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Antihypertensive effect of a standardized aqueous extract of Cecropia glaziovii Sneth in rats: an in vivo approach to the hypotensive mechanism.

Abstract

Cecropia glaziovii Sneth is a common tree at the Southeastern Brazilian coast. As many other species of the genus, it shares the reputed folk use to treat heart failure, cough, asthma and bronchitis. The plant has been cultivated under controlled conditions and the 2% aqueous extract (AE) prepared with the dried leaves was standardized by its chemical contents on catechins, flavonoids and procyanidins. The present paper reports the antihypertensive activity of AE and of n-butanol fraction (BuF), an enriched semi-purified butanolic fraction used to isolate the main chemical constituents. Oral administration of AE and BuF induced hypotension in normotensive rats. The effect of AE (0.5 g/kg/bi, p.o.) was time and dose-dependent peaking at 2-3 weeks after daily administration. BuF was faster but not more active than AE. Both extracts decreased the hypertension of spontaneous hypertensive rats, the hypertension induced in rats by L-NAME treatment and that induced by constriction of one renal artery. The antihypertensive effect was maintained for as long as 60 days of treatment and was reversible upon drug washout at the same rate of its establishment. Acute i.v. administration of BuF to anesthetized rats induced a fast short-lasting hypotension and inhibited the pressor responses to noradrenaline, angiotensin I and angiotensin II by 40%. These results were indirect indications that the hypotension induced by AE is not related to ACE inhibition, increased NO synthesis, or specific blockade of [alpha]1 and AT1 receptors. It can be suggested that BuF interferes with the calcium handling mechanisms in smooth muscle cells and neurons. Intravenous injection of five out of nine compounds isolated from BuF produced immediate but short-lasting hypotension that does not correlate with the onset of the hypotension after oral treatment. This finding suggests that they may not be the compounds directly responsible for the delayed and sustained hypotension after per os administration of AE. The many compounds isolated from AE are under evaluation to determine its pharmacokinetics, mechanisms of action and interactions necessary to yield the plant effect. Although its mechanism is still unknown, AE seems to be an effective and safe antihypertensive phytomedicine.

[c] 2007 Elsevier GmbH. All rights reserved.

Keywords: Cecropia glaziovii; Medicinal plants; Antihypertensive activity; Phytomedicine

Introduction

Cecropia glaziovii Sneth (Cecropiaceae) and more than 70 other species of the genus are widespread in America's tropical regions. Their crude extracts have been used in Brazilian's phytotherapy (Matta, 1913; Braga, 1960) and in other Latin America's countries (Gupta, 1995) as cardiotonic, diuretic and as relief for cough, bronchitis and asthma. A pharmacological account of C. glaziovii cardiovascular activity aiming its therapeutic relevance for public healthcare was presented in 1997 (Lapa et al., 1999). Other pharmacological screening of standardized Cecropia extracts, if any, past unnoticed, but studies using intravenous (iv.) injection of crude extracts and in vitro studies of several species extract are found in the literature. For example, i.v. injection of a Cecropia adenopus crude extract produced bradycardia in dogs (Sivori, 1933) and hypotension in rats (Consolini and Migliori, 2005); cardiotonic effect was described in vitro (Consolini et al., 2006); the extract of C. carbonara produced intestinal relaxation in vitro (Vieira et al., 1968); the iv. injection of Cecropia obtusifolia crude extracts induced hypotension in rats either anesthetized (Vidrio et al., 1982) or conscious (Salas et al., 1987a, b), whereas slight increase in urinary flow occurred after intragastric administration (Vargas Howell and Ulate Montero, 1996). Mechanistically it has been suggested that the extract of C. glaziovii might block noradrenergic and serotoninergic receptors (Nicolau et al., 1988); the extract of C. obtusifolia inhibited binding to angiotensin and endothelin receptors (Caballero-George et al., 2001) or inhibited the central sympathetic tonus (Consolini and Migliori, 2005); Cecropia lyratiloba extract stimulated the release of endothelial NO (Almeida et al., 2006) and C. glaziovii extracts inhibited the angiotensin converting enzyme (ACE) (Castro Braga et al., 2000; Lacaille-Dubois et al., 2001).

Chemical studies of the genus Cecropia detected aminoacids and sugars (Neidlein and Koch, 1980), 8-methyl-azabicyclo (1,2,3) octane (Villar et al., 1988) and isovitexin (Della Monache et al., 1988), flavonoids, catechins and procyanidins (Lacaille-Dubois et al., 2001) all of them putatively related to Cecropia effects. However, correlation of specific pharmacological effects and plant constituents is lacking.

