Quercetin as a Possible Cardiovascular Agent

Abstract

Diseases of the cardiovascular system are among the most common causes of morbidity and mortality in the adult population in developed countries. In addition to the possibilities of pharmacological treatment, the positive (and negative) influence of diet and its components is well documented in many cardiovascular diseases. Atherosclerosis is one of the main causes of chronic cardiovascular diseases. It is a chronic inflammatory disease of the vascular wall associated with disorders of lipid metabolism, endothelial dysfunction, migration, and proliferation of smooth muscle cells of the vascular media, oxidative stress, and many other mechanisms. Reactive oxygen species (ROS) contribute to the pathogenesis of many cardiovascular diseases. An imbalance between the formation of ROS and the ability of antioxidant systems to eliminate them leads to oxidative stress. Inhibition of ROS generation and function is thought to be a potential therapy to attenuate the extent of various cardiovascular diseases. The results of several studies indicate that the cardioprotective effect of quercetin could be related to its antioxidant properties. In the presented chapter, we will discuss the possible effects of quercetin on the prevention and treatment of various mechanisms supporting atherogenesis and thus the development of cardiovascular diseases.

1. Introduction

The most common cause of death in the world is cardiovascular diseases (CVDs). It is estimated that about 17.9 million people worldwide die of cardiovascular diseases every year. In recent decades, CVDs have been the primary cause of death in developed countries, but currently, developing countries are rapidly approaching them [1]. The basic pathology of atherosclerotic blood vessel involvement results in the development of coronary artery diseases, peripheral vascular diseases, cerebrovascular diseases, and subsequent development of complications of these diseases. The main risk factors for the development and progression of atherosclerosis are relatively well known. For didactic reasons, atherosclerosis risk factors can be divided into influenceable and uninfluenceable. Uninfluenceable factors include, for example, male gender, age, and positive family history. Influenceable factors include arterial hypertension, lipid metabolism disorders, smoking, diabetes, abdominal obesity, lack of physical activity, and many other factors that can be influenced by non-pharmacological procedures or pharmacologically [2]. The preventive measures within the framework of cardiovascular diseases focus precisely on influencing those risk factors, either by non-pharmacological or pharmacological approaches. Flavonoids have recently been the subject of considerable interest by many experts due to their wide range of possible benefits. Due to their wide distribution in nature and their general availability, they have become the subject of many studies aimed at preventing and treating cardiovascular diseases [3]. In 1998, the first randomized clinical trial that investigated the effect of quercetin on cardiovascular health in healthy subjects was conducted [4]. One of the problems and a possible explanation for the inconsistent results of clinical trials with quercetin is its low bioavailability. This is mainly influenced by its low solubility in the gastrointestinal tract and rapid biodegradation into inactive metabolites. Moreover, there is probably a high inter-individual variability in the absorption of quercetin, glucosidase activity as well as variations in the performance of metabolic enzymes, which leads to different results even when using the same doses and forms of quercetin [5]. The increasing amount of evidence in favor of positive cardiovascular effects has supported the clinical relevance of modified dosage forms of quercetin using different carriers, such as nanoparticles and microemulsions, in the following years.

