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Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension.

Summary

Cardiovascular (systolic and diastolic blood pressure, heart rate), antihyperlipidemic (tryglycerides, total cholesterol and lipoprotein fractions), antioxidant (glutathione peroxidase -- GPx, and superoxide dismutase -- SOD), diuretic/saluretic and hypoglycemic activity of 98% pure oleanolic (QA) and ursolic (UA) acid were studied in Dahl salt-sensitive (DSS), insulin resistant rat model of genetic hypertension. Both OA and UA displayed low toxicity, with [LC.sub.50] 0.10 and 0.95 mg/ml, respectively. Although both triterpenoids did not have direct hypotensive effect, after 6-week application in a daily dose 60 mg/kg b.w., i.p., they prevented the development of severe hypertension. The antihypertensive effect was attributed to their potent diuretic-natriuretic-saluretic activity; direct cardiac effect (heart rate decrease by 34% and 32%, respectively); antihyperlipidemic (more than two times decrease of LDL and triglycerides); antioxidant (GPx increase by 12% and 10%, respectively; SOD increase by 12% and 2 2%, respectively), and hypoglycemic (blood glucose decrease by 20% and 50%, respectively) effects on the DSS rats. Except for the antihyperlipidemic effects, the other described above in vivo antihypertensive effects of OA and UA are reported for the first time and the underlying mechanisms are currently under investigation.

Key words: oleanic acid, ursolic acid, experimental hypertension, salt-sensitivity, insulin resistance

Introduction

Oleanolic acid (3[beta]-hydroxy-olea-12-en-28-oic acid) and its isomer, ursolic acid (3[beta]-hydroxy-urs-12-en-28-oic-acid) (Fig. 1), are triterpenoid compounds that exist largely in food products (vegetable oils) (Perez-Camino and Cert, 1999), and in more than 120 plant species (Price et al. 1987), many of them used as medicinal plants in traditional medicine (Hutchings et al. 1996). They are distributed in the natural plants in the form of free acid or aglycomes for triterpenoid saponins (Mahato et al. 1988; Wang and Jiang, 1992). Oleanolic and ursolic acid share many common pharmacological properties (Liu, 1995). Other triterpenoids may have similar properties but in general they have not been studied in as much details.

Ginseng (roots of Panax ginseng C. A. Meyer), containing oleanolic acid as the main aglycone (Shibata, 1977; Shibata, 2001), has been used int he folk medicine in East Asian countries since ancient times as a drug for longevity and as an anti-tumor drug. We found that many African medicinal plants, containing triterpenoids, were used broadly in African folk medicine (Hutchings, 1989).

The main biopharmacological effects shared by the oleanolic and ursolic acid, as listed by Duke (1992) and Liu (1995) are antiinflammatory (Tsuruga et al. 1991; Simon et al. 1992; Han et al. 1997; Honda et al. 2000); hepatoprotective (Ma et al. 1982; Saraswat et al. 2000; Kuzuhara et al. 2000); antitumor (Young et al. 1994; Shibata 2001); antidiabetogenic (Liu et al. 1994; Matsuda et al. 1998; Yoshikawa and Matsuda, 2000); antioxidant (Balanehru and Nagarajan, 1991; Kitani et al. 1999; Zhang et al. 2001); anti-hyperlipidemic (;Ma, 1986; Liu et al. 1987); anti-ulcer (Gupta et al. 1981; Wrzeciono et al. 1985); cardiotonic and diuretic (cited by Duke, 1992). Antifertility effect of oleanolic acid in male rats was reported by Rajasekaran et al. (1988). Recently anti-HIV activity of both oleanolic (OA) and ursolic (UA) acid was described (Kashiwada et al. 1998 and 2000).

Our interest in GA and UA arised from the fact that they are present in many local African plants, they have very low toxicity (Xu, 1985; Lin, 1995), and they have antioxidant and diuretic activity, as mentioned above. In addition to that, GA and UA have been tested successfully as antiatherosclerotic agents in experimental animals (Parfent'eva et al. 1980; Vasilenko et al. 1982).