Therefore, the aim of the present paper was to compare the antihypertensive activity of a standardized aqueous extract (AE) of C. glaziovii and of its purified fraction on validated models of hypertension seeking for a definition of the mechanism of action after per os (p.o.) administration.

Materials and methods

Botanical material

C. glaziovii Sneth was cultivated from a germoplasm kept at CPQBA's (Centro Pluridisciplinar de Pesquisas Quimicas, Biologicas e Agronomicas) farm, a research center at the University of Campinas, Sao Paulo, Brazil (Magalhaes, 2000). A specimen voucher is deposited at that Center Herbarium under the number CPQBA 78.

Extraction and purification

To obtain the tea used in folk medicine, the ground dried leaves were extracted in hot water (2.0%, 72 [degrees]C) for 30 min (yield 20%). The AE was concentrated under vacuum to a fifth of its volume, freeze-dried and the powder was freshly dissolved in tap water before administration p.o. in the gastric lumen.

The concentrated AE was partitionated in n-butanol (3 x 0.21) and both the resulting aqueous fraction (AF) and the n-butanol fraction (BuF) were freeze-dried after evaporation of the solvent. The major compounds in the pharmacologically active BuF were chemically identified as flavonoids, catechins and procyanidins (Tanae et al., 2007).

General pharmacological screening

All the experimental protocols were approved by the Institutional Ethical Committee (CEP-UNIFESP 1233/00).

Three-month-old mice and rats were treated with the AE (0.01; 0.1 and 1.0 g/kg, p.o. and 0.01 and 0.1 g/kg, i.p.) in volumes not exceeding 5 ml/kg. In few animals the toxicity was determined after intraperitoneal administration. Control animals were treated with the same volume of saline i.p. or water p.o. Changes in behavior and other signs were recorded hourly for 6, 12 and 24h after administration.

Blood pressure in anesthetized rats

Normotensive Wistar rats of local breed (2-BAW) were anesthetized with pentobarbital (40 mg/kg, i.p.), one carotid artery was used to record blood pressure (BP) changes and the drugs were injected in the iliac vein. Only purified extracts conveniently diluted in saline were injected i.v. in doses ranging from 0.01 to 30.0 mg/kg. For those extracts producing hypotensive responses, the animals were treated with atropine (1.0 mg/kg, i.v.) before a new dose of the extract was injected. In every animal the vascular reactivity was tested with acetylcholine (0.1-1.0 [micro]g/kg), noradrenaline (0.1-2.0 [micro]g/kg), angiotensin I (0.01-0.10 [micro]g/kg) and angiotensin II (0.01-0.10 [micro]g/kg) injected before and after the extract. In some animals artificial respiration was provided.

BP in non-anesthetized rats

Normotensive rats and spontaneous hypertensive rats (SHR--Wistar Kyoto) 2.5-3-month old at the beginning of the experiments were treated with AE (0.01; 0.1 and 1 g/kg, i.p.). Drugs were diluted to be administered on a maximal volume of 5 ml/kg p.o. or 10 ml/kg, i.p. To get acquainted to the gavage procedure, all the animals received water (5 ml/kg/day, p.o.) during 2-4 weeks before random selection for drug treatment. The control group received water throughout experiment. Hypertension was induced in normotensive rats after L-NAME treatment ([N.sup.[omega]]-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, 10 mg/kg/bid, p.o.), or by constriction of one renal artery (Goldblatt model 2K1C) (Wilson and Byrom, 1939). Systolic BP in non-anesthetized rats was measured once or twice a week with non-invasive tail-cuff plethysmography (IITC Inc), in long-term or short-term experiments, respectively. To improve recording, the animals were kept at 45 [degrees]C for 5min and BP measurement done in triplicate. The animal's weight, food and water intake were determined weekly and the BP measurement always preceded the animal treatment.

Statistical analysis

Data were expressed as means [+ or -] SEM. Statistical significance of the data was determined using one-way analysis of variance followed by the Tukey's method using a GraphPad-Prism software. Data were considered different at the level of p < 0.05.

