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BMC Research Notes

Open Access

Angiotensin II status and sympathetic activation among hypertensive patients in Uganda: a cross-sectional study

  • Jonathan Mayito1Email author,
  • Michael Mungoma2,
  • Barbara Kakande3,
  • Dove Clement Okello1,
  • Humphrey Wanzira4,
  • James Kayima1 and
  • Charles Kiiza Mondo2, 5
BMC Research Notes20158:586

https://doi.org/10.1186/s13104-015-1544-7

Received: 17 February 2015

Accepted: 5 October 2015

Published: 20 October 2015

Abstract

Background

Sympathetic activation and renin-angiotensin system are essential for development and sustenance of hypertension. However, the status of these systems has not been well evaluated among patients in an African setting. This study therefore set out to assess the angiotensin II status and sympathetic activation among hypertensive patients in Uganda.

Methods

In this cross sectional study conducted at Mulago, the national referral hospital, blood samples were taken to measure angiotensin II, metanephrines and normetanephrines. Urine samples were also taken for measuring urine creatinine and sodium. The angiotensin II categories were defined using the Mosby’s Diagnostic and Laboratory Test References. 9th ed while the metanephrines and normetanephrine categories were defined using the Makerere University Biosafety II Immunology Laboratory reference values.

Results

162 patients were consented and enrolled into the study, of these 136 (84 %) had low, 15 (9 %) had normal, while, 11 (7 %) had high angiotensin II levels. 142 (88 %) participants had normal levels of metanephrine, while 20 (12 %) had high levels. Only 88 were assessed for metanephrines and of these 85 (97 %) had normal, while 3 (3 %) had raised levels. Urine sodium was associated with low and normal angiotensin II levels (P value 0.007). Female gender and diastolic blood pressure were associated with a protective effect against high normetanephrines (OR 0.29, P value 0.015), 80–89 mmHg (OR 0.19, p value 0.053), above 100 mmHg (OR 0.27, p value 0.022). Current smoking status was associated with high risk for abnormal normetanephrines (OR 17.6, P value −0.022) while former smoking was associated with high risk for abnormal metanephrines (OR 18.7, p value 0.022). After multivariate analysis, all the significant variables at bivariate analysis were still significant except those who stopped smoking and those with a BP at 80–89 which were not significant.

Conclusions

Hypertensive patients in this setting have predominantly low angiotensin II hypertension as a result of high salt intake. Sympathetic activation is not a significant mechanism of hypertension in this study population, more so in the females, with the exception of smokers who have a highly activated sympathetic system. Therefore, the use of agents targeting renin angiotensin and sympathetic systems as single first line antihypertensive agents in this setting should be re-evaluated if such patients are to be treated effectively.

Keywords

Angiotensin II statusSympathetic nervous activityHypertension

Background

Hypertension is one of the most prevalent and major contributors to atherosclerotic cerebral and cardiovascular disease, increasing the risk by two to threefold [1]. Treatment of hypertension is associated with decline in the risk of stroke (30–40 %), coronary artery disease (20 %) and other major cardiovascular diseases (21–28 %) [2].

Hypertension is a result of the interaction between genetic and environmental factors. This interaction influences intermediary phenotypes such as sympathetic nervous activity, renin angiotensin aldosterone, renin-kallikrein—kinin systems, and endothelial factors [3]. These phenotypes in turn influence other intermediary phenotypes such as sodium excretion, vascular reactivity, and cardiac contractility, which, determine total vascular resistance and cardiac output, and therefore blood pressure [3].

More than 70 % of hypertensive patients have renin related mechanisms as the aetiology of their hypertension. About 20 % of these have inappropriately normal or high renin values, and 30 % have low renin values, with the remaining half distributed between these two extremes [4]. Angiotensin II on the other hand has been shown to cause hypertension and vasculopathy through the activation of the mitogen-activated protein (MAP) kinase activity which mediates vascular smooth muscle proliferation [5] The effects of angiotensin II are compartmentalised mainly in the medulla and tubule of the kidney, where it regulates medulla and tubular function through its type 1 receptor [6]. The Na+/H+ exchanger 3 in the proximal tubule is also key in maintaining basal blood pressure and the development of angiotensin II hypertension [7], a phenomena that should be of interest in blacks that predominantly have salt sensitive and low renin hypertension compared to the white population [8].

