as a percentage of Max. The control of baroreflex on renal sympathetic nerve activity was evaluated as Δ renal sympathetic nerve activity (% of baseline)/Δ blood pressure (mm Hg).
Throughout the surgery, core body temperature was maintained at 36.5°C‐37.5°C by rectal probe attached to a heating pad (Physitemp Instruments Inc, Clifton, NJ, USA).
2.9. Statistical analysis
The investigators were blinded to the animal groups when they assessed the blood pressure, the BRS, or other indexes. The animals were randomly assigned using the random permutations table. Continuous variables were expressed as mean ± standard deviation (s.d.), and categorical variables were expressed as frequency (percentage). Student's t test was used for comparisons between 2 groups. One‐way analysis of variance (ANOVA) test was used to compare more than two groups for continuous variables, and Student‐Newman‐Keuls t test was used for multiple comparison. Chi‐square test was used to compare the group with and without hypertension. ANOVA for repeated measurement data was used to comparison between 2 strains at different ages. Univariate regression analysis was used to evaluate the relationship between BRS and blood pressure. The Pearson r values were calculated. All hypothesis tests used two‐sided tests, and a P‐value less than 0.05 was considered to be statistical significant. Statistical analysis system 9.4 (SAS 9.4) was used to perform Statistical analyses.
2.10. Ethical approval for animal studies
All animal procedures were approved by the ethics committee of the Second Military Medical University and performed in compliance with the institutional guide for care and use of laboratory animals.
3. RESULTS
3.1. Founder population and selective breeding
We first began large‐scale artificial selection for deficient and normal BRS with the genetically heterogeneous stock of SD rats as the founder population. Rats were three months old upon arrival. Then, we conducted blood pressure continuous recording and BRS measurement in conscious state. The average BRS and SBP of the founder population were 0.77 ms/mm Hg and 130 mm Hg, respectively. There were no differences in blood pressure or lipid levels between male and female rats. Based on the average BRS, we defined rats with BRS < 0.6 ms/mm Hg as ABR‐DRs, and BRS > 0.8 ms/mm Hg as ABR‐NRs. Because BRS and sympathetic activation might be affected by hypertension,20, 21, 22 we only selected the rats with normal blood pressure for breeding (SBP < 140 mm Hg and DBP < 90 mm Hg). Using above criteria, we selected 20 rats (♂:♀=1:1) as the founder of ABR‐DRs and 20 rats (♂:♀=1:1) as the founder of ABR‐NRs. For each line, they were paired randomly for mating. For subsequent generations, rats underwent strict brother‐sister mating (♂:♀=1:1) at the age of 3 months old. After the offspring were weaned, only their fathers underwent continuous blood pressure recording and BRS measurement in conscious state. The offspring had the chance of growing up if their father met the criteria in the original line. Otherwise, they were sacrificed.
3.2. Twenty generations of selective breeding in rats results in two divergent strains
Twenty generations of selection produced ABR‐DRs and ABR‐NRs that differed in BRS by ≈ 2.5‐fold change (Figure 1A). Age itself is known to affect BRS.23 So at generation 20, we measured BRS in male rats at different ages (1, 2, 4, 6, and 8 months). In 1‐month‐old animals, the BRS in ABR‐DRs was significantly lower than ABR‐NRs (0.25 ± 0.08 ms/mm Hg vs 0.72 ± 0.25 ms/mm Hg, P < 0.01, Figure 2A). In 8‐month‐old ABR‐NRs, BRS increased to 1.19 ms/mm Hg, while in ABR‐DRs, only increased to 0.45 ms/mm Hg (P < 0.01, Figure 2A). We also measured BRS, blood pressure and heart rate in 6‐month‐old female rats both at generation 19 and 20 and got similar results (Table 1). Accordingly, for the rest of this study, we only used male rats.
Figure 1.
Twenty generations of selective breeding in rats results in two divergent strains. A, BRS, SBP, DBP, and heart rate for two populations of rats across 20 generations. B, Incidence of hypertension across 20 generations. Chi‐square test was used to compare the group with and without hypertension. C, Representative scatter plots showed the significant and negative relationships between BRS and mean blood pressure (MBP) at generation 20, n = 48. Data are expressed as mean ± s.d. For ABR‐NRs, n = 819 in total; for ABR‐DRs, n = 779 in total. ANOVA for repeated measurement data was used to compare 2 strains of animals at different ages for (A). *P < 0.05,**P < 0.01
Figure 2.
