Single- or Double-Blind Treatment With Balsamodendron tnukul and Nifedipine in Hypertensive Patients

Authors

  • Jayabal Panneerselvam MSc,

    1. From the Department of Biochemistry, Annamalai University, Annamalainagar, India;1 and the Professor Maniarasan Memorial Polyclinic, Chidambaram, India2
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  • 1 Ganapathy Sambandam MBBS, FCCP,

    1. From the Department of Biochemistry, Annamalai University, Annamalainagar, India;1 and the Professor Maniarasan Memorial Polyclinic, Chidambaram, India2
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  • and 2 Namasivayam Nalini PhD 1

    1. From the Department of Biochemistry, Annamalai University, Annamalainagar, India;1 and the Professor Maniarasan Memorial Polyclinic, Chidambaram, India2
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Namasivayam Nalini, PhD, Reader, Department of Biochemistry, Annamalai University, Annamalainagar, Tamilnadu, India 60S 002
E-mail: nalininam@yahoo.com

Abstract

Editor's note: This preliminary report on the results of treatment with a plant extract alone and in combination with a calcium channel blocker suggests that we should be alert to the potential benefit of some naturally occurring substances. These should be carefully evaluated for the treatment of hypertension and dyslipidemia. Foxglove and rauwolfia are just two examples of how careful observations led to useful therapeutic aspects.

This study assessed and compared the effects of Balsamodendron mukul (an extract of the gum of a small tree) and nifedipine (a calcium-channel-blocking reference drug) on blood pressure, lipids, lipoproteins, and phospholipids in randomly selected patients with essential hypertension. Fifty-seven newly diagnosed hypertensive patients were randomly divided into three groups. They received either single-blind B. mukul (1.5 g/d) or single-blind nifedipine (10 mg/d) double-blind therapy with nifedipine (10 mg/d) and B. mukul (1.5 g/d) for 6 weeks. These groups were compared with control subjects. On treatment with B. mukul, levels of systolic blood pressure, diastolic blood pressure, plasma total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, triglycerides, free fatty acids, and phospho-lipid levels were significantly reduced, and high-density lipoprotein cholesterol levels were significantly elevated, as compared with untreated hypertensive patients. Combined therapy with B. mukul and nifedipine was more beneficial than the treatment with B. mukul alone. Our study suggests that B. mukul may be an effective antihypertensive and hypolipidemic agent.

Hypertension is a major public health problem among men and women worldwide; it is also one of the important risk factors for cardiovascular (CV) mortality and morbidity.1 Hypertension may result in serious complications such as stroke, myocardial infarction, heart failure, chronic kidney disease, progressive atherosclerosis, and dementia.1–3 Over the past few decades, numerous epidemiologic studies and clinical trials have shown that controlling blood pressure (BP) can reduce the incidence of CV diseases by more than 50%.4 Hypertension is characterized by multiple alterations in the structure and function of the cell membrane, often associated with important metabolic abnormalities, including those concerning lipid metabolism.5 Epidemiologic studies have clearly demonstrated that hypertension,6–8 dyslipidemia,6–8 smoking,6,7 and hyperinsulinemia are well recognized risk factors for CV disease.9 Several classes of antihypertensive drugs are available. One of these, the calcium channel blocking agents, is effective in controlling both systolic blood pressure (SBP) and diastolic blood pressure (DBP).10 Nifedipine, a calcium antagonist, is a safe, established drug with high antihypertensive efficacy.11

Certain recent research has focused on natural antihypertensive agents to control blood pressure (BP). Balsamodendron mukul is a small, thorny tree of the Burseraceae family, four to six feet tall, and has been used in traditional Hindu Ayurvedic medicine for nearly 3000 years.12 It has been used predominantly as a hypolipidemic agent.13B. mukul is known to possess anti-inflammatory, antibacterial and antiatherosclerotic properties.14B. mukul is also known to activate lipolytic enzymes, inhibit hepatic cholesterol biosynthesis, and reduce total serum lipid levels.15 The aim of the present study was to assess and compare the effects of B. mukul and nifedipine (a reference drug) on BP, lipids, lipoproteins and phospholipids in randomly selected patients with essential hypertension. We studied the effect of B. mukul and/or nifedipine on total cholesterol (TC), triglycerides, high-density lipoproteins (HDL), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), free fatty acids (FFA), and phospholipids in hypertensive subjects.

MATERIALS AND METHODS

Gum of B. mukul was thoroughly cleaned and boiled after adding water (1 kg/L). The contents were filtered and the filtrate was again boiled and filtered. The filtrate thus obtained was dried and the resulting powder was put into capsules (750 mg per capsule).16 Two capsules per day (one in the morning and one at night after food) were given every day.

Fifty-seven newly diagnosed hypertensive patients of both sexes aged 35-70 years with essential hypertension from the outpatient unit of Professor Maniarasan Memorial Polyclinic volunteered for this study. The diagnosis of hypertension was based on the World Health Organization criteria for mild to moderate hypertension. The definition of hypertension was an SBP ≥140 mm Hg and DBP ≥90 mm Hg on at least three different occasions. The BP of the subjects was measured and recorded at 15-day intervals from the beginning until the end of the study. Sixteen age-matched healthy volunteers served as controls. Oral consent was obtained from both the hypertensive patients and normal subjects before the study. The study was carried out in a ccordance with the guidelines of the Human Ethical Committee of Raja Muthiah Medical College and Hospital, Annamalai University.