Sympathetic neural mechanisms are also important in the development and progression of hypertension. The magnitude of sympathetic activation is proportional to the degree of elevation in blood pressure and development of hypertension-related target organ damage [9]. It has been suggested that repeated stress-induced sympathetic activation contributes to the pathophysiology of hypertension in blacks unlike in white populations [10, 11]. Increased serum and urinary metanephrines and normetanephrines are a measure of sympathetic activation and are used in the diagnosis of pheochromocytoma [12, 13].

Much has been studied about the renin angiotensin and sympathetic nervous systems’ role in the pathophysiology of hypertension. Despite this, data on this subject in an African setting is limited. The closest data often cited for black populations is from the African Americans who may be genetically and environmentally distinct from blacks in an African setting. There is a need to fill this knowledge gap with data from an appropriate population. We therefore set out to assess the angiotensin II status and sympathetic activation of hypertensive patients in Uganda attending the national referral hospital. Such information is extremely useful, especially in our low resource settings, where appropriate treatment of chronic conditions, basing on scientific evidence, is prudent. We also sought to seek for any factors associated with the prevailing status of these parameters.

Methods

This was a cross sectional study conducted at Mulago, the only National referral hospital in Uganda.

All study participants were recruited from the Mulago Hospital hypertension clinic. We recruited both newly diagnosed adult hypertensive patients (with no history of antihypertensive medication) and previously treated hypertensive patients but who had defaulted their medication for at least 1 week. Exclusion criteria included; pregnant women, patients currently or within 1 week of using oral contraceptive therapy or adrenaline, patients with deranged renal function tests and urinalysis, patients with diabetes mellitus and confirmed pheochromocytoma.

A formula by Eng [14] was used to estimate the sample size. A total of 162 respondents were computed basing on 95 % confidence interval, a precision of 5 and 10 % of the sample size used to compensate for non-respondents.

The study participants were consecutively recruited from the waiting area in the hypertension clinic and screened using the study eligibility criteria. Those eligible were informed about the study and requested to give a written informed consent to participate in the study.

Study participants responded to a pre-coded, pre-tested and standardized questionnaire which covered demographic details, duration of hypertension, duration off antihypertensives, type of antihypertensives that were being taken before defaulting, alcohol consumption, salt intake and smoking. They then underwent measurement of height, weight and blood pressure, and then gave an arterial blood and urine sample as elaborated below.

The body mass index (BMI) was calculated using the formula; weight (kg)/height (m2) and then categorized into underweight (<18.5), Normal weight (18.5–24.9), overweight (25–29.9) and obese (>30) using the world health organisation criteria of categorization of BMI, 2004 [15].

The blood pressure was measured on the left arm after the subject had sat for at least 10 min, using an Omron M7 (HEM-780-E) oscillometric blood pressure monitoring sphygmomanometer with the subject in the sitting position, legs uncrossed, the arm resting on a table and the ante-cubital fossa at the level of the lower sternum. The Omron M7 (HEM-780-E) is validated according to the British hypertension Society protocol and is recommended for professional and home use [16].

An appropriate cuff (with bladder length >80 % of the arm circumference) was used. Two readings were taken 3 min apart and the average was used to describe the blood pressure of the patient. If the readings differed by 10 mmHg, a third reading was taken and the blood pressure was then taken to be the average of the closest two. Blood pressure was then categorized using the JNC 7 [17].

The participant was laid on the examination couch in supine position for at least 15 min before the blood sample was drawn. Using a 10 ml syringe and observing aseptic conditions, 6 ml of blood was drawn from the femoral artery. Pressure was applied to the puncture site for 7 min to stop any bleeding. Four ml was introduced into an iced pre-labelled EDTA vacutainer, mixed gently by tilting the vacutainer top to bottom and vice versa eight times to mix the blood with the anticoagulant.

The sample was kept under ice in an ice box carrier immediately. It was then transported within 1 h to the laboratory where it was centrifuged at 4500 rotations per minute at 4 °C for 5 min to separate the plasma. The plasma was stored at −80 °C till analysis. The remaining ml were used for determination of plasma creatinine and sodium at the Mulago Hospital clinical chemistry laboratory.

All the samples were analysed within 5 months from the time of collection at the Makerere University Biosafety II Immunology Laboratory, using the AssayMax Human Angiotensin II Elisa Kit from ASSAYPRO, Germany and 2-MET Plasma Elisa fast track from Labor Diagnostic Nord, Germany.

