Natural products inhibitors of the angiotensin converting enzyme (ACE): a review between 1980 - 2000

Produtos naturais inibidores da enzima conversora de angiotensina (ECA): uma revisão entre 1980 - 2000

REVISÃO

Natural products inhibitors of the angiotensin converting enzyme (ACE). A review between 1980 - 2000

Produtos naturais inibidores da enzima conversora de angiotensina (ECA). Uma revisão entre 1980 - 2000

José M. Barbosa-Filho^*; Valeska K.M. Martins; Luiza A. Rabelo; Marcelo D. Moura; Marcelo S. Silva; Emidio V.L. Cunha; Maria F.V. Souza; Reinaldo N. Almeida, Isac A. Medeiros^*

Laboratório de Tecnologia Farmacêutica "Prof. Delby Fernandes de Medeiros", Universidade Federal da Paraíba, Caixa Postal 5009, 58051-970, João Pessoa, PB, Brazil

ABSTRACT

Inhibition of Angiotensin Converting Enzyme (ACE) is a modern therapeutic target in the treatment of hypertension. Within the enzyme cascade of the renin-angiotensin system, ACE removes histidyl-leucine from angiotensin I to form the physiologically active octapeptide angiotensin II, one of the most potent known vasoconstrictors. Therefore, a rationale for treating hypertension would be to administer drugs or natural compounds which selectively inhibit ACE. The present work constitutes a review of the literature of plants and chemically defined molecules from natural sources with in vitro anti-hypertensive potential based on the inhibition of ACE. The review refers to 321 plants, the parts utilized, type of extract and whether they are active or not. It includes also the names of 158 compounds isolated from higher plants, marine sponges and algae, fungi and snake venom. Some aspects of recent research with natural products directed to produce anti-hypertensive drugs are discussed. In this review, 148 references were cited.

Keywords: Angiotensin converting enzyme, anti-hypertensive effect, hipotensive agents.

RESUMO

A inibição da Enzima Conversora da Angiotensina (ECA) é um alvo terapêutico moderno e eficaz no tratamento da hipertensão arterial. Na cascata enzimática que envolve o sistema renina-angiotensina, a ECA promove a remoção dos aminoácidos histidil-leucina da angiotensina I para formar o octapeptídio angiotensina II, a qual é fisiologicamente ativa em diversos sistemas, e considerado como um dos mais potentes vasoconstrictores endógenos conhecido. Portanto, uma racionalidade no tratamento da hipertensão seria administrar drogas ou compostos de origem natural que inibam seletivamente a ECA. O presente estudo constitui uma revisão da literatura sobre plantas e moléculas de origem natural com potencial anti-hipertensivo, baseado na inibição in vitro da ECA. A revisão referencia 321 plantas, partes usadas, tipo de extrato e se é ativo ou não. Inclui ainda o nome de 158 compostos isolados de plantas superiores, esponjas e algas marinhas, fungos e venenos de cobra. Alguns aspectos de pesquisa recente com produtos naturais direcionados à produção de drogas anti-hipertensivas também são discutidos. Nesta revisão 148 referências foram consultadas.

Unitermos: Enzima conversora da angiotensina, efeito anti hipertensivo, agentes hipotensivos.

INTRODUCTION

The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure defines hypertension as systolic blood pressure (SBP) of 140 mm Hg or greater, diastolic blood pressure (DBP) of 90 mm Hg or greater, or taking anti-hypertensive medication. The objective of identifying and treating high blood pressure is to reduce the risk of cardiovascular disease and associated morbidity and mortality. To that end, it is useful to provide a classification of adult blood pressure for the purpose of identifying high-risk individuals and to provide guidelines for treatment. The positive relationship between SBP and DBP and cardiovascular risk has long been recognized. This relationship is strong, continuous, graded, consistent, independent, predictive, and etiologically significant for those with and without coronary heart disease (Stamler, 1991, Flack et al., 1995). Therefore, although classification of adult blood pressure is somewhat arbitrary, it is useful to clinicians who must make treatment decisions based on a verification of factors including the actual level of blood pressure. Hypertension detection begins with proper blood pressure measurements. Repeated blood pressure measurements will determine whether initial elevations persist and require prompt attention or have returned to normal. According to the National Heart, Lung and Blood Institute (1997), heart disease and stroke remain the first and third leading causes of death, respectively, in the United States and impose an enormous financial and social burden on Americans. In particular, the continued high prevalence of hypertension and hypertension-related complications of stroke, heart failure, and end-stage renal disease in the southeastern United States makes these diseases a public health concern for all who reside in this region, particularly African Americans (Hall et al., 1997). Approximately 50 million adult Americans have hypertension and are still unaware that they have high blood pressure (Burt et al., 1995). In addition, most persons with hypertension have additional risk factors for cardiovascular disease (Furster; Pearson, 1996). Thus, prevention and treatment of hypertension and target organ disease remain important public health challenges that must be addressed as we enter the new millennium.