It has been suggested that oxidative stress plays a role in hypertension, increasing pressure values and leading to complications (Somova et al. 2001a). Oxidative stress, at present, appears as one of several metabolic abnormalities described in essential hypertension. Antioxidant therapy could be useful to counteract the effects of oxidative stress on blood vessels, arterial pressure and low-density lipoproteins (Digiesi et al. 2001).

The present study is part of a large project of evaluation of the biopharmacological effects of triterpenoids of African medicinal plants. Since we did not find reports on the cardiovascular effects of GA and UA, the aim of this study was to evaluate the antihypertensive and antiaterosclerotic effects of OA and UA in experimental hypertension. The rat model of Dahl salt-sensitive rat was used since, due to salt-sensitivity and insulin resistance of these genetically hypertensive rats, they are prone to develop an early atherosclerosis. Also, salt-sensitive hypertension is considered the most common type of hypertension in the African population (Mufunda and Somova, 1993).

Materials and Methods

The procedures followed were approved by the Ethics Committee of the University of Durban-Westville. The principles of laboratory animal care (WIH publication 85-23, revised in 1985) were observed. Dahl salt-sensitive (DSS) genetically hypertensive and the control normotensive Dahl salt-resistant (DSR) rats were imported from Sprague Dawly Inc., USA. Male weanling (4 weeks old) rats, weighing 35-40 g at the beginning of the experiment, were used. They were housed in the University Biomedical Resource Center, exposed to a 12-h light:12-h dark cycle and constant humidity. Water and standard food were provided ad libitum. The animals were treated daily with 60 mg/kg b.w. i.p. for 6 consecutive weeks.

Gleanolic acid isolated from cloves (Syzygium aromaticum, Myrtaceae), and ursolic acid isolated from thyme (Thymus vulgaris L., Lamiaceae) were purchased from Africa International Food and Cosmetic Technologies, South Africa. Their purity (about 98%) was confirmed by spectroscopic techniques (1H and 13C-NMR).

The acids were dissolved in DMSO which is indifferent to any of the studied parameters.

Tests for toxicity

Acute toxicity of the extract was evaluated using brine shrimp (Artemia salina) bioassay (Meyer et al. 1982). [LC.sub.50] and 95% confidence intervals were determined from the 24 h counts of the survived naupii by intersection. For qualitative/semiquantitative determination of toxicity, the hippocratic test on rats was used (Malone, 1983) in a 5 day follow-up period after a single intraperitoneal (i.p.) injection (60 mg/kg b.w.).

Hemodynamic screening

Eight DSS rats were used per compound, in addition to 8 untreated control DSR and 8 untreated DSS rats. A tail-cuff computerized blood pressure monitor (IITC Life Sciences 31, USA) was used. The method was standardized and used routinely in our laboratory and is described in details elsewhere (Somova et al. 1999).

Two types of measurements were performed:

* After a single peritoneal application of the drug, systolic and diastolic blood pressure and heart rate were monitored for 60 min in 10 min intervals.

* The same parameters were monitored for 6 consecutive weeks after a single intraperitoneal (i.p.) daily application. The drugs were applied after early morning measured of blood pressure.

Diuretic and saluretic activity in rats

The Lipschitz test was used (Vogel and Vogel, 1997). "The Lipschitz-value" of diuretic activity is the quotient between excretion by the test animals (six per group) and excretion by the urea control. The rats were placed in individual Nalgene metabolic cages at standard conditions. The test compound was applied i.p. in a dose 60 mg/kg in 5 ml distilled water per kg body weight, and the urea - in a dose of 1 g/kg b.w. Urine excretion was recorded after 5 and after 24 h. The electrolyte content of the urine was analyzed by using Beckman Synchron EL-ISE Electrolyte System (Germany).

The sum of Na + and CT excretion was calculated as a parameter of saluretic activity. The ratio Na +/K+ was calculated for natriuretic activity. The ratio C1-/Na+ + K + (ion quotient) was calculated to estimate carbonic anhydrase inhibition.

Biochemical determinations At the end of 6-week experiment the animals were fasted overnight and sacrificed after anesthesia (40 mg/kg b.w. i.p. sodium thiopentone, Rhone-Poulenc, SA) by exsanguination via cannulated left carotid artery. The collected heparmnazed blood was used for the biochemical determinations.