BRS (A), heart rate (B), SBP, and DBP (C,D) were measured in different ages of male ABR‐NRs and ABR‐DRs from generation 20 (1, 2, 4, 6, and 8 months, n = 7‐10 in different ages). Data are expressed as mean ± s.d. ANOVA for repeated measurement data was used to compare two strains of animals at different ages. *P < 0.05, **P < 0.01
Table 1.
BRS, SBP, DBP, and heart rate of female ABR‐NRs and ABR‐DRs from generation 19 and 20
| Parameter | ABR‐NRs | ABR‐DRs | P value |
|---|---|---|---|
| Generation 19 (6‐month‐old) | |||
| BRS (ms/mm Hg) | 1.31 ± 0.31 | 0.56 ± 0.21 | <0.001 |
| SBP (mm Hg) | 127 ± 5.4 | 132 ± 6.2 | 0.038 |
| DBP (mm Hg) | 88.9 ± 6.8 | 96.9 ± 5.3 | 0.003 |
| Heart rate (beat per min) | 370 ± 39 | 385 ± 38 | 0.347 |
| Generation 20 (6‐month‐old) | |||
| BRS (ms/mm Hg) | 1.31 ± 0.36 | 0.39 ± 0.15 | < 0.001 |
| SBP (mm Hg) | 123 ± 9.5 | 134 ± 8.3 | 0.009 |
| DBP (mm Hg) | 83 ± 9.5 | 97 ± 6.7 | < 0.001 |
| Heart rate (beat per min) | 367 ± 43 | 400 ± 34 | 0.06 |
Data were expressed as mean ± s.d. For Generation 19, ABR‐NRs n = 12, ABR‐DRs n = 11. For Generation 20, n = 7 per group. Unpaired Student's t test was used.
3.3. Metabolic syndrome emerges in ABR‐DRs
The metabolic syndrome is a cluster of cardiovascular risk factors (including obesity, hyperglycemia, dyslipidemia, and hypertension).24, 25 In this study, we found that ABR‐DRs showed metabolic syndrome. Hypertension, overweight, hyperlipemia, and hyperglycemia emerged in ABR‐DRs.
3.4. ABR‐DRs show hypertension
Hypertension is the leading risk factor for acute and chronic cardiovascular diseases at different age groups.26 In our study, although all the offspring of hypertensive rats (SBP > 140 mm Hg and/or DBP > 90 mm Hg) were terminated reproduction, the ABR‐DRs had higher blood pressure than normal rats. In young adult rats (4‐6 months old), the differences in SBP and DBP became significant from generation 9 (Figure 1A). Both SBP and DBP in ABR‐DRs were higher than that of normal rats by about 10 mm Hg from generation 10 to 20 (Figure 1A).
At generation 20, we measured the blood pressure at 5 different ages (1‐, 2‐, 4‐, 6‐, and 8‐month‐old). From 1‐month‐old, the values of blood pressure of ABR‐DRs were significantly higher than in ABR‐NRs (Figure 2C,D). SBP and DBP in ABR‐DRs were both significantly increased in 5 different age groups. More importantly, in ABR‐DRs, the incidence of hypertension was significantly higher (Figure 1B). At generation 20, the relationship between BRS and mean arterial pressure was also assessed by univariate regression analysis (n = 48, including ABR‐DRs and ABR‐NRs). The blood pressure is significantly and negatively correlated with BRS (Figure 1C).
3.5. ABR‐DRs show overweight, hyperlipemia, and higher levels of leptin and uric acid
Overweight and obesity are disorders of excess body fat. They are important risk factors linked to increased cardiovascular morbidity and mortality.27 In this study, we measured body weight and the chow diet intake of 2 groups (n = 20) at generation 20, from 1‐ to 12‐month‐old. From 9 to 12 months, ABR‐DRs even consumed less food than normal rats (Figure 3A,B). However, ABR‐DRs gained significantly more body weight from 7 months onwards (Figure 3A,B). At 12 months, the body weight of ABR‐DRs was greater by 81 g. Compared to ABR‐NRs, fat tissue was greater by about 45 g in ABR‐DRs (Table 2). In addition, cholesterol, triglyceride, low‐density lipoprotein, and leptin levels in the serum were also greater in ABR‐DRs. The parameters, such as alanine transaminase, urea nitrogen, and uric acid, related to the function of liver and kidney, were also significantly greater in ABR‐DRs.
