INTRODUCTION:

Several lignans and neolignans with cAMP and cGMP based phosphodiesterase inhibitory activity have been reported from many of the plants and their phytomolecules. Several lignans and neolignans were found to have such type of activity; Gomisin J (GJ), a lignan which is a well-known medicinal herb for improvement of cardiovascular symptoms in Korean Traditional system and isolated from Schisandra chinensis, induces vascular relaxation via activation of endothelial nitric oxide synthase and Calcium-dependent activation of eNOS with subsequent production of endothelial NO^1-2.

Yangambin, a furofuran lignan isolated from Ocotea duckei Vattimo, showed significant inhibition of the Ca²⁺ influx through voltage-gated Ca²⁺ channels blockade, PAF antagonism, inhibition of cyclic AMP phosphodiesterase and activation of eNOS. Sesamin is one of the major lignans in sesame seeds which ameliorates arterial dysfunction in spontaneously hypertensive rats via down regulation of NADPH oxidase subunits and upregulation of eNOS expression. Various chemicals have been identified from the plant, including diterpenes, flavonoids, xanthones, noriridoides, and other random substances^3-9. There have been reports of the plant's anti-microbial, cytotoxic, anti-protozoan, anti-inflammatory, antioxidant, immunostimulant, anti-diabetic, anti-infective, anti-angiogenic, hepato-renal protective, sex hormone/sexual function modulation, liver enzymes modulation, insecticidal, and toxicological actions in extract and pure chemicals. Numerous tests to determine the toxicity of extracts and metabolites extracted from this plant did not uncover any appreciable acute toxicity in test animals. Future research must include a more thorough and detailed toxicity profile on mammalian tissues and organs¹⁰.

METHODS:

Materials:

A literature search for articles published in peer-reviewed articles, as well as electronic database searches using PubMed, Scopus, Science Direct, Google Scholar. Were used to gather the information on various plants based lignans and neolignans that have historically been used for pharmacological, ethnomedicinal, phytochemical, and the treatment of cardiovascular disorders.

Pharmacological mechanism of antihypertensive drugs:

1. Inhibition of cyclic AMP and cyclic GMP phosphodiesterase:

Many of lignans and neolignans have been found to inhibit cAMP and cGMP dependent phosphodiesterase (PDEs) activity. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP¹¹. They regulate the localization, duration, and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules. Phosphodiesterase enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors of PDE can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP by inhibition of their degradation by PDE. Different PDEs of the same family are functionally related despite the fact that their amino acid sequences can show considerable divergence¹².

Some are cAMP-selective hydrolases (PDE4, 7 and 8); others are cGMP-selective (PDE5, 6, and 9). Others can hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10, and 11). PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase. Although PDE2 can hydrolyze both cyclic nucleotides, binding of cGMP to the regulatory GAF-B domain will increase cAMP affinity and hydrolysis to the detriment of cGMP. This mechanism, as well as others, allows for cross-regulation of the cAMP and cGMP pathways¹³. It is generally accepted that, when stimulated, the adenylate cyclase enzyme converts adenosine triphosphate (ATP) into cAMP¹⁴. This second messenger initiates a series of phosphorylation reactions by protein kinases, which mediate the influx of extracellular Ca²⁺ through the slow calcium channels and by release of stored calcium ions by the sarcoplasmic reticulum. A phosphodiesterase III enzyme then inactivates cAMP by converting it into the inert 5'-adenosine monophosphate (5'-AMP)¹⁵. It is likely that the rise in intracellular cellular cAMP may be the result of increases in levels of prostacyclin. One studyhave shown that prostacyclin was both a potent vasodilator, leading to increases in coronary perfusion rate, and stimulator of cAMP production¹⁶.

Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. It’s most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface. Guanylate cyclase (GC) catalyzes cGMP synthesis. This enzyme converts GTP to cGMP¹⁷. Peptide hormones such as the atrial natriuretic factor activate membrane-bound GC, while soluble GC (sGC) is typically activated by nitric oxide to stimulate cGMP synthesis. sGC can be inhibited by ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one)¹⁸. There are two main classes of cardiotonic agents; those that affect intracellular cyclic 3',5'-adenosine monophosphate (cAMP) levels and those that act independently of this mechanism. Compounds in the cAMP-dependent class mediate cardiac contractility by increasing the levels of intracellular cAMP or by inhibiting its metabolism. These include the α-adrenergic agonists, the adenylate cyclase activators, eg forskolin from Coleus forskolii and the phosphodiesterase inhibitors. Of the cAMP-independent class of compounds, one important group, eg cardiac glycosides, inhibit the Na⁺/K⁺-ATPase enzyme¹⁹.