Blood glucose was estimated by Glucometer Elite, Bayer Diagnostics in whole blood. Lipid analysis (plasma tryglycerides, total cholesterol and its lipoprotein fractions) was assayed using commercially available Boehringer-Mannheim (Germany) monotest kits.

Glutathione peroxidase (GPx) in whole blood was assayed using Ransel-Randox (Britain) kit, based on the original method of Paglia and Valentine (1967). Superoxide dismutase (SOD) was assayed using Randos-Randox (Britain) kit, based on the original method of Winterboum et al. (1975). In both cases of estimation of GPx and SOD, before introduction of the kit, the method was standardized in our laboratory by comparing with the original biochemical method. Both enzymes, GPx and SOD are routinely used to determine the therapeutic efficacy and antioxidant potential of drugs.

Statistical analysis

Values are expressed as mean +/- SEM. For statistical analysis, where applicable, the Instat V2.04 programme was used, including one-way Student's t test. A p value of <0.05 was considered statistically significant.

Results

The brine shrimp test showed that both GA and UA have low toxicity with LC50 0.10 and 0.95 mg/ml, respectively. During the hyppocratic test, apart from slight diarrhea on day 4 and 5, both acids showed no toxicity at a dose 60 mg/kg b.w.

The results of the in vivo experiment are presented in Table 1-4. At the age of 10 weeks (the end of 6-week experiment), DSS untreated rats developed spontaneously hypertension with significantly increased heart rate. Since this strain of rats are insulin resistant (Somova et al. 1999) they had significantly increased blood glucose by 26% and they were prone to develop an early atherosclerosis with significantly increased total cholesterol by 108%, increased more than 4 times LDL cholesterol and triglycerides. DSS rats showed compromized antioxidant status with significantly decreased blood GPx by 22% and red blood cells SOD by 25%, compared to the control normotensive DSR rats.

All of the above biochemical parameters normalized almost completely after 6 weeks treatment of DSS rats with GA and UA, showing a potent hypoglycemic, antihyperlipidemic (antiatherosclerotic) and antioxidant activity.

The results of the blood pressure and heart rate follow-up after single i.p. application (60 mg/kg b.w.) are presented in Table 2. They showed no effect of both GA and UA during 60 mm follow-up period, except of significant bradicardia 60 mm after application.

The results of blood pressure and heart rate after 6 weeks daily i.p. treatment with OA and UA (60 mg/kg b.w.) showed that both drugs prevented development of hypertension in DSS rats, with significant bradicardia (Table 3).

Both OA and UA showed potent diuretic activity, and comparable natriuretic and saluretic activity to that of hydrochlorothiazide, suggesting inhibition of [Na.sup.+] and [K.sup.+] reabsorption in the early portion of the distal tubule. No carbonic anhydrase inhibition was detected (Table 4).

Discussion

Recently, we reported (Somova et al. 2001b) that some diterpenoid kaurene derivatives have significant systemic hypotensive and coronary vasodilatory effect attributed to calcium antagonistic mechanism. We expected a similar cardiovascular effect of the triterpenoids oleanolic (OA) and ursolic (UA) acid, with different, non-calcium dependent (Zhong and Jiang, 1997) mechanism, since it was reported (Wang and Polya, 1996) that oleanolic, ursolic acid and related compounds had the most potent non-aromatic plant-derived selective inhibition of cyclic AMP-dependent protein kinase. In the present study we did not find direct hypotensive effect of OA and UA, but a potent antihypertensive effect of both triterpenoids. This antihypertensive effect can be attributed mainly to the potent antihyperlipidemic and antioxidant activity, combined with diuretic, natriuretic and saluretic activity, due to inhibition of Na+ and K+ re-absorption in the early portion of the distal tubule. Since the hypertensive model of Dahl salt- sensitive rat, used in this study, is a model of salt-sensitive, insulin resistant hypertension (the most common type of hypertension in the African population), we can assume that the hypoglycemic effect of OA and UA might contribute to the overall antihypertensive effect of the triterpenoids. The significant bradycardia produced by OA and UA in both short-term (60 min) and chronic (6 weeks) application study, suggested a direct cardiac effect of the drugs, which can contribute to the antihypertensive effect.