Results and discussion

General effects

Mice and rats treated with the AE (0.1 and 1.0 g/kg, i.p. or p.o.) were slightly more reactive than controls to auditory stimulus. One hour after injection, the animals were less active than controls but without ataxia or other signs of CNS depression. After 8h they did not differ from control animals. Intraperitoneal injection of AE was followed by evident writhing upon the higher doses but no treatment was lethal within 24 h.

Effect of Cecropia extracts on BP of non-anesthetized normotensive rats

Administration of AE (0.15-0.5 g/kg/day, p.o.) for 3 months to 90-day-old male rats did not significantly alter the rate of the animals' weight gain (from 240 [+ or -] 10 to 270 [+ or -] 10 g) or the food and water intakes comparatively to the control group. Likewise, no other parameter of the toxicity study changed upon AE administration up to the dose of 1.0 g/kg during 90 days (A.J. Lapa, in preparation).

During the control period before drug administration, the recorded BP was constant ranging from 125 to 130 mm Hg in all the experimental groups (mean = 126 [+ or -] 1 mm Hg, n = 30). After repeated administration of AE (0.15 g/kg, p.o.), the BP decreased at a rate of about 0.3 mm Hg per day, stabilizing at 107 [+ or -] 2mm Hg, after 65 days. The hypotension was faster after administration of high doses of AE (0.5 g/kg/day, p.o.) leveling at 103 [+ or -] 2.5 mm Hg, after 35 days (rate 0.7 mm Hg/day). These values differ from those of the control group recorded at the same time (124 [+ or -] 1 mm Hg) (Fig. 1A). Switching AE (0.15 g/kg/day) to BuF (0.1 g/kg/day, p.o.) administration, the BP remained low by 21-24 mm Hg, indicating that the hypotensive compounds were high at the butanolic fraction (Fig. 1A). Comparatively, switching AE (0.5 g/kg/day, p.o.) administration to water, the BP returned to the control values at a rate of 0.7 mm Hg per day (Fig. 1A). The above results indicated that the hypotension produced by AE of C. glaziovii was delayed and dose-related, reaching a maximum of about 20 mm Hg at different time intervals. This effect was reversible after drug washout.

[FIGURE 1 OMITTED]

The data indicate also, that hypotension is probably produced by low polarity compounds because, after partition, the hypotensive activity was high in the less polar fraction (BuF). In fact, Fig. 1B shows that treating naive normotensive rats with BuF (0.1 g/kg/day, p.o.) reduced the control BP (117 [+ or -] 1 mm Hg, n = 6) to 109 [+ or -] 1 mm Hg after 4 days, and to 103 [+ or -] 1 mm Hg after 14 days of administration, at a calculated rate of about 1.5 mm Hg per day (Fig. 1B). Comparatively, administration of the polar fraction AF (0.1 g/kg/day, p.o.) obtained after partition in n-butanol, did not significantly change BP up to 2 weeks, when a 5 mm Hg hypotension was recorded, indicating that a low activity was present in the polar fraction. Actually, HPLC fingerprint of both fractions revealed some but faint overlapping (Tanae et al., 2007).

Effects of Cecropia extracts on hypertensive rats

Several mechanisms could explain the hypotensive effect of Cecropia extracts. For example, central and peripheral sympatholitic effects; blockade of the Renin-Angiotensin-System (RAS), either by inhibition of the Angiotensin I Converting Enzyme (ACE) or blockade of the angiotensin AT1 receptors; direct or indirect enhancement of NO production, changes in calcium homeosthasis, among other mechanisms (Izzo and Black, 1999).

These possibilities were investigated on three experimental models of hypertension: (1) the SHR, a well-established phenotype-driven model of polygenic hypertension attributed to both neural and vascular alterations (Lerman et al., 2005); (2) the renovascular-type of hypertension induced in rats after unilateral reduction of the renal blood flow (Goldblatt 2K1C) a model suitable to investigate the role of the RAS (Wilson and Byrom, 1939; Lerman et al., 2005) and (3) the hypertension induced in rats by L-NAME administration, a model in which inhibition of NO-synthase permits the evaluation of the nitric oxide pathway (Lerman et al., 2005).

Effect of Cecropia extracts on SHR rats

In female SHR treated with AE (0.5 g/kg, bid, p.o.) BP was reduced from 162 [+ or -] 1 mm Hg (n = 10) to 149 [+ or -] 1 mm Hg within 5 days (Fig. 2). In normotensive female AE-treated rats a similar rate of hypotension from 119 [+ or -] 4 mm Hg to 107 [+ or -] 0.1 mm Hg (n = 10) was observed (Fig. 2).