There are different way to treat the problem related to arterial hypertension. Treatment leading to lower levels may be useful, particularly to prevent stroke (Du et al., 1997), to preserve renal function (Lazarus et al., 1997) and to prevent or slow heart failure progression (Krumholz et al., 1997, Neaton et al., 1993). The goal may be achieved by lifestyle modification, alone or with pharmacological treatment.

Non-Pharmacological treatment of arterial hypertension

The main objective of hypertensive treatment is to reduce the high morbidity and mortality. As well as reducing the pressure, an important objective of treatment is to control other cardiovascular risk factors. Lifestyle modifications offer the potential for preventing hypertension, have been shown to be effective in lowering blood pressure, and can reduce other cardiovascular risk factors at little cost and with minimal risk (Appel et al., 1997). Even when lifestyle modifications alone are not adequate in controlling hypertension, they may reduce the number and dosage of anti-hypertensive medications needed to manage the condition (Neaton et al., 1993, Singer et al., 1995).

Pharmacological treatment of arterial hypertension

Reducing blood pressure with drugs clearly decreases cardiovascular morbidity and mortality. Protection has been demonstrated for stroke, coronary events, heart failure, progression of renal disease, progression to more severe hypertension, and all-cause mortality (Psaty et al., 1997, Moser; Hebert, 1996).

Actually, there are a lot of alternatives available to treat arterial hypertension, both in schemes of monotherapy and/or combined therapy. The efficacy, security and effects of the different drugs are fundamental criteria to be considered in choosing the anti-hypertensive treatment scheme for each patient. In Table 1 the conventional pharmacological anti-hypertensive medications are presented, further details see references.

Mechanism of anti-hypertensive effect based on the inhibition of the angiotensin converting enzyme (ACE)

The renin-angiotensin-aldosterone system plays a pivotal role in the maintenance of vascular tone vis à vis peripheral resistance. Renin produced from the juxtaglomerular apparatus of the kindney, splits angiotensinogen to produce the inactive decapeptide angiotensin I. The latter is then converted to the powerful octapeptide vasoconstrictor, angiotensin II by the action of angiotensin converting enzyme (ACE). Angiotensin II also stimulates the synthesis and release of aldosterone from the adrenal cortex, which increases blood pressure by promoting sodium retention (and thereby water retention) in the distal tubules (Ahnfelt-Ronne, 1991). Research suggests that angiotensin II stimulates the production of superoxide anion and hydrogen peroxide in the polymorphonuclear leucocytes, which inactivates the vasodilatory compounds endothelial derived vascular relaxing factor (nitric oxide – NO) and prostacyclin (PGI₂) (Kumar; Das, 1993). ACE also inactivates the vasodilating nonapeptide bradykinin, which theoretically contributes to the hypertensive effects of ACE activity (Ahnfelt-Ronne, 1991) (Figure 1).

Therefore, a good rationale for treating hypertension would be to administer drugs or natural compounds which selectively inhibit ACE. Such selective inhibitors would be capable of decreasing blood pressure and producing natriuresis and diuresis.

In a previous paper this research group has reviewed crude plant extracts and chemically defined molecules with potential antitumor activity for mammary (Moura et al., 2001), cervical (Moura et al., 2002) and ovarian neoplasias (Silva et al., 2003), as inhibitors of HMG CoA reductase (Gonçalves et al., 2000), central analgesic activity (Almeida et al., 2001), employed in prevention of osteoporosis (Pereira et al., 2002), for the treatment of Parkinson's disease (Morais, 2003), with antileishmanial (Rocha et al., 2005), hypoglycemic (Barbosa-Filho et al., 2005), antiinflammatory activity (Falcão et al., 2005, Barbosa-Filho et al., 2006a) and inhibitors of the enzyme acetylcholinesterase (Barbosa-Filho et al., 2006b).