With this study we addressed another, largely debated in cardiology question, whether antioxidant therapy could be used in addition to traditional antihypertensive drugs, to counteract the effects of oxidative stress on blood vessels, arterial pressure and low-density lipoproteins (Digiesi et al. 2001). Indeed, reactive oxygen species play a pivotal role in many physiological reactions, and their excessive inhibition could be dangerous. In this study we showed that without being hypotensives, OA and UA could prevent development of severe salt-sensitive, insulin resistant hypertension on the basis of their potent diuretic/saluretic, antihyperlipidemic, antioxidant and hypoglycemic effects. Although the toxicity of the triterpenoids is very low, further controlled, randomized long-term trials with antioxidants (triterpenoids) in hypertension are necessary to establish the efficacy and tolerability of triterpenoids in the adjuvant therapy of hypertension.

Current studies in experimental hypertension, to establish the mechanisms of the described effects of OA and UA and potential sedative effecct on CNS, are in progress.
Table 1

Blood glucose, plasma lipids and antioxidants in control, normotensive
Dahl-Salt Resistant (DSR), untreated Dahl Salt-Sensitive hypertensive
(DSS) rats, and DSS rats treated with oleanolic and ursolic and ursolic
acid for 6 weeks.

Group/ Blood Total
Parameter Glucose Cholesterol
 (mmol/1) (mg/dl)

Control DSR 5.00 [+ or -] 0.2 1.57 [+ or -) 0.09
Untreated DSS 6.80 [+ or -] 0.2 3.27 [+ or -) 0.09 +
Oleanolic and 4.58 [+ or -] 0.08 * 2.65 [+ or -] 0.18 +
Ursolic acid 4.60 [+ or -] 0.23 * 1.59 [+ or -] 0.23 *

Group/ HDL LDL
Parameter Cholesterol Cholesterol
 (mg/dl) (mg/dl)

Control DSR 0.92 [+ or -] 0.04 0.45 (+ or -)0.07
Untreated DSS 1.06 [+ or -] 0.10 1.88 [+ or -] 0.13 +
Oleanolic and 1.76 [+ or -] 0.22 * 0.86 [+ or -] 0.19 *
Ursolic acid 1.82 [+ or -] 0.12 * 0.52 [+ or -] 0.04 *

Group/ Trig- Glutathione
Parameter glycerices peroxidase
 (mg/dl) (units/ml)

Control DSR 0.44 (+ or -) 0.05 103.03 [+ or -] 2
Untreated DSS 1.45 (+ or -) 0.23 80.47 [+ or -] 1.67 +
Oleanolic and 0.77 (+ or -) 0.06 * 90.3 (+ or -] 5.1 *
Ursolic acid 0.40 [+ or -] 0.07 * 88.5 [+ or -] 3.1 *

Group/ Superoxide
Parameter Dismutase
 (units/ml)

Control DSR 278.07 [+ or -] 2
Untreated DSS 210.40 [+ or -] 5
Oleanolic and 236.68 [+ or -] 11.32 *
Ursolic acid 257.41 [+ or -] 12.09 *

[+ or -] * SEM. The phytochemicals were applied i.p. in a dose 60 mg/kg
b.w.

* The difference is significant compared to the DSS untreated group

+ The difference is significant between DSR normotensive and DSS
hypertensive untreated rats.

Table 2

Follow-up changes in blood pressure (mm Hg) and heart rate (beats/min)
after a single intraperitoneal injection of oleanolic and ursolic acid
(60 mg/kg b.w.i.p.).

Group/ Baseline 10 minutes
Parameter SBP DBP HR SBP

Oleanolic 145 102 460 141
acid [+ or -]3.1 [+ or -]1.6 [+ or -]16.2 [+ or -]1.4
Ursolic 147 104 480 150
acid [+ or -]3.1 [+ or -]1.6 [+ or -]16.2 [+ or -]1.4

Group/ 10 minutes 20 minutes
Parameter DBP HR SBP DBR

Oleanolic 95 490 145 98
acid [+ or -]1.3 [+ or -]17.2 [+ or -]3.6 [+ or -]3.8
Ursolic 103 432 142 102
acid [+ or -]1.3 [+ or -]17.2 [+ or -]3.6 [+ or -]3.8