These results show that the pressure response to AE is alike in normotensive and hypertensive animals, characterizing the antihypertensive activity of Cecropia extracts. However, the polygenic nature of the SHR model (Pinto et al., 1998) limits a clear mechanistic explanation for the observed antihypertensive effect.

Renoclip model of hypertensive rats

In the Goldblatt model (2K1C), the hypertension is induced primarily by increased renin release, angiotensin II (AII) synthesis and activation of AT1 and AT2 receptors (Regitz-Zagrosek et al., 1995, 1996; Oparil et al., 2005); the stimulation of aldosterone secretion, and inhibition of prostaglandin synthesis (Oparil and Weber, 1999; Zaman et al., 2002) are secondary but also relevant.

In our experiments, 1 month after constriction of the rat renal artery, BP was 146 [+ or -] 5 mm Hg (n = 10) significantly higher than BP in non-operated rats of the same strain (119 [+ or -] 4 mm Hg). Five of these animals were randomly selected and treated with water (5 ml/kg/day, p.o.) or with AE (0.5 g/kg/day, p.o.) during 60 days. In the water group, BP progressively increased from 141 [+ or -] 5 to 170 [+ or -] 11 mm Hg but in AE-treated rats BP was unaltered in the same period, suggesting that AE might be blocking the RAS (Fig. 3). In fact, results from other groups indicated that extracts of several Cecropia species and substances isolated from them, inhibit in vitro ACE activity (Castro Braga et al., 2000; Lacaille-Dubois et al., 2001).

[FIGURE 2 OMITTED]

To determine the putative correlation of in vitro ACE inhibition and the in vivo antihypertensive effect of C. glaziovii, two sets of experiments were done: (1) ACE activity was indirectly evaluated through the effect induced by angiotensin I before and after i.v. injection of Cecropia extracts and (2) the response to AI and the plasmatic ACE activity were measured in rats chronically treated with AE (0.3 g/kg/day, p.o. during 75 days). In either case, noradrenaline (2 [micro]g/kg), angiotensin I (AI 0.05 [micro]g/kg) and angiotensin II (AII 0.05 [micro]g/kg) were controls injected in the same rats as explained in methods.

[FIGURE 3 OMITTED]

Injection of BuF (3.0; 10.0 and 30.0 mg/kg, i.v.) to anesthetized rats produced hypotension related to the dose (13 [+ or -] 2, 21 [+ or -] 1 and 34 [+ or -] 6 mm Hg, respectively). This effect was reverted within 5min without changing the heart rate. The hypotension was not blocked by pretreatment with atropine (1.0 mg/kg).

In control conditions, the pressor responses to AI (0.05 [micro]g/kg), AII (0.05 [micro]g/kg) and noradrenaline (2[micro]g/kg) were 76 [+ or -] 8.0 mm Hg; 59 [+ or -] 5.9 mm Hg and 53 [+ or -] 5.2 mm Hg, n = 5, respectively. After injection of BuF (30.0 mg/kg, i.v.) these responses were reduced by 47.6 [+ or -] 12.2%, 42.8 [+ or -] 11.7%, and 45.6 [+ or -] 10.8%, respectively. Because the AI effect was reduced by the same proportion as did AII and noradrenaline responses, whose effects do not depend on ACE activity, the results are an indirect indication that ACE activity is not affected by BuF.

Likewise, the responses to AI (0.3 [micro]g/kg) and AII (0.2 [micro]g/kg) in rats pretreated with AE (0.3 g/kg/day, p.o.) during 75 days did not differ from the responses obtained in control water-treated rats (17 [+ or -] 2 and 31 [+ or -] 2 mm Hg, respectively). The results do not favor the involvement of the RAS system on the antihypertensive effect of Cecropia extracts. Therefore, the data do not support the finding that ACE is inhibited by C. glaziovii extracts (Lacaille-Dubois et al., 2001). The direct measurement of plasmatic ACE activity during prolonged p.o. treatment of rats with AE did not detect enzyme inhibition during the hypotensive response (Ninahuaman, 2002; Ninahuaman et al., 2007), nor did the i.v. injection of BuF, rich in catechins and procyanidins, in the present study. This latter result differed from those of Terencio et al. (1991) after injection of a tetrameric procyanidin.