Synthetic phosphodiesterase inhibitors, such as amrinone and milrinone, although initially promising as therapeutic agents, have yielded disappointing results largely because, unlike the digitalis compounds, these cardiotonic drugs lose their effectiveness in severe heart failure. They can exacerbate ventricular arrhythmias, provoke myocardial ischemia and accelerate the progression of the underlying disease²⁰.

Several lignans and neolignans with cAMP and cGMP based phosphodiesterase inhibitory activity have been reported from many of the plants and their phytomolecules;

(±)-Torreyunlignans A-D, neolignan enantiomers as phosphodiesterase-9A inhibitors from Torreyayunnanensis. Erythro-(7S,8R)-7-acetoxy-3,4,3',5'-tetramethoxy-8-O-4'-neolignan (EATN), a neolignan compound isolated from Myristica fragrans, that caused an increase in cyclic AMP (cAMP) levels and attenuated intracellular Ca⁽²⁺⁾ mobilization in thrombin-activated human platelets²¹.

Sesamin, an active lignan isolated from sesame seed and oil, is a novel skin-tanning compound could activate protein kinase A (PKA) via a cAMP-dependent pathway²².

Yangambin, a furofuran lignan isolated from Ocotea duckeiVattimo, showed significant inhibition of the Ca²⁺ influx through voltage-gated Ca²⁺ channels blocker, PAF antagonist, inhibit cyclic AMP phosphodiesterase and activates eNOS²³.

Denudatin B, a neolignan and an antiplatelet agent isolated from the flower buds of Magnolia fargesii relaxed vascular smooth muscle by inhibiting the Ca²⁺ influx through voltage-gated and receptor-operated Ca²⁺ channels; its effect to increase cGMP may enhance the vasorelaxation²⁴.

2. Activate of endothelial nitric oxide synthase:

Nitric oxide (NO) is a potential biochemical marker in many of the cardiovascular diseases including endothelial dysfunction. Endothelial function played a very vital role in the regulation of vascular tone, cellular proliferation, leukocyte adhesion and platelet aggregation through NO donor eNOS in the vascular endothelium. NO produced and catalyzed by 3 different isoforms of the enzymes such as NO synthases (eNOS, iNOS and nNOS). These isoforms altered NO level and are associated with obesity, insulin resistance, diabetes and cardiovascular diseases (CVD). Their activity and NO production are regulated by various hormones under physiological and pathophysiological condition. Therefore, a functional eNOS is essential for a healthy cardiovascular system. The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. NO is a well-known second messenger involved in many cellular signalling pathways²⁵.

In the vascular system, the best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) produced by endothelial NO-synthase (eNOS) or released by NO donors acts in vascular smooth muscle cells, the binding of NO to Fe2+-heme of soluble guanylyl cyclase (sGC) activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The second messenger (cGMP) activates protein kinase G and the signalling cascade, including opening of K⁺channels. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarization, EDH-mediated responses) through activation of K⁺channels leads to cell membrane hyperpolarization and further, Ca²⁺ channels blockade, which induce vascular relaxation through inhibition of intracellular Ca²⁺ channels²⁶.

Several lignans and neolignans were found to have such type of activity; Gomisin J (GJ), a lignan which is a well-known medicinal herb for improvement of cardiovascular symptoms in Korean Traditional system and isolated from Schisandra chinensis, induces vascular relaxation via activation of endothelial nitric oxide synthase and Calcium-dependent activation of eNOS with subsequent production of endothelial NO. Yangambin, a furofuran lignan isolated from Ocotea duckei Vattimo, showed significant inhibition of the Ca²⁺ influx through voltage-gated Ca²⁺ channels blockade, PAF antagonism, inhibition of cyclic AMP phosphodiesterase and activation of eNOS. Sesamin is one of the major lignans in sesame seeds which ameliorates arterial dysfunction in spontaneously hypertensive rats via down regulation of NADPH oxidase subunits and upregulation of eNOS expression^27-29.

3. Antagonism of platelet activating factor (PAF) receptors:

The discoveries of platelet activating factor antagonists (PAF antagonists) during herbal medicine research are going on with different framework, but their efficiency was studying in vitro and in vivo test models. It is assumed that PAF play a central role in etiology of many chronic diseases in humans such as asthma, neuronal, migraine, cardiac diseases, inflammatory, headache etc³⁰.

