The vasodilatory effects of medicinal herbs on the cardiovascular system: A systematic review

Introduction Vasodilatation is well-known as one of the main therapeutic strategies to treat some cardiovascular diseases with high blood pressure (1,2). Vasodilators are drugs that induce or start the widening of blood vessels, which are commonly applied to treat disorders with irregularly high blood pressure, including hypertension, congestive heart failure, and angina (3-5). At present, there are many agents that have been shown to have vasodilation effects by various mechanisms, such as inhibiting angiotensin-converting enzyme (ACE), blocking calcium channels, opening potassium channel, or inhibiting cGMP-specific 3’,5’-cyclic phosphodiesterase (PDE5) (6,7). However, despite the potential effects of the existing vasodilators, recent studies have indicated some limitations of these drugs, including drug resistance, drug dependence, reducing the systemic vascular resistance through renal retention of sodium and water, orthostatic http://www.herbmedpharmacol.com doi: 10.34172/jhp.2021.43


Introduction
Vasodilatation is well-known as one of the main therapeutic strategies to treat some cardiovascular diseases with high blood pressure (1,2). Vasodilators are drugs that induce or start the widening of blood vessels, which are commonly applied to treat disorders with irregularly high blood pressure, including hypertension, congestive heart failure, and angina (3)(4)(5).
At present, there are many agents that have been shown to have vasodilation effects by various mechanisms, such as inhibiting angiotensin-converting enzyme (ACE), blocking calcium channels, opening potassium channel, or inhibiting cGMP-specific 3' ,5'-cyclic phosphodiesterase (PDE5) (6,7). However, despite the potential effects of the existing vasodilators, recent studies have indicated some limitations of these drugs, including drug resistance, drug dependence, reducing the systemic vascular resistance through renal retention of sodium and water, orthostatic hypotension and syncope upon standing, increasing the heart rate and inotropy (8,9). Therefore, the development and discovery of novel agents as blood vessel dilators are promising among researchers. Medicinal plants have always been used by humans throughout history. The use of plants, plant materials, plant compounds has been introduced as herbal medicine all over the world (10,11). On the other hand, the return to nature and the reuse of drugs of plant and natural origin takes place in a situation where today's man has faced the side effects of these drugs. Scientific research has proven the effectiveness and safety of some complementary medicine methods, including herbs, in the treatment of some diseases (12,13). The present study aims to systematically review the studies on the vasodilation effects of some medicinal herbs.

Search strategy
This study was done according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines (14) and registered in the CAMARADES-NC3Rs Preclinical SyRF database. Various English databases, such as Scopus, PubMed, Web of Science, EMBASE, and Google Scholar, were used to find publications about the vasodilation effects of medicinal herbs up to 2020. The searched words and terms were: "medicinal herbs", "medicinal plants", "vasodilator", "vasorelaxant", "hypertension", "high blood pressure", "vasodilation", "extract", "essential oil" (Figure 1). Quality assessment and article selection Initially, the publications were imported to the EndNote X9 software based on the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE); whereas the duplicate papers were omitted. Then, three independent authors tested the titles and abstracts of the papers, and the relevant publications were included for further analysis. The same authors carefully analyzed the publications, and the suitable papers with acceptable inclusion criteria were selected. Any disagreement between the authors were resolved through the corresponding author Inclusion and exclusion criteria All papers evaluating the vasodilation effects of medicinal plants were included, whereas the studies with only abstract, inadequate information, failure to match methods with results, and inappropriate interpretation of the results were excluded ( Figure 1).

Data extraction
The independent researchers extracted data, including the name of plant, plant family, the part used, type of extraction, concentration, and important results.

Discussion
According to the WHO reports, herbal medicines and their derivatives because of low or no industrial handling and toxicity have been extensively used to treat various diseases such as diabetes, cancer, cardiovascular, and gastrointestinal problems, by local or regional healing methods in developed and developing countries (10,11).
Reviews have previously demonstrated that the biological activities and treating properties of medicinal plants are due to the secondary metabolites existing in plants making them a reliable source for providing of new agents (12,13). Flavonoids are considered one of the key secondary metabolites of plants, which have numerous pharmacological and therapeutics properties in the cardiovascular system, including vasodilation, antiatherogenic, antihypertensive, antioxidant, and antiplatelet properties (46,47). These compounds show their vasodilation and antihypertensive effects through inhibiting tyrosine kinase Pyk2 as the main enzyme to regulate calcium channels, activation of the cAMP/protein kinase A cascade, modulating the renin-angiotensinaldosterone system, adapting the contraction of vessels of smooth muscles, activating the potassium channels, and decreasing calcium ions in cells by delaying voltage-gated calcium channels, etc (48).
Other important compounds in plants, which have exhibited considerable vasodilation and antihypertensive effects, are phenolic compounds (49,50). Studies have reported that polyphenols display their effects through some mechanisms such as increasing endotheliumderived nitric oxide bioactivity, suppression of smooth muscle activation, regulating calcium channels, etc (51,52).
Terpenes are well-known as the key herbal compounds with a broad spectrum of pharmacological and therapeutic activities, including antihypertensive and vasodilation properties (53). Reviews demonstrated that these secondary metabolites act through a direct effect on vascular smooth muscle, an effect on the peripheral vascular resistance, no release of NO, activating the NO-cGMP pathway, and inhibition of Ca 2+ influx, etc (54).
The present review showed that aerial parts, especially the leaves, were the most common parts of medicinal plants used for their vasodilatory activities. Reviews have demonstrated that leaves are well-known as the favored part of plants for therapeutics aims due to having a high percentage of bioactive composites; and convenience in harvesting without any damage to the herb (55)(56)(57)(58).
We found that ethanolic extract, aqueous extract, and methanolic extract were the most used plant formulations. A previous study revealed that the general use of these extracts represents the role of solvents in the extraction of potential bioactive components from different plants and various parts of these herbs (59). The adverse side effects of herbal medicines are linked to a number of factors, including the toxicity of main constituents, lack of suitable manufacturing techniques, and consequently, heavy metals or microbes contaminations, and side effects on consumers, which are dependent on age, genetic and the underlying diseases of them (60)(61)(62). Today, exposure of a plant extracts in humans can be evaluated by detecting the increasing effects and doses that cause toxicity, such as carcinogenic, mutagenic, and teratogenic problems (63). A number of toxicity tests are necessary to assess the level of damages triggered by herbal extracts and their derivatives (63). In all in vivo studies, including in the present review, the used doses of medicinal herbs for evaluation of their vasodilation/vasorelaxation activities were based on the reliable toxicity tests such as acute toxicity, sub-chronic toxicity, the fixed-dose procedure indicating that these medicinal herbs in used doses have no significant toxicity in tested animals.

Limitations
The main limitations of the present study are the lack of phytochemical analysis on most plants to identify the main components of the plant, the lack of basic vasodilation mechanisms of some plants, and the lack of clinical studies.

Conclusion
Recently, numerous studies have been carried out on the antihypertensive and vasodilation effects of herbal extracts and essential oils alone or in combination with existing drugs. The results revealed that the herbal vasodilatory agents might be used as an alternative and complementary