In this work we present such natural products, in other words, plant extracts, semi purified fractions, chemically defined molecules isolated from plants and metabolites from fungi that act specifically inhibiting the angiotensin converting enzyme (ACE), which is one of the most powerful known vasoconstrictors.

MATERIAL AND METHODS

The keyword for this revision was ACE (Angiotensin Converting Enzyme). We made a data search in the Chemical Abstracts, Biological Abstracts and the NAPRALERT (trademark, NAtural PRoducts ALERT) database at the Illinois University, Chicago. The specialized magazines referenced were than searched.

RESULTS AND DISCUSSION

Plants which inhibit the angiotensin converting enzyme

Screening for anti-hypertensive effects in traditional medicines has been performed over many years and several animal models have been used (Villar et al., 1986). In western medicine, drug development has become increasingly more mechanistic in focus with the aim of excluding unwanted side-effects. The rationale behind this approach is to identify a molecular target (receptor or enzyme) which has an essential role in the regulation of the disease and then search for ligands, substrates or inhibitors of the target.

In the treatment of hypertension, inhibition of the angiotensin converting enzyme (ACE) is established as a modern therapeutic principle.

Elbl and Wagner (1991) introduced an in vitro assay for the detection of ACE inhibitors in plant extracts. This method is based on the ACE-catalyzed cleavage of the chromophore-fluorophore labelled substrate, dansyltriglycine, into dansylglycine, which is quantitatively measured by HPLC (high performance liquid chromatography). By using this technique, a number of plant species have been found to be active (Elbl; Wagner, 1991).

Williams et al. (1997) using another bioassay, but also involving ACE inhibition, verified that the leaves and stems of Euphorbia hirta inhibited the activity of angiotensin converting enzyme by 90% and 50% at 500 mg and 150 mg respectively using enzyme linked immunosorbent assay (ELISA). The data are presented in Table 2. The study also revealed that the most active ACE inhibitory compounds were present in the polar and very polar fractions of the medium.

The results of the literature survey are presented in Table 3, which lists the effects on angiotensin converting enzyme of 321 plant extracts. The plants are arranged in alphabetical order. Each entry gives the following information in sequence: botanical name, family, part used, type of extract or fraction, whether active or not and reference.

From these studies, is appears to be the possibe, using biomonitored phytochemical methods, to find out new substances potentially active, which may prove important for the development of new substances inhibitors of the angiotensin converting enzyme.

Chemically defined molecules inhibitors of the angiotensin converting enzymes

Synthetic drugs such as captopril (Ondetti et al., 1977) or teprotide (Ferreira, 1965), a nonapeptide isolated from the venom of Bothrops jararacussu with established ACE inhibiting activity are used as first line drugs in both secondary and primary hypertension. The rising cost of these and other imported anti-hypertensive drugs stimulates the evaluation of new products as a source of cheaper agents. Several classes of ACE inhibitory compounds were isolated from plants, for example, flavonoids (Wagner et al., 1991; Wagner; Elbl, 1992; Hansen et al., 1996b), xanthones (Chen et al., 1992), secoiridoids (Hansen et al., 1996a). For a comprehensive review of these compounds, see Hansen (1995).

The results of the literature are presented in Table 4, which lists the effects on angiotensin converting enzyme of 158 chemically defined molecules. The compounds are arranged in alphabetical order. Each entry gives the following information in sequence: chemical name, class, whether active or not and reference.

CONCLUSION

This revision focussed initially on the search for information about natural product inhibitors of the angiotensin converting enzyme (ACE). From the literature searched, 321 species of plants and 158 natural substances which inhibit ACE were identifed. These natural products may become important for human clinical treatments.

ACKNOWLEDGEMENTS

The authors express their sincere thanks to the College of Pharmacy, The University of Illinois at Chicago, Chicago, Illinois 60612-7231, U.S.A., for helping with the computer aided NAPRALERT search of angiotensin-converting enzyme and CNPq/CAPES - Brazil for financial support.

Received 10/24/05

Accepted 04/22/06

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Publication Dates

• Publication in this collection
  28 Jan 2008
• Date of issue
  Sept 2006

History

• Received
  24 Oct 2005
• Accepted
  22 Apr 2006