Group/ 20 minutes 30 minutes
Parameter HR SBP DBP HR

Oleanolic 470 145 98 480
acid [+ or -]14.6 [+ or -]3.4 [+ or -]4.2 [+ or -]18.2
Ursolic 377 140 102 450
acid [+ or -]14.6 [+ or -]3.4 [+ or -]4.2 [+ or -]18.2

Group/ 60 minutes
Parameter SBP DBP HR

Oleanolic 140 96 406
acid [+ or -]4.2 [+ or -]3.7 [+ or -]14.6
Ursolic 140 100 406
acid [+ or -]4.2 [+ or -]3.7 [+ or -]14.6*

Means [+ or -] SEM; SBP - Systolic Blood Pressure; DBP - Diatolic Blood
Pressure; HR - Heart Rate

* Significant compared to baseline value

Table 3

Changes in blood pressure (mm Hg) and heart rate (beats/min) of Dahl
Salt-Sensitive hypertensive rats treated with the oleanolic and ursolic
acid for 6 weeks.

Group/ Control 1 week
Parameter SBP DBP HR SBP

Control untreated 124 82 332 121
DSS rats [+ or -]2.8 [+ or -]2.1 [+ or -]14.6 [+ or -]2.5
Oleanic 123 83 405 122
acid [+ or -]1.9 [+ or -]2.6 [+ or -]22.0 [+ or -]3.6
Ursolic 129 82 437 123
acid [+ or -]3.4 [+ or -]1.6 [+ or -]19.8 [+ or -]3.5

Group/ 1 week 2 weeks
Parameter DBP HR SBP DBP

Control untreated 95 404 140 102
DSS rats [+ or -]4.4 [+ or -]27.0 [+ or -]3.5 [+ or -]4.3
Oleanic 88 402 140 104
acid [+ or -]4.1 [+ or -]24.4 [+ or -]2.9 [+ or -]3.2
Ursolic 89 358 140 98
acid [+ or -]4.1 [+ or -]26.4 [+ or -]3.2 [+ or -]3.0

Group/ 2 weeks 3 weeks
Parameter HR SBP DBP

Control untreated 451 140 115
DSS rats [+ or -]16.2 [+ or -]5.4 [+ or -]5.8
Oleanic 480 143 100
acid [+ or -]14.6 [+ or -]4.6 [+ or -]1.5
Ursolic 448 136 94
acid [+ or -]12.0 [+ or -]5.6 [+ or -]2.2

Group/ 3 weeks 4 weeks
Parameter HR SBP DBP

Control untreated 483 148 106
DSS rats [+ or -]20.4 [+ or -]2.3 [+ or -]2.0
Oleanic 471 135 100
acid [+ or -]16.4 [+ or -]2.9 * [+ or -]2.0
Ursolic 362 138 102
acid [+ or -]12.8 * [+ or -]1.0 * [+ or -]2.1

Group/ 4 weeks 5 weeks
Parameter HR SBP DBP

Control untreated 458 155 120
DSS rats [+ or -]18.7 [+ or -]2.2 [+ or -]2.8
Oleanic 403 143 110
acid [+ or -]16.0 * [+ or -]1.5 * [+ or -]2.7 *
Ursolic 408 145 114
acid [+ or -]12.2 * [+ or -]1.6 * [+ or -]2.6

Group/ 5 weeks 6 weeks
Parameter HR SBP DBP

Control untreated 466 167 128
DSS rats [+ or -]14.7 [+ or -]2.7 [+ or -]3.5
Oleanic 417 144 116
acid [+ or -]20.0 [+ or -]1.0 * [+ or -]1.3 *
Ursolic 427 140 109
acid [+ or -]12.8 [+ or -]4.0 * [+ or -]4.0 *

Group/ 6 weeks
Parameter HR

Control untreated 462
DSS rats [+ or -]14.3
Oleanic 304
acid [+ or -]10.2 *
Ursolic 313
acid [+ or -]10.0 *

Means [+ or -] SEM; SBP - Systolic Blood Pressure; DBP - Diastolic Blood
Pressure; HR - Heart Rate

The phytochemicals were applied intraperitoneally in a dose 60 mg/kg
b.w.

