Elsevier

Phytomedicine

Volume 14, Issue 5, 21 May 2007, Pages 314-320
Phytomedicine

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

https://doi.org/10.1016/j.phymed.2007.03.003Get rights and content

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 α1 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.

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 (i.v.) 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 i.v. injection of Cecropia obtusifolia crude extracts induced hypotension in rats either anesthetized (Vidrio et al., 1982) or conscious (Salas et al., 1987a, Salas et al., 1987b), 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.

Section snippets

Botanical material

C. glaziovii Sneth was cultivated from a germoplasm kept at CPQBA's (Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agronômicas) farm, a research center at the University of Campinas, São Paulo, Brazil (Magalhães, 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 °C) for 30 min (yield 20%). The AE was concentrated under vacuum to a fifth of

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 8 h 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

Acknowledgments

The technical assistance of C.M. Dores, M.C. Gonçalo, 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 Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).

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      While the antidepressant activity of ButF was measured in rat models [2], the anxiolytic effect of AE was observed in mice [4]. Hypotensive activity occurs when the relaxation of smooth muscles takes place, which can be stimulated by several mechanisms [5–15] such as the following: blockage of L-type calcium channels [7–20], action on β-2 adrenergic receptors [21], and/or participation of the nitric oxide pathway [20–23]. Previous studies carried out in our laboratory have demonstrated the hypotensive and antihypertensive activities of the aqueous extract (AE) and the butanolic fraction (ButF) isolated from Cecropia glaziovii Sneth.

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      In folk medicine, the leaves of Cecropia glaziovii Snethl are used in the treatment of various diseases, including the control of blood pressure [1]. Some literature studies have reported a hypotensive effect for plant preparations [2, 3], which has been attributed to a synergism between C-glycosylflavonoids and proanthocyanidins as these compounds showed to be inactive when tested separately [4]. Preliminary phytochemical studies have reported the presence of catechins, procyanidins and flavonoids in standardized aqueous extracts of C. glaziovii [5].

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