The Mosby’s Diagnostic and Laboratory Test References. 9th ed angiotensin II reference ranges (0.01–0.06 ng/ml) and the Makerere University Biosafety II Immunology Laboratory reference values for metanephrine (<90 pg/ml) and normetanephrine (<180 pg/ml) were used to categorise these measurements into low, normal, and high [18, 19].

Patients were instructed to collect a mid-stream urine sample after washing with soap the head of the penis and the retracted foreskin (for men) or the separated skin folds covering the urinary opening (for females). The urine sample was transported within 1 h to the laboratory for determination of urine sodium and creatinine.

Data analysis

Data analysis was done with the assistance of a statistician. Data were double entered using EPI-INFO 6.0 and then exported to STATA version 12.0 (StataIC Corporation, College Station, TX, USA) for analysis.

The independent variables which included: social demographics, alcohol intake, smoking history, salt intake, treatment history of hypertension, physical measurements, and fraction excretion of sodium were organised into categories. The outcomes of interest in this study were percentages and their confidence intervals of the participants with low, moderate and high angiotensin II, metanephrine and normetanephrines levels.

Logistics regression model was used to assess for factors associated with the three parameters outcomes by estimating the odds ratio and accompanying 95 % confidence interval. Only variables that were significant in the bivariate analysis (gender, smoking and diastolic BP) were considered for multivariate analysis, and a forward fitting regression model was used to assess for effect modification and confounders. In all analyses, a P value of ≤0.05 was considered to be statistically significant.

Supporting data

The full dataset for this study is available on Zenodo data repository. DOI 10.5281/Zenodo.31479.

Ethical approval

Written informed consent was obtained from all study participants. The study protocol was approved by the Makerere University School of Medicine Research and Ethics Committee, and Uganda National Council of Science and Technology.

Results

162 Patients were recruited for the study as shown in Fig. 1. Majority of the participants were female, 131 (81 %), and Baganda were the most represented ethnic group, 116 (71.6 %).
Fig. 1

Flow chart for participants’ selection

There were more senior citizens, 122 (75 %), above 45 years and 61 (38 %) above 60 years with hypertension compared to the younger participants 40 (25 %) below 45 years and 6 (4 %) participants below 30 years (Table 1).
Table 1

Baseline characteristics

Characteristic

Study participants

Number, total = 162

%

Age in years

 ≤45

40

25

 >45

122

75

Age distribution

 18–40

25

15

 41–60

76

47

 >60

61

38

Gender

 Male

31

19

 Female

131

81

Tribe

 Buganda

116

72

 Basoga

7

4

 Banyankole

13

8

 Banyoro

5

3

 Others

21

23

Occupation

 Peasant/farmer

69

43

 Manual labourer

50

31

 Office worker

7

4

 Unemployed

36

22

Level of education

 No formal

22

14

 Primary

96

59

 Secondary

37

23

 Tertiary

7

4

Marital status

 Single

11

7

 Married

80

49

 Divorced/separated

71

44

Sixty-seven (42 %) of the participant added raw salt to their food. Among the 162 participants, majority 64 (40 %) of them added one table spoon to their food as they prepared it, closely followed by 54 (33 %) who added half a table spoon.

Majority of the participants, 136 (84 %) had normal pulse rates and majority had a systolic blood pressure of more than 160 mmHg and a diastolic blood pressure of more than 100 mmHg, 108 (67 %) and 89 (55 %) respectively. Twenty-nine (18 %) participants had grade one obesity while 9 (6 %) were morbidly obese. See Table 2.
Table 2

Physical measurements

Characteristic

Study participant

Number, total = 162

%

Pulse rate

 <60

8

5

 61–100

136

84

 >100

18

11

Systolic blood pressure

 <120

3

2

 120–139

12

7

 140–159

39

24

 >160

108

67

Diastolic blood pressure

 <80

22

14

 80–89

25

15

 90–99

26

16

 ≥100

89

55

BMI

 <18.5

9

6

 18.5–24.9

63

39

 25–29.9

51

32

 30–34.9

29

18

 >35

9

6

Sixteen (10 %) participants were recently diagnosed with hypertension compared to 146 (90 %) who had a known diagnosis of hypertension but had defaulted taking their medications. Among the 146 previously treated defaulting participants, 34 (23 %) of them had been on single drug therapy while 112 (77 %) had been on combination therapy. The most commonly used class of single drug therapy was calcium channel blockers, 13 (38 %) while the most commonly used combination therapy was a diuretic with a calcium channel blocker and either an ACEI or ARB 27 (24 %). See Table 3.
Table 3

Treatment history

Characteristic

Study participant

Number, total = 146

%

Time off antihypertensives

 1 week

50

34

 1 to <2 weeks

42

29

 2 to ≤4 weeks

17

12

 1 month

13

9

 >1 month

22

15

 No record

2

1

Single drug antihypertensives

 Duiretic

2

6

 Calcium channel blocker

13

38

 Beta blocker

8

24

 ACEI/ARBs

9

26

 Others

1

3

 No record

1

3

Combination drug antihypertensive

 Duiretic and Calcium Ch.