As described before, BuF decreased the responses to AI, AII and noradrenaline by the same intensity but the occurrence of simultaneous blockade of AT1 and [alpha]1 adrenergic receptors is unlike. Therefore, our data differ from the blockade of AT1 and endothelin receptors described in vitro (Caballero-George et al., 2001). Most probably, Cecropia extract should block a single pathway common to the effects of all the agonists studied. This might be a specific blockade of [Ca.sup.++] channels as shown by Lapa et al. (1999) or a release of NO from endothelial cells after interacting with the phenolic compounds (Almeida et al., 2006). The latter possibility was evaluated in the following experiment.

L-NAME-induced hypertensive rats

The administration of L-NAME (10 mg/kg bid, p.o.) to otherwise normotensive rats increased the systolic BP from 127 [+ or -] 2 mm Hg (n = 10) to 147 [+ or -] 3mm Hg (n = 10) leveling from the 4th to the 9th week of treatment. Adding AE (0.5 g/kg/day, p.o.) to the rat treatment after the BP leveling, caused a significant and persistent reduction in BP (Fig. 4). These results indicate that the nitrergic system does not seem to play a significant role in the antihypertensive effect of the Cecropia extracts.

Therefore, evidences so far obtained favor the putative blockade of calcium channels by the Cecropia extracts. Direct evaluation of this effect used in vitro preparations incubated with BuF (Lapa et al., 1999). Although results were reproducible and specific, quantitative molecular interaction could not be established. Purification of the active semi-purified BuF yielded procyanidin B5, procyanidin B3 isomer, catechin, procyanidin B2, epicatechin, procyanidin C1, orientin, isoorientin and isovitexin (Tanae et al., 2007). Preliminary results (n = 4) have shown that i.v. injection of all the catechins and procyanidins induced pronounced hypotension in anesthetized rats, whereas the flavonoids were not as active (Fig. 5). Evaluation of the purified compounds on cell membranes and ionic channels are in progress to clarify the putative calcium channel blockade.

Altogether the results obtained in vivo indicated that oral treatment with AE or BuF decrease BP of normotensive and hypertensive rats. In either case, the effect was established after 4-15 days treatment, it leveled faster after high doses, but it was not more intense. The hypotension was not correlated to ACE inhibition, or to NO synthesis and was apparently independent of specific [alpha]1 or AT1 blockade. Previous experiments have shown that BuF decreases calcium influx and smooth muscle contraction (Lapa et al., 1999). It is not known whether the phenolic substances like catechins, procyanidins and flavonoids isolated from the plant extract act on calcium channels at the membrane surface, or may cross the cell membrane to inhibit intracellular pathways. It is evident, however, that the delayed onset of the hypotension after oral administration and the slow washout, contrast with the fast and short-lasting effect of the isolated compounds injected i.v. Maybe metabolites, rather than compounds of the plant, are the direct responsible for the hypotension. To evaluate this possibility, new pharmacodynamic and pharmacokinetic studies of the plant chemical constituents should be developed. Important to notice that at no time the plant extract interfered with the animal growth. Coupled to the information that 90-day chronic treatment did not alter the plasma biochemistry, the blood parameters or the histopathological analyses in rats and dogs (A.J. Lapa, data to be published), C. glaziovii seems to be a reliable substrate for an effective and safe phytomedicine.

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

Acknowledgments

The technical assistance of C.M. Dores, M.C. Goncalo, and J. F. R. Santos is acknowledged. The authors also thank T.M.A. Lima for the help with some of the blood pressure recordings. This work was supported by grants from Central de Medicamentos (CEME--MS), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP).

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M.T.R. Lima-Landman (1), A.C.R. Borges (1), R.M. Cysneiros (1), T.C.M. De Lima (2), C. Souccar (1), A.J. Lapa (1,*)

(1) Natural Products Section, Department of Pharmacology, UNIFESP/ Escola Paulista de Medicina, 04044-020 Sao Paulo, SP, Brazil

(2) Laboratory of Neuropharmacology, Department of Pharmacology, Federal University of Santa Catarina/UFSC, Florianopolis, SC, Brazil

Received 8 June 2006; accepted 21 September 2006

*Corresponding author. Tel.: + 55 11 5572 5129; fax: + 55 11 5576 4499.

E-mail address: ajlapa@farm.epm.br (A.J. Lapa).
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Author:Lima-Landman, M.T.R.; Borges, A.C.R.; Cysneiros, R.M.; De Lima, T.C.M.; Souccar, C.; Lapa, A.J.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Clinical report
Date:May 1, 2007
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