* The difference is significant compared to the control untreated group

Table 4

Diuretic, saluretic and natriuretic activity of oleanolic acid and
ursolic acid, compared to the effects of urea and hydrochlorothiazide.

Group/ 5 hours after administration
Parameter Diuresis Lipschitz
 (ml/100 g b.w.) Value (T/U)


Urea (1 g/kg b.w.) 1.4 [+ or -] 0.2 -
Hydrochlorothiazide 3.5 [+ or -] 0.6 2.5
 (25 mg/kg b.w.)
Oleanic acid 1.4 [+ or -] 0.2 * 1.0
Ursolic acid 1.6 [+ or -] 0.3 * 1.1

Group/ 5 hours after administration
Parameter Na + Cl Na/K
 (mmol/l) (mmol/l)


Urea (1 g/kg b.w.) 440 [+ or -] 12.6 1.67 [+ or -] 0.17
Hydrochlorothiazide 520 [+ or -] 8.4 3.44 [+ or -] 0.10
 (25 mg/kg b.w.)
Oleanic acid 376 [+ or -] 15.7 *+ 1.07 [+ or -] 0.12 +
Ursolic acid 442 [+ or -] 12.8 + 1.47 [+ or -] 0.17 +

Group/ 5 hours after
 administration
Parameter Cl
 Na + K
 (mmol/l)

Urea (1 g/kg b.w.) 0.654 [+ or -] 0.02
Hydrochlorothiazide 0.834 [+ or -] 0.002
 (25 mg/kg b.w.)
Oleanic acid 0.618 [+ or -] 0.05 +
Ursolic acid 0.466 [+ or -] 0.03 *+

Group/ 24 hours after administration
Parameter Diuresis Lipschitz Value
 (ml/100 g b.w.) (T/U)


Urea (1 g/kg b.w.) 7.0 [+ or -] 0.6 -
Hydrochlorothiazide 14.6 [+ or -] 0.5 2.08
 (25 mg/g b.w.)
Oleanic acid 7.0 [+ or -] 0.4 + 1.00
Ursolic acid 6.8 [+ or -] 0.4 + 0.97

Group/ 24 hours after administration
Parameter Na + Cl Na/K
 (mmol/l) (mmol/l)


Urea (1 g/kg b.w.) 281 [+ or -] 10.0 1.32 [+ or -] 0.12
Hydrochlorothiazide 382 [+ or -] 7.6 2.43 [+ or -] 0.12
 (25 mg/g b.w.)
Oleanic acid 269 [+ or -] 8.4 + 0.92 [+ or -] 0.13 +
Ursolic acid 227 [+ or -] 12.2 + 0.83 [+ or -] 0.10 +

Group/ 24 hours after
 administration
Parameter Cl
 Na + K
 (mmol/l)

Urea (1 g/kg b.w.) 0.648 [+ or -] 0.01
Hydrochlorothiazide 0.672 [+ or -] 0.01
 (25 mg/g b.w.)
Oleanic acid 0.539 [+ or -] 0.01 +
Ursolic acid 0.566 [+ or -] 0.02 +

Means [+ or -] SEM ; The phytochemicals were applied intraperitoneally
in a dose 60 mg/kt b.w.

* The difference is significant compared to the effect of urea

+ The difference is significant compared to the effect of
hydrochlorothiazide

T/U "Lipschitz-value" ratio in which T is the response of the tested
compound and U is the urea response


Acknowledgements

Acknowledgement is due to Africa International Food and Technologies Co., SA. for the kind supply of purified oleanolic and ursolic acid and C. Govender for accurate typing of the manuscript.

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L.O. Somova, (1) A. Nadar, (1) P. Rammanan, (1) and F.O. Shode (2)

(1.) Department of Human Physiology

(2.) Department of Chemistry, University of Durban-Westville, Durban, South Africa

Address

L. I. Somova, Department of Human Physiology, University of Durban-Westville, Private bag X54001, Durban 4000, South Africa

e-mail: somova@pixie.udw.ac.za
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Author:Somova, L.O.; Nadar, A.; Rammanan, P.; Shode, F.O.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:1USA
Date:Mar 1, 2003
Words:4749
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