13

12

 Duiretic and ACEI/ARB

5

4

 Calcium Ch and beta blocker

10

9

 Calcium Ch. and ACEI/ARB

19

17

 Beta block + ACEI/ARBs

6

5

 Duiretic + calcium ch + ACEI/ARB

27

24

 Others

27

24

The smoking rates in this study were very low, with 3 (1.9 %) and 12 (7 %) being current and former smokers respectively. The participants currently taking alcohol were 35 (22 %). Among the 35 participants, 18 (51 %) were taking beer, followed by local gin (waragi) at 12 (34 %). Among the 31 who took quantifiable amounts of alcohol, the majority took 1–6 bottles of beer per week while only one participant took a glass of wine daily.

Renin angiotensin status

Eighty-four percent (136) of the participants had low angiotensin II levels. This represented a proportion of 78–90 % of the reference population as shown by the 95 % confidence interval. Among the participants with low angiotensin II levels, 130 (97 %) had normal, 4 (3 %) had low while none had high urine excretion of sodium. In contrast however, majority with low angiotensin II levels, 120 (90 %), had a fractional excretion of sodium of less than 1 %. Urine sodium was the only factor significantly associated with low and normal angiotensin II levels, P value = 0.007 as illustrated in Table 4.
Table 4

Bivariate for angiotensin II levels and associated factors

Risk factor

Angiotensin II categories

<0.01 (low)

0.01–0.06 (normal)

>0.06 (high)

P value

Number (%)

Number (%)

Number (%)

Age in years

 ≤45

32 (23.53)

6 (40.00)

2 (18.18)

0.326

 >45

104 (76.47)

9 (60.00)

9 (81.82)

Gender

 Male

25 (18.38)

5 (33.33)

1 (9.09)

0.257

 Female

111 (81.62)

10 (66.67)

10 (90.91)

Smoking

 No

2 (1.47)

0

1 (9.09)

0.111

 Stopped

126 (92.65)

12 (80.00)

9 (81.82)

 Yes

8 (5.88)

3 (20.00)

1 (9.09)

Alcohol

 Yes

30 (22.22)

2 (13.33)

3 (27.27)

0.657

 No

105 (77.78)

13 (86.67)

13 (86.67)

Systolic BP

 <120

3 (2.21)

0

0

0.930

 120–139

10 (7.35)

1 (6.67)

1 (9.09)

 140–159

34 (25.00)

2 (13.33)

3 (27.27)

 >160

89 (65.44)

12 (80.00)

7 (63.64)

Diastolic BP

 <80

22 (16.18)

0

0

0.221

 80–89

19 (13.97)

4 (26.67)

2 (18.18)

 90–99

24 (17.65)

1 (6.67)

1 (9.09)

 ≥100

71 (52.21)

10 (66.67)

8 (72.73)

Pulse rate

 <60

8 (5.88)

0

0

0.373

 61–100

112 (82.35)

15 (100)

9 (81.82)

 >100

16 (11.76)

0

2 (18.18)

Salt intake

 Yes

56 (41.18)

7 (46.67)

4 (36.36)

0.865

 No

80 (58.82)

8 (53.33)

7 (63.64)

Urine sodium (mmol/l)

 <20

4(2.99)

3 (20.00)

0

0.007

 20–350

130 (97.01)

12 (80.00)

11 (100)

FENa

 <1

120 (89.55)

14 (93.33)

7 (70.00)

0.059

 1–2

9 (6.72)

0

3 (30.00)

 >2

5 (3.73)

1 (6.67)

0

Time since diagnosis

 <1 month

11 (8.09)

3 (20.00)

2 (18.18)

0.697

 1 to <6 months

8 (5.88)

1 (6.67)

0

 6 to <12 months

9 (6.62)

1 (6.67)

1 (9.09)

 >1 year

108 (79.41)

10 (66.67)

8 (72.73)

Time off antihypertensives

 1 week

45 (36.59)

2 (15.38)