Figure 3.
ABR‐DRs show over weight, impaired glucose, and insulin tolerance. (A) Representative image of ABR‐DRs and ABR‐NRs. (B) Body weight and diet intake for ABR‐NRs and ABR‐DRs at different ages (1‐12 months) of generation 20, n = 20. (C) Glucose tolerance test (GTT), the area under the curve (AUC), and insulin concentration during the GTT (n = 10). (D) Insulin tolerance test (ITT, left), Glucose during ITT presented as the percentages over the baseline level (middle) and the percentage changes of AUC over control (right). n = 9. Data are expressed as mean ± s.d. ANOVA for repeated measurement data was used to compare two groups at different ages for (B) and at different time for (C) and (D). Student's t test was also used for (C) and (D). *P < 0.05,**P < 0.01
Table 2.
Fat tissue weight and metabolic parameters of ABR‐NRs and ABR‐DRs at the age of 8 months
| Parameter | ABR‐NRs | ABR‐DRs | P value |
|---|---|---|---|
| Body weight (g) | 522 ± 36 | 618 ± 36 | <0.001 |
| Total fat tissue weight (g) | 47.0 ± 5.63 | 92.3 ± 11.9 | <0.001 |
| Subcutaneous fat (%) | 3.32 ± 0.33 | 7.04 ± 0.74 | <0.001 |
| Epididymal fat (%) | 1.02 ± 0.08 | 1.24 ± 0.19 | 0.012 |
| Mesenteric fat (%) | 1.20 ± 0.12 | 1.89 ± 0.22 | <0.001 |
| Perirenal and retroperitoneal fat (%) | 2.45 ± 0.23 | 3.11 ± 0.18 | <0.001 |
| Interscapular fat (‰) | 6.43 ± 0.90 | 11.2 ± 1.80 | <0.001 |
| Perigastric fat (‰) | 3.73 ± 0.68 | 4.82 ± 0.41 | <0.001 |
| Periaortic fat/aortic length (mg/cm) | 44.9 ± 9.07 | 74.3 ± 11.3 | <0.001 |
| Cholesterol (mmol/L) | 1.57 ± 0.24 | 2.10 ± 0.33 | <0.001 |
| Triglyceride (mmol/L) | 1.12 ± 0.41 | 1.59 ± 0.53 | 0.044 |
| Low‐density lipoprotein (mmol/L) | 1.16 ± 0.16 | 1.52 ± 0.34 | 0.008 |
| Leptin (ng/mL) | 3.94 ± 1.55 | 7.17 ± 1.48 | <0.001 |
| Fasting glucose (mmol/L) | 4.94 ± 0.48 | 6.18 ± 0.63 | < 0.001 |
| Insulin (ng/mL) | 0.74 ± 0.17 | 0.70 ± 0.20 | 0.363 |
| Alanine transaminase (U/L) | 39.9 ± 5.28 | 48.7 ± 6.14 | 0.003 |
| Urea nitrogen (mmol/L) | 6.66 ± 0.54 | 8.01 ± 0.68# | <0.001 |
| Uric acid (mmol/L) | 168 ± 36.5 | 224 ± 17.8 | 0.001 |
| Creatinine (μmol/L) | 46.0 ± 4.09 | 46.1 ± 4.38 | 0.95 |
Data were expressed as mean ± s.d. n = 10. Student's t test was used for comparison.
3.6. ABR‐DRs show hyperglycemia
Hyperglycemia or impaired glucose tolerance is an important risk factor for cardiovascular diseases.28 We used 10‐month‐old rats to assess the carbohydrate metabolism. Compared to normal rats, glucose levels was higher in ABR‐DRs (Table 2). We then assessed glucose and insulin tolerance. Blood glucose rose to much higher levels (n = 10, P < 0.05), the area under the curve for glucose (AUCglucose) and insulin secretion induced by glucose were both much higher in ABR‐DRs (Figure 3C). Insulin tolerance test showed that the reduction in glucose induced by insulin was lower in ABR‐DRs (Figure 3D). These data indicate that ABR‐DRs exhibit hyperglycemia and impaired glucose and insulin tolerance.