All hypertensive patients and normal subjects were nonsmokers. None had concomitant diseases such as diabetes mellitus, heart failure, stroke, or renal failure. Hypertensive patients were randomly divided into three groups. They received either single-blind nifedipine (10 mg/d), single-blind B. mukul (1.5 g/d), or double-blind therapy with nifedipine (10 mg/d) and B. mukul (1.5 g/d) for a total treatment period of 6 weeks. Table I shows the study design.

Table I.  Study Design: Balsamodendron mukul and Nifedipine in Hypertensive Patients
GroupnTreatment Condition
116Normotensive control subjects
219Hypertensive patients given B. mukul (1.5 g/d) for 42 days; single-blind
319Hypertensive patients given nifedipine (10 mg/d) for 42 days; single-blind
419Hypertensive patients given B. mukul (1.5 g/d) and nifedipine (10 mg/d) for 42 days; double-blind

At Day 1 and at Day 43 (end of 6 weeks) venous blood samples were collected after an overnight fast of 12 hours and analyzed for lipids.17 Plasma TC, HDL, and triglycerides were assayed by enzymatic methods (Span Diagnostic Ltd., Surat, India). LDL cholesterol was calculated by the Friedewald formula, FFA by the method of Falholt et al.,18 and phospholipids by the method of Stewart.19

The results obtained are expressed as means ± SD. Statistical evaluation was done using one way analysis of variance followed by Duncan's multiple range test. The statistical significance was set at p<0.05.

RESULTS

Table II shows the effect of B. mukul and/or nifedipine on SBP, DBP, and body mass index (BMI) in hypertensive patients. On treatment with B. mukul and/or nifedipine, SBP, DBP, and BMI were decreased compared with baseline. There was no significant alteration found in the body weight and BMI levels on treatment with B. mukul and/or nifedipine in hypertensive patients.

Table II.  Effect of Balsamodendron mukul and/or Nifedipine on Blood Pressure (BP) in Patients With Hypertension
 Systolic BP (mm Hg) Diastolic BP (mm Hg) Body Mass Index (kg/2)
GroupBaselineDay 15Day 30Day 45BaselineDay 15Day 30Day 45BaselineAfter
1127.25±3.21a127.01±3.28a126.86±2.57a125.30±4.37a82.67±3.11a81.69±3.47a80.86±1.24a80.18±2.69a23.18±1.64a23.40±1.37a
2145.84±9.38b142.51±7.21b136.74±4.38b*125.61±4.01a**96.02±3.52b94.58±5.67b93.87±2.57b87.11±2.32b*27.01±1.34b26.58±1.08b
3150.11±6.56b146.28±3.51c134.56±3.48b*129.23±8.04a**92.42±3.39b90.12±3.87b89.75±6.37c90.01±3.52b27.08±1.72b26.77±1.39b
4151.63±15.61a138.51±4.61c*130.21±6.42b**124.80±4.61a†98.75±6.92b93.48±5.64b*89.29±7.51c83.48±6.75a**27.84±1.48b25.84±1.06b
Values are means ± SD from each group. Values not sharing a common superscript (a, b, c) between groups differ significantly at p<0.05. *p<0.05, **p<0.01,p<0.001 compared with before treatment

Figure 1 shows the effect of B. mukul and/or nifedipine on plasma TC and lipoprotein levels in hypertensive patients. At baseline, plasma levels of TC, LDL, and VLDL were elevated while the HDL levels were lower in hypertensive patients compared with control subjects (group 1). Treatment with B. mukul significantly reduced the plasma TC (p<0.001), LDL (p<0.05), and VLDL (p<0.05), and significantly elevated the HDL (p<0.001) levels. Combined therapy with nifedipine showed better reduction in LDL and VLDL (p<0.001) as compared with B. mukul alone (p<0.05).

Figure 1.

Effect of Balsamodendron mukul and/or nifedipine on plasma total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) in patients with hypertension. Values are means ± SD. See Table I for treatment groups. Values not sharing a common letter (a, b, c) between groups differ significantly at p<0.05. *p<0.001, **p<0.01,p<0.05 in each case compared with baseline

Figure 2 shows the effect of B. mukul and/or nifedipine on plasma triglycerides, phospholipids and FFA in hypertensive patients. At baseline, plasma levels of triglycerides, phospholipids, and FFA were elevated in hypertensive patients as compared with control subjects (group 1). On treatment with B. mukul (group 2) the levels of triglycerides, phospholipids, and FFA were significantly decreased. The decrease in triglycerides and FFA was more pronounced in patients who received both B. mukul and nifedipine (p<0.001) as compared with patients who received B. mukul (p<0.05) alone. No changes were observed in nifedipine-only treated hypertensive patients. Phospholipids were significantly reduced (p<0.01) in all hypertensive patients regardless of the treatment.