3 (37.50)

0.360

 1 to <2 weeks

34 (27.64)

7 (53.35)

1 (12.50)

 2 to ≤4 weeks

14 (11.38)

1 (7.69)

2 (25.00)

 1 month

11 (8.94)

2 (15.38)

0

 >1 month

19 (15.45)

1 (7.69)

2 (25.00)

FENa fraction excretion of urine sodium

The p values in italics indicate factors associated with angiotensin II at α = 0.05

Sympathetic nervous activity

Majority of the participants, 142 (88 %) had normal normetanephrine levels representing a range of 83–93 % in the reference population as shown by the 95 % confidence intervals. A similar proportion, 85 of the 88 (97 %) participants with metanephrine results had normal metanephrine levels representing 92–100 % of the reference population as shown by the 95 % confidence intervals.

Among the participants with normal metanephrines, 60 (71 %) had a systolic blood pressure of more than 160 mmHg compared to 94 (66 %) with normal normetanephrines. The percentage of participants with normal metanephrines and normetanephrines who had a diastolic blood pressure of more than 100 mmHg was similar, 55 and 56 % respectively.

Distribution by the other variable is shown in Table 5.
Table 5

Distribution of metanephrines and normetanephrines by different variables

Characteristic

Metanephrines

Normetanephrines

Normal, N = 85 (%)

High, N = 3 (%)

Normal, N = 142 (%)

High, 20 (12 %)

Gender

 Male

21 (25)

2 (67)

23 (16)

8 (40)

 Females

64 (75)

1 (33)

119 (84)

12 (60)

Age

 <45

24 (28)

2 (67)

36 (25)

4 (25)

 ≥45

61 (72)

1 (33)

106 (75)

16 (75)

Systolic BP

 <140

5 (6)

0

14 (10)

1 (5)

 140–160

20 (24)

1 (33)

34 (24)

5 (25)

 >160

60 (71)

2 (67)

94 (66)

14 (70)

Diastolic BP

 <90

23 (27)

1 (33)

38 (27)

9 (45)

 90–100

7 (8)

0

25 (18)

1 (5)

 >100

55 (65)

2 (67)

79 (56)

10 (50)

Pulse

 <60

6 (7)

 

7 (5)

1 (5)

 60–100

67 (79)

 

119 (84)

17 (85)

 >100

12 (14)

 

16 (11)

2 (10)

Being female was associated with a significant protective effect from high normetanephrine OR 0.29 (0.11–0.79), P = 0.015 and so was diastolic blood pressure of 80–89 mmHg OR 0.19 (0.03–1.02), p = 0.053, 90–99 mmHg OR 0.86 (0.01–0.77), P = 0.028 and >100 mmHg OR 0.27 (0.83–0.89, p = 0.022, as shown in Table 6.
Table 6

Bivariate analysis for factors associated with metanephrines and normetanephrines

Risk factor

Metanephrines

Normetanephrines

Odds (95 % CI)

OR (95 % CI)

p value

Odds (95 % CI)

OR (95 % CI)

p value

Age in years

 ≤45

0.08 (0.02–0.35)

  

0.11 (0.04–0.31)

  

 >45

0.02 (0.00–0.12)

0.20 (0.02–2.37)

0.154

0.15 (0.08–0.26)

1.4 (0.43–4.33)

0.604

Gender

 Male

0.10 (0.02–0.41)

  

0.35 (0.16–0.78)

  

 Female

0.02 (0.00–0.11)

0.16 (0.01–2.00)

0.106

0.10 (0.06–0.18)

0.29 (0.11–0.79)

0.015

Smoking

 No

0.01 (0.00–0.10)

Reference

 

0.11 (0.07–0.19)

Reference

 

 Stopped

0.25 (0.05–1.18)

18.75 (1.53–230.42)

0.022

0.33 (0.09–1.23)

2.93 (0.72–12.03)

0.135

 Yes

0

2.00 (0.18–22.06)

17.6 (1.50–205.82)

0.022

Alcohol

 Yes

0.11 (0.03–0.48)

  

0.21 (0.09–0.50)

  

 No

0.02 (0.00–0.11)

0.14 (0.01–1.69)

0.069

0.13 (0.07–0.22)

0.60 (0.21–1.71)

0.342

Systolic BP

 <120

0

  

0.50 (0.05–5.51)

Reference

 

 120–139

0

  

0

 140–159

0.05 (0.01–0.37)

Reference

 

0.15 (0.06–0.38)