3.7. Cardiac function and aconitine‐induced arrhythmia are not different between ABR‐NRs and ABR‐DRs
In generation 20, we measured cardiac function by echocardiography in 2 strains at 8 months of age. Echocardiography detection and morphological examination did not show significant differences in most of cardiac indexes between 2 groups (Tables 3 and 4).
Table 3.
Echocardiographic analysis in ABR‐NRs and ABR‐DRs at the age of 8 months
| Parameter | ABR‐NRs | ABR‐DRs | P value |
|---|---|---|---|
| Left ventricular internal diameter; diastole (mm) | 5.62 ± 0.71 | 5.40 ± 0.69 | 0.537 |
| Left ventricular internal diameter; systole (mm) | 2.08 ± 0.40 | 2.32 ± 0.42 | 0.307 |
| Left ventricular posterior wall; diastole (mm) | 2.16 ± 0.23 | 2.67 ± 0.45 | 0.012 |
| Left ventricular posterior wall; systole (mm) | 3.37 ± 0.26 | 3.98 ± 0.46 | 0.006 |
| Left ventricular anterior wall; diastole (mm) | 2.24 ± 0.27 | 2.38 ± 0.30 | 0.309 |
| Left ventricular anterior wall; systole (mm) | 3.45 ± 0.23 | 3.77 ± 0.22 | 0.011 |
| Left ventricle Vol; diastole (μL) | 159 ± 49 | 152 ± 38 | 0.784 |
| Left ventricle Vol; systole (μmol/L) | 15.1 ± 7.5 | 20.3 ± 9.0 | 0.264 |
| Stroke volume (μL) | 138 ± 34 | 127 ± 37 | 0.520 |
| Ejection fraction (%) | 88.3 ± 5.5 | 88.0 ± 6.7 | 0.903 |
| Fractional shortening (%) | 60.0 ± 6.9 | 61.0 ± 10.4 | 0.832 |
| Cardiac output (%) | 0.140 ± 0.035 | 0.133 ± 0.034 | 0.694 |
Data were expressed as mean ± s.d. n = 8. Unpaired Student's t test was used.
Table 4.
Morphological examination of heart, aorta, and kidney in BRS normal and low rats at the age of 8 months
| Parameters | ABR‐NRs | ABR‐DRs | P value |
|---|---|---|---|
| Body weight (g) | 539 ± 27 | 603 ± 38 | 0.002 |
| Heart weight/body weight | 2.53 ± 0.25 | 2.56 ± 0.12 | 0.7033 |
| Left ventricle weight/body weight | 1.32 ± 0.13 | 1.25 ± 0.06 | 0.1991 |
| Right ventricle weight/body weight | 0.39 ± 0.07 | 0.39 ± 0.04 | 0.8166 |
| Aortic weight (mg/cm) | 11.6 ± 1.4 | 13.8 ± 1.5 | 0.027 |
| Right kidney weight/body weight | 2.81 ± 0.27 | 2.28 ± 0.16 | 0.0003 |
Data were expressed as mean ± s.d. n = 8 in each index except n = 6 for aortic weight. Unpaired Student's t test was used.
We used aconitine to induce arrhythmia in all animals of the same age by the reported method.29 The threshold doses of aconitine required for ventricular premature beat, ventricular fibrillation, and cardiac arrest were used to evaluate the sensitivity to develop cardiac arrhythmia (n = 6). Doses required to induce ventricular premature beat (34.9 ± 4.8 μg/kg vs 37.3 ± 6.9 μg/kg in ABR‐NRs, P > 0.05), ventricular fibrillation (60.5 ± 11.8 μg/kg vs 61.5 ± 5.8 μg/kg in ABR‐NRs, P > 0.05), or cardiac arrest (93.2 ± 12.5 μg/kg vs 90.9 ± 24.8 μg/kg in ABR‐NRs, P > 0.05) were similar in the two groups (Figure 4A). Thus, it appears that impaired BRS may be not a factor for the occurrence of cardiac dysfunction and arrhythmia.