Several lignans and neolignans which antagonize the platelet activating factor (PAF) receptors activity have been reported from many of the plants and their phytomolecules; five benzofuran neolignans (-)-denudatin B (II), kadsurenin M (7S,8S-3,4,3'-trimethoxy-7'-oxo-nor-8',9'-7.O. 4',8,5'-neolignan, V), kadsurenon (I), (-)-acuminatin(III) and (+)-licarin A(IV) have been isolated from the aerial part of Piper kadsura (Choisy) Ohwi, a Chinese traditional drug, Aglafoline, isolated from Aglaia elliptifolia Merr, showed effective PAF antagonistic activity in vitro and in vivo model, bicyclo[3.2.1]octanoid neolignans from leaves of Ocotea macrophylla Kunth., Yangambin, a furofuran lignan isolated from Ocotea duckeiVattimo, 6(7)-Dehydroschisandrol A, a derivative of schisandrol A lignan isolated from Schisandra chinensis, (2S,3R,4R)-tetrahydro-2-(3,4-dimethoxyphenyl)-4-(3,4-dimethoxybenzoyl)-3-(hydroxymethyl) furan (magnone A, 1) and (2S, 3R, 4R)-tetrahydro-2-(3,4,5-trimethoxyphenyl)-4-(3,4-dimethoxybenzoyl)-3(hydroxymethyl) furan (magnone B, 2)³¹.

Magnones A and B two new lignan compounds were isolated from the flower buds of Magnolia fargesii, showed antagonistic activity against PAF [3H] receptor binding assay, Niranthin lignan isolated from Phyllanthus amarus, A new neolignan, piperwalliol A , and four new aromatic glycosides, piperwalliosides A-D were isolated from the stems of Piper wallichii, along with 25 known compounds, including 13 lignans, six aromatic glycosides, two phenylpropyl aldehydes, and four biphenyls showed good in vivo antithrombotic effect and many other natural PAF antagonists natural products and plants extracts or even crude drugs having PAF antagonist properties are being used currently against different inflammatory pathologies³².

4. Blocking of L-type Ca²⁺ channels:

Several lignans and neolignans with calcium channel blocker based VDCC inhibitory activity have been reported from many of the plants and their phytomolecules; compound such as Cinnamophilin (8R,8'S)-4,4'-dihydroxy-3,3'-dimethoxy-7-oxo-8,8'-neolignan), isolated from Cinnamomum philippinense, was studied in isolated rat aorta, guinea-pig trachea and rabbit platelets and act as a selective thromboxane A2 receptor antagonist especially in rat aorta, and also possesses voltage-dependent Ca²⁺ channel blocking properties. Yangambin, a furofuran lignan isolated from Ocotea duckeiVattimo, showed significant inhibition of the Ca²⁺ influx through voltage-gated Ca²⁺ channels, PAF antagonism, inhibition of cyclic AMP phosphodiesterase and activation of eNOS. Liriodendrin and syringaresinol mono-β-D-glucoside were extracted from Boerhaavia diffusa L., which belongs to the same chemical class as yangambin (furofuran lignan), showed significant Ca²⁺ channel blocking effect on frog heart isolated cells, using the whole-cell voltage clamp method. 2,3- dibenzylbutane-1,4-diol; a major mammalian lignan isolated from Schisandra chinensis (Turcz.) Baill., inhibited Ca²⁺ channel in rabbit femoral artery and guinea pig ileum. Honokiol and magnolol lignans are extracted from the Magnolia officinalis showed blocking of Ca²⁺-dependent oscillatory contractions on uterine artery^33-44.

DISCUSSION:

The traditional used medicine for cardiovascular diseases has made substantial use of natural products. The majority of the plant's pharmacological abilities are found in its aerial parts, which are used to treat several disease. Lignans and neolignans, which are this species' main phytochemical ingredients, as well as flavonoids have been identified through phytochemical research from its aerial portions. The roots have been used to separate a variety of chemicals, including uncommon and trace and macro elements. It has been demonstrated that various formulations, extracts, and pure chemicals made from these plant based lignans and neolignans have other biological properties such as antimicrobial, antiinflammatory, antioxidant, antidiabetic, cytotoxicity, immunological modulatory, sex hormone modulatory, anti-angiogenic, and hepato-renal protective activity³⁵.

CONCLUSION:

The phytochemical investigation of different antihypertensive lignan and neolignans, therapeutic applications, and pharmacological mechanism of natural products. These plants compounds have all been thoroughly explored in this review for their different mechanism to treat hypertension. However, more research on the phytochemistry and the mechanisms of action of isolated substances is required to completely comprehend the phytochemical profile and the intricate pharmacological effects of these plant based lignans and neolignans are involved. To further ensure this plant's safety and suitability as a source of modern medicine, clinical and laboratory investigations on the toxicity of all plant part extracts as well as other pure phytochemicals obtained from it are crucial.

CONFLICT OF INTEREST:

The author has no conflicts of interest.

ACKNOWLEDGMENTS:

The author would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.

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Received on 16.12.2022 Modified on 19.05.2023

Asian J. Research Chem. 2023; 16(5):394-398.

DOI: 10.52711/0974-4150.2023.00064