Figure 2.

Effect of Balsamodendron mukul and/or nifedipine on plasma triglycerides, free fatty acids, and phospholipids in patients with hypertension. Values are means ± SD. See Table I for treatment groups. Values not sharing a common letter (a, b, c) between groups differ significantly at p<0.05. *p<0.01, **p<0.001,p<0.05 in each case compared with baseline

DISCUSSION

Hypertension and dyslipidemia are recognized as two major risk factors in the development of coronary artery disease (CAD).20 Hypertensive patients treated for 6 weeks with B. mukul, nifedipine, or B. mukul plus nifedipine showed lowered SBP and DBP, although the changes with nifedipine alone were not significant. There are a number of reports demonstrating the effect of nifedipine in lowering BP in both elderly and nonelderly patients with hypertension.21 Nifedipine binds to the L-type calcium channels found in cardiac and smooth muscle cells22 and blocks calcium channels. This results in vasodilation and lowering of systemic peripheral resistance and BP.23 Effectiveness in lowering BP with B. mukul may be due to its hypolipidemic effect, which may alter impaired endothelial function and vascular tone frequently observed in hypertensive patients. Moreover, when B. mukul was administered in combination therapy with nifedipine, DBP was significantly decreased compared with nifedipine alone. BMI was also slightly reduced in hypertensive patients treated with B. mukul as compared with baseline.

In addition to hypertension, obesity, and smoking, proatherogenic alterations in plasma lipids are also considered to be major risk factors in the development of CAD.24 Elevated plasma TC levels in hypertensive patients are common.25 Lowered plasma TC levels were observed in B. mukul-treated hypertensive patients, which may be due to inhibition of cholesterol biosynthesis and/or elevated excretion of cholesterol as bile acids. Earlier studies have shown that B. mukul reduces liver cholesterol biosynthesis by inhibiting the activity of 3-hydroxy 3-methyl glutaryl coenzyme A reductase (HMG CoA reductase) and enhancing the rate of excretion of cholesterol by increasing fecal excretion of bile acids.15

Nifedipine, an antihypertensive drug, has been shown to prevent the induction of the HMG CoA reductase gene, thereby reducing cellular cholesterol biosynthesis.26 Block et al.26 have shown that nifedipine induces LDL-receptor gene expression as well as surface expression on the plasma membrane. These mechanisms may be responsible for the lowering of cholesterol observed in the hypertensive patients in this study who were treated with nifedipine. Our study also shows that the lowering of plasma cholesterol levels was more pronounced when B. mukul was given with nifedipine. In previous studies, the use of calcium channel blockers has generally been found to be lipid-neutral.

Several prospective studies have observed a positive relationship between plasma triglycerides and obesity, and a negative relationship between triglycerides and HDL-supporting the concept that triglycerides may be another risk factor for CAD.27 Hypertension, dyslipidemia, and obesity, moreover, have been reported to be closely associated with insulin resistance.28 Insulin resistance and hyperinsulinemia result in the increased availability of FFA, leading to increased synthesis of triglycerides.29 Increased synthesis of VLDL in the liver and/or lowered rate of VLDL catabolism due to decreased lipoprotein lipase activity may be the cause for increased triglyceride levels observed in our study in hypertensive patients.

Elevated circulating FFA along with increased triglyceride levels in hypertensive patients compared with the normal subjects were also noted at baseline in our study. Increased FFA in the blood may result in impaired endothelium-dependent relaxation and contribute to CV disease.30 Treatment with B. mukul and B. mukul plus nifedipine significantly lowered the plasma FFA and triglyceride levels in hypertensive patients compared with untreated hypertensive patients. The use of nifedipine alone did not significantly reduce the parameters.

Lipoprotein disorders in patients with essential hypertension are characterized by hypertriglyceride-mia, especially increased VLDL, LDL, and decreased HDL levels.31,32 There is also increasing evidence that LDL is oxidized to a greater extent in vivo and is more susceptible to oxidation in vitro in hypertensives than in normotensives.33 Abnormalities of lipoproteins, such as high VLDL and low HDL in hypertensive patients, may be mediated by insulin resistance—which leads to a reduced rate of hydrolysis of VLDL, resulting in lowered synthesis of HDL.34 Elevated plasma LDL and VLDL, and decreased HDL, are common in hypertensive patients.35 Low HDL is known to be associated with endothelial dysfunction, resulting in noncompliant vessels, which eventually may manifest as hypertension.36 HDL levels are known to strongly inversely correlate with CAD risk.37 Szapary, et al.38 have observed that B. mukul elevates HDL levels in hypercholesterol-emic patients. On treatment with B. mukul, lipoprotein levels were improved, especially in the group of patients who received combined therapy compared with those treated with nifedipine alone.

CONCLUSIONS

Our study suggests that B. mukul may be an effective antihypertensive and hypolipidemic agent. Combined therapy with B. mukul and nifedipine was comparatively more beneficial than treatment with B. mukul alone. Further research in our laboratory is in progress to isolate and study the effectiveness of the active principle of B. mukul in the treatment of hypertension. Larger studies are clearly necessary to confirm these preliminary observations.

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