Figure 4.
ABR‐DRs do not show the sensitivity of cardiac arrhythmia. They have normal sympathetic function and impaired parasympathetic function. (A) The threshold doses of aconitine required for ventricular premature beat (VPB), ventricular fibrillation (VF), and cardiac arrest (CA), n = 6. (B) Baseline of renal sympathetic nerve activity (RSNA). (C) The response of RSNA to blood pressure (BP) elevation. (D) Change of heart rate in response to the BP elevation. For panels (B‐D), n = 5. Data are expressed as mean ± s.d. Student's t test was used. **P < 0.01, n.s., no significance
3.8. ABR‐DRs show parasympathetic dysfunction
We first measured the sympathetic activation by recording the renal sympathetic nerve activity and observed that BRS normal and low rats had similar sympathetic nerve activity at baseline (% maximum, Figure 4B). The change of sympathetic nerve activity was not different between 2 groups (Figure 4C), which indicated that the sympathetic component of baroreflex was not affected in ABR‐DRs. We also recorded the change of heart rate, reflecting the parasympathetic function, observed that this phenomenon was significantly impaired in ABR‐DRs (Figure 4D).
4. DISCUSSION
According to our data, metabolic syndrome (including hypertension and other metabolic disorders) emerged in BRS low animals. For hypertension, it has been known for many years that BRS is lower in hypertensive patients.30 However, whether impaired BRS could also be a cause of hypertension remained unsolved. For a long time, impaired baroreflex was supposed to be unsubstantial for the development of essential hypertension.31, 32 It was supposed that the function of baroreflex was the short‐time regulation of blood pressure. Recently, a successful application of chronic electrical stimulation of the carotid baroreceptor on resistant hypertensive patients (Rheos Pivotal Trial) supported the role of baroreflex in the long‐term control of blood pressure.33 Baroreflex activity therapy substantially reduced blood pressure and maintained over long‐term for most patients. The function of baroreflex on the regulation of blood pressure should be re‐evaluated.
In our opinion, impaired BRS might be one cause of hypertension based on the interpretation of our following data. First, during the selective breeding, although all hypertensive rats of different generations were discarded, the BRS low animals had higher blood pressure than ABR‐NRs. Second, the incidence of hypertension is significantly higher in BRS lower animals. At generation 19, more than half animals of ABR‐DRs are hypertensive, while no animals in ABR‐NRs are hypertensive. Third, although the sympathetic activity is normal, the impaired BRS might be inadequate to balance or depress the normal sympathetic activity.34 All these data indicate that BRS may play an important role in the development of hypertension.
Besides hypertension, other metabolic disorders also emerged in ABR‐DRs. Hypertension and these metabolic disorders may be defined as metabolic syndrome. The metabolic syndrome is a cluster of overweight, hyperglycemia, hyperlipemia, etc.24, 25 These manifestations are consistent with the dysfunction of vagus nerve function.35, 36, 37 The vagal afferents, central nervous system (including nucleus ambiguus), vagal efferents, and peripheral organs are essential pathway in the regulation of food intake and energy metabolism. The abnormality of the vagal related pathway is also involved in the obesity and diabetes, and has become a target for weight loss therapy.38 So their dysfunction might be an important factor to elicit such risk in ABR‐DRs.
5. CONCLUSION
In summary, our study demonstrates that selection for low versus normal intrinsic BRS simultaneously generate a differential load of metabolic syndrome. Restoration of impaired BRS may be a potent target of therapeutic intervention in hypertension and metabolic disorder.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Zhang L‐L, Zhang Y, Cheng Y‐Q, et al. Metabolic syndrome emerges after artificial selection for low baroreflex sensitivity. CNS Neurosci Ther. 2018;24:828–836. 10.1111/cns.12999
Funding information
This work was supported by the National Natural Science Foundation of China (81273505, 81230083, 81473207), and Shanghai Pujiang Program (17PJD046).
The first two authors contributed equally to this work.
Contributor Information
Ding‐Feng Su, Email: dfsu@smmu.edu.cn.
Ai‐Jun Liu, Email: mrliuaijun@163.com.
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