0.29 (0.02–3.87)

0.352

 >160

0.03 (0.01–0.14)

0.67 (0.06–7.88)

0.746

0.15 (0.08–0.26)

0.30 (0.03–3.50)

0.336

Diastolic BP

 <80

0.10 (0.01–0.78)

Reference

 

0.47 (0.19–1.14)

Reference

 

 80–89

0.087 (0.02–0.37)

0.19 (0.03–1.02)

0.053

 90–99

0.04 (0.01–0.30)

0.86 (0.01–0.77)

0.028

 ≥100

0.04 (0.01–0.15)

0.36 (0.03–4.40)

0.426

0.12 (0.07–0.24)

0.27 (0.89–0.83)

0.022

Pulse rate

 <60

0

0.14 (0.02–1.16)

Reference

 

 61–100

0.04 (0.01–0.14)

0.14 (0.09–0.24)

1 (0.12–8.64)

1.00

 >100

0

0.13 (0.03–0.54)

0.88 (0.07–11.31)

0.919

Salt intake

 Yes

0.07 (0.02–0.29)

  

0.16 (0.08–0.31)

  

 No

0.02 (0.00–0.13)

0.26 (0.02–3.08)

0.249

0.07 (0.07–0.25)

0.84 (0.33–2.17)

0.724

FENa

 <1

0.04 (0.01–0.13)

  

0.13 (0.08–0.22)

Reference

 

 1–2

0

0.20 (0.04–0.91)

1.56 (0.31–7.77)

0.586

 >2

0

0.20 (0.02–1.71)

1.56 (0.17–14.23)

0.692

Time since diagnosis

 <1 month

0

Reference

 

0.07 (0.01–0.50)

Reference

 

 1 to <6 months

0.17 (0.02–1.38)

0.86 (0.04–18.73)

0.922

0.50 (0.13–2.00)

7.50 (0.65–87.19)

0.107

 6 to <12 months

0.14 (0.01–1.16)

0.10 (0.00–1.97)

0.060

0.22 (0.05–1.03)

3.33 (0.26–42.21)

0.353

 >1 year

0.02 (0.00–0.12)

  

0.13 (0.07–0.22)

1.88 (0.23–15.30)

0.557

FENa fractional excretion of sodium. Logistic regression model was used to determine the differences between the metanephrine and normetanephrine categories

The p values in italics indicate factors associated with metanephrines and normetanephrines at α = 0.05

Current smoking status was associated with a significantly increased risk of abnormal normetanephrine levels OR 17.6 (1.50–205.820), P value −0.022, while former smoking status was associated with increased risk of elevated metanephrines OR 18.75 (1.53–230.42), P = 0.022, as shown in Table 6.

After multivariate analysis, all the significant variables at bivariate analysis were still significant except those who stopped smoking and those with a BP at 80–89 which were not significant (Table 7).
Table 7

Multivariate analysis for associated factors normetanephrines

Normetanephrine

Adjusted OR (95 % CI)a

p value

Gender

 Male

  

 Female

0.25 (0.08–0.77)

0.016

Smoking

 No

Reference

 

 Stopped

2.16 (0.47–9.96)

0.323

 Yes

21.03 (1.52–290.63)

0.023

Diastolic BP

 <80

Reference

 

 80–89

0.18 (0.03–1.10)

0.063

 90–99

0.10 (0.01–0.98)

0.048

 ≥100

0.22 (0.06–0.73)

0.014

aAdjusted for gender, smoking and diastolic BP

Discussion

The major finding in this study was that majority of the participants had low angiotensin II levels, which, correlated with the finding that majority of participants had a fractional excretion of sodium of less than 1 %. This clinical state is similar to patients with pre-renal azotemia whereby they are highly conserving sodium and water leading to a high effective circulatory volume. It is possible that high salt intake in this population suppresses angiotensin II release as majority of the participants reported taking salt in their diet, especially raw salt and urine sodium was associated with low angiotensin II levels. It would have been important to correlate the angiotensin II levels with renin levels as previous studies have shown majority of blacks to have a low renin hypertension [8] as a result of negative feedback from angiotensin II in a form of apparent minero-corticoid excess [20]. A full evaluation of the renin aldosterone angiotensin axis would have enabled more concrete conclusions. The fact that blacks are more responsive to diuretics and that addition of a diuretic improves efficacy of other antihypertensives in black populations unlike in white populations [21], further shows that salt plays a major role in the mechanism of hypertension in blacks. Other syndromes associated with conservation of sodium and water include; increased endothelin-1 activity [22] or a mutation in the epithelial sodium receptor (ENaC) [23] and these would require further evaluation in this study.

Findings from this study suggest that sympathetic nervous activation may not be a dominant mechanism in the pathophysiology of hypertension in this study population. This is in contrast to previous studies that have shown increased sympathetic nervous out flow in patients with accelerated or malignant hypertension, where, the sympathetic out flow is due to the increased endogenous renin-angiotensin axis which stimulates it at the sympathetic ganglia [24] and centrally [25]. These findings are also at variance with the suggestions that repeated stress-induced sympathetic activation initiates a cycle of increased vascular resistance and vascular hypertrophy leading to hypertension in black populations [10, 11]. We however, acknowledge that the smaller number of samples analysed for metanephrines could have under powered this study for making conclusions about the sympathetic activity. These results support the fact that beta blockers are not effective first line antihypertensive therapy, especially in black population and should therefore be reserved for compelling situations or improved by addition of a diuretic [26]. Furthermore, female gender was associated with a protective effect against high normetanephrines. This finding concurs with earlier findings which showed that autonomic blood pressure support is blunted in females more so in young women [27]. This attenuation of the sympathetic nervous system in females may be due to dampened sympatho-adrenal stimulation or augmented sympatho-adrenal inhibition [28].

More to the above, current smoking status was associated with increased stimulation of the sympathetic nervous activation meaning that smoking may be a contributing mechanism to developing hypertension in smokers. This finding is similar to results of other studies which showed that smoking has a direct peripheral and a centrally mediated effect on both blood pressure and pulse through stimulation of the sympathetic nervous system [29]. However, we acknowledge that the number of smokers was very low and this could have led to an over effect in assessing the associations.

It was also seen in this study that increase in diastolic blood pressure showed dampening or protection against increased sympathetic nervous activity. The diastolic blood pressure is related to relaxation of the cardiac muscle which occurs with reduced sympathetic outflow and sustained by residual pressure retained by the elasticity of the arterial system [30]. The sympathetic nervous system may therefore not play a significant role in diastolic hypertension in this study population.

Conclusions

Hypertensive patients in this setting have predominantly low angiotensin II hypertension as a result of high salt intake. Sympathetic nervous activation is not a significant mechanism of hypertension in patients in this setting, more so in the females, but may be exaggerated in current smokers. Use of agents targeting renin angiotensin and sympathetic systems as single first line antihypertensive agents in this setting needs to be re-evaluated for better management of patients in this setting.

Declarations

Authors’ contributions

JM, CKM, MM, BK and JK contributed to the design of the study. JM, PB and DCO participated in recruitment of patients and data collection. JM and WH analyzed the data. JM, CKM, BK, and MM interpreted the data. JM drafted the first version. All authors read and approved the final manuscript.

Acknowledgements

The authors thank the study patients and the laboratory team.

Funding

Research reported in this publication was supported by the Fogarty International Center, the National Heart Lung and Blood Institute, and the Common Fund of the National Institutes of Health under Award Number R24 TW008861. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Medicine, College of Health Sciences, Makerere University
(2)
Department of Medicine, Mulago Hospital
(3)
Uganda Heart Institute
(4)
Infectious Diseases Research Collaboration
(5)
Non Communicable Disease Alliance

References

  1. MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335(8692):765–74.View ArticlePubMedGoogle Scholar
  2. Neal B, MacMahon S. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2000;356(924):1955–64.PubMedGoogle Scholar
  3. Oscar AC. Essential hypertension part i: definition and etiology. Circulation. 2000;101:329–35.View ArticleGoogle Scholar
  4. Vikrant S, Tiwari SC. Essential hypertension—pathogenesis and pathophysiology. J Indian Acad Clin Med. 2001;2(3):141–61.Google Scholar
  5. Muthalif MM, et al. Angiotensin II-induced hypertension contribution of Ras GTPase/mitogen-activated protein kinase and cytochrome P450 metabolites. Hypertension. 2000;36:604–9.View ArticlePubMedGoogle Scholar
  6. Navar LG, et al. Regulation of intrarenal angiotensin II in hypertension. Hypertension. 2002;39:316–22.PubMed CentralView ArticlePubMedGoogle Scholar
  7. Li XC, et al. Role of the Na +/H + exchanger 3 in angiotensin II-induced hypertension. Physiol Genom. 2015;47(10):479–87.View ArticleGoogle Scholar
  8. John MF, Steven AA, James LP. Renin-angiotensin aldosterone system and hypertension: current approaches and future directions. Suppl J Manag Care Pharm. 2007;13(8):S9–20.Google Scholar
  9. Guido G, Seravalle G, Fosca QT. The ‘neuroadrenergic hypothesis’ in hypertension: current evidence. Exp Physiol. 2010;1(95):581–6.Google Scholar
  10. Treiber FA, et al. One year stability and prediction of cardiovascular functioning at rest and during laboratory stressors in youth with family histories of hypertension. Int J Behav Med. 1994;1:335–53.View ArticlePubMedGoogle Scholar
  11. Calhoun D, et al. Normotensive blacks have heightened sympathetic response to cold pressor test. Hypertension. 1993;22:801–5.View ArticlePubMedGoogle Scholar
  12. Marini M, Fathi M, Vallotton M. Determination of serum metanephrines in the diagnosis of pheochromocytoma. Ann Endocrinol (Paris). 1994;54(5):337–42.Google Scholar
  13. Kanakamani J, et al. The role of urinary fractionated metanephrines in the diagnosis of phaeochromocytoma. Indian J Med Res. 2013;132(2):316–23.Google Scholar
  14. Eng J. Sample size estimation: how many individuals should be studied? Radiology. 2003;227:309–13.View ArticlePubMedGoogle Scholar
  15. http://apps.who.int/bmi/index.jsp?introPage=intro_3.html. Accessed 15 Oct 2015.
  16. Coleman A, et al. Validation of the Omron M7 (HEM-780-E) oscillometric blood pressure monitoring device according to the British Hypertension Society protocol. Blood Press Monit. 2008;13(1):49–54.View ArticlePubMedGoogle Scholar
  17. Chobanian Aram V, et al. The seventh report of the joint national Committee on prevention, detection, evaluation and treatment of high blood pressure American Heart Association. Hypertension. 2003;42:1206–52.View ArticlePubMedGoogle Scholar
  18. Pagana K, Pagana T. Mosby’s diagnostic and laboratory test reference. 9th ed. St. Louis: Mosby Inc; 2009. p. 649.Google Scholar
  19. Makerere University BioSafety II Immunology Laboratory reference ranges for metanephrines and normetanephrines (Unpublished data).Google Scholar
  20. Ferrari P, Lovati E, Frey FJ. The role of the 11 beta-hydroxysteroid dehydrogenase type 2 in human hypertension. J Hypertens. 2000;18(3):241–8.View ArticlePubMedGoogle Scholar
  21. Flack JM. Antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide in adult African Americans with mild to moderate hypertension. Clin Ther. 2001;23(8):1193–208.View ArticlePubMedGoogle Scholar
  22. Adviye E. Hypertension in black patients an emerging role of the endothelin system in salt-sensitive hypertension. Hypertension. 2000;36:62–7.View ArticleGoogle Scholar
  23. Shawna N, Ronald G. V, Pathogenesis of Hypertension in African Americans. CHF. 2004;10:24–9.Google Scholar
  24. Lewis RD, Reit E. The action of angiotensin II and bradykinin on the superior cervical ganglion of the cat. J Physiol. 1965;179:538–53.PubMed CentralView ArticlePubMedGoogle Scholar
  25. Bickerton RK, Buckley JP. Evidence for a central mechanism in angiotensin induced hypertension. Proc Soc Exp Biol Med. 1961;106:834–6.View ArticleGoogle Scholar
  26. M’Buyamba-Kabangu JR, Tambwe M. The efficacy of beta-adrenoceptor and calcium-entry blockers in hypertensive blacks. Cardiovasc Drugs Ther. 1990;4(2):389–94.View ArticlePubMedGoogle Scholar
  27. Kneale BJ, et al. Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J Am Coll Cardiol. 2000;36:1233–8.View ArticlePubMedGoogle Scholar
  28. Hinojosa-Laborde C, et al. Gender differences in sympathetic nervous system regulation. Clin Exp Pharmacol Physiol. 1999;26(2):122–6.View ArticlePubMedGoogle Scholar
  29. Niermaier ON, et al. Influence of cigarette smoking on human autonomic functio. Circulation. 1993;88:562–71.View ArticleGoogle Scholar
  30. http://library.med.utah.edu/WebPath/TUTORIAL/HYPERTEN. Accessed 15 Oct 2015.

Copyright

© Mayito et al. 2015

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