2. Pathogenesis of atherosclerosis—influence of oxidative stress

The development of individual stages of atherosclerosis is caused by many molecular and cellular events at each level—from an early lesion of fatty streaks to a highly dangerous plaque prone to rupture. As mentioned above, the production of ROS such as superoxide anion, hydrogen peroxide, lipid peroxides, and peroxynitrite and their dominance over antioxidant systems leads to oxidative stress, which, together with endothelial dysfunction, is one of the important processes in the initiation and progression of atherosclerosis. Dietary antioxidants (natural free radical scavengers) and enzymes, e.g., glutathione peroxidase, can inactivate various species of ROS. Therefore, the low concentrations of these substances act as proatherosclerotic factors [6, 7]. High levels of oxidative stress are mediated by many factors, including abnormal sodium metabolism control in the kidneys, increased activity of angiotensin II, and smoking also occurs in conditions such as hypertension. Reactive oxygen species are produced by multiple enzyme systems found throughout the whole vascular system. Important sources of vascular ROS include the mitochondrial electron transport chain. NADPH oxidases (NOX), xanthine oxidase, and endothelial nitric oxide synthase (eNOS) [8]. All of the above enzymes catalyze the transfer of electrons from their respective substrates to oxygen molecules, reducing oxygen molecules. Basal production of ROS is essential to ensure signaling and cellular homeostasis. The increased concentrations of ROS can be beneficial in some cases, particularly in the oxidative burst of macrophages that is required to eliminate pathogens. Oxidative stress occurs when there is an excess of ROS, whether due to their increased formation and/or a decrease in antioxidant capacity. Increased levels of ROS in the subendothelial space cause oxidation of LDL (low density lipoproteins) particles. This is one of the first steps toward atherosclerosis [9]. Monocytes entering the subendothelial space transform themselves into macrophages, which are then transformed into foam cells under the influence of oxidized cholesterol-rich LDL particles. At the same time, the process of low-grade chronic inflammation is activated. Many cytokines, including interleukin-1 (IL-1), interferon-γ (IFN-γ), tumor necrosis factor-β (TNF-β), and angiotensin II, as well as several chemokines (monocyte chemoattractant protein-1—MCP 1, interleukin-8—IL-8, CXC cytokines and eotaxin) increase the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), P- and E-selectin. Increased activity of adhesion molecules attracts inflammatory and immune cells from the bloodstream (including monocytes, T and B lymphocytes, leukocytes, and mast cells) [10]. Leukocytes bound to adhesion molecules also enter the subendothelial space. At the same time, smooth muscle cells migrate from the intima to the medium and their proliferation and collagen secretion with the formation of an atherosclerotic plaque. These processes are mainly induced by growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor β (TGF-β). These lesions develop through remodeling and neovascularization, which can consequently cause CVD events [11]. The critical component of atherogenesis is dysfunctional endothelium characterized by endothelial leakage, increased production of ROS, secretion of proinflammatory cytokines, increased expression of surface adhesion markers, and decreased production of nitric oxide (NO) [12]. Endothelial dysfunction increases the risk of LDL passing into subendothelial space, where LDL can be oxidated with the participation of ROS. Due to the constitutive expression of eNOS, endothelial cells are the main source of NO. On the other hand, they are also important sources of superoxide and peroxynitrite due to the uncoupling of eNOS in response to BH4 depletion [13]. As showed by Ponnuswamy et al., eNOS deficiency in ApoE−/− mice reduces superoxide production, which indicates that eNOS uncoupling occurs during atherosclerosis [14]. Thus, the endothelium is both a source and a target of ROS. Oxidative stress supports endothelium in a proinflammatory state, which is essential for atherosclerosis. Supplementation with hydrogen peroxide increases the expression of the granule membrane protein, which facilitates the binding of neutrophils to the surface of endothelial cells [15]. Excess ROS and oxidative stress also induce NFκB, which promotes the expression of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin, and cytokines such as TNF-α, as mentioned above [16].

3. The effect of quercetin on atherosclerosis

Quercetin and quercetin glycosides act as strong antioxidants by scavenging free radicals, causing oxidative stress through their phenolic hydroxyls. It seems that the basic mechanism of the antiatherosclerotic effects of quercetin and its glycosides is an indirect antioxidant activity. It is likely that these compounds are involved in modulating the expression and activity of enzymes responsible for the regulation of oxidative stress. They also reduce the inflammatory response to various insults by suppressing the production of proinflammatory substances (e.g., several enzymes and cytokines) [17, 18].

Possible mechanisms of anti-inflammatory action of phenolic compounds include:

• Inhibition of the NFκB signaling pathway. This inhibition leads to downregulation of gene expression of proinflammatory enzymes, e.g., inducible NOS (iNOS), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX), and proinflammatory cytokines (IL-1β, IL-6, TNF-α) [19].

• Reduction of monocyte adhesion to endothelial cells by suppressing the expression of E-selectin, MCP-1, ICAM-1, and VCAM-1 [20].

• Reduction of endothelial oxidative stress by inhibition of ROS production dependent on NOX.

• Increasing the levels of the endothelial antiatherosclerotic factor NO by acceleration of eNOS phosphorylation via mechanisms dependent on AMPK (AMP-activated protein kinase).

• Elevation of eNOS expression by activation of Nrf2 E2 (nuclear factor erythroid 2-related factor 2) pathway [21].

• Suppression of vascular smooth muscle cells (VSMC) migration by inhibition of platelet-derived growth factor signaling molecules, such as phosphoinositide-3-kinase (PI3K).

• Suppression of VSMC growth by inducing apoptosis via P38 mitogen-activated protein kinase and p53 signaling pathways activation [22, 23].

A recently published systematic meta-analysis of 16 RCTs (randomized controlled trials) published between 2007 and 2017 focused on the effects of quercetin on the lipid profile in subjects with metabolic syndrome. The authors of the meta-analysis report that quercetin led to significant reductions in total and LDL cholesterol without affecting triglyceride levels. Unfortunately, daily doses and treatment durations used in the trials varied considerably. Treatment duration varied from 3 to 12 weeks, and daily doses from 3.12 to 3000 mg [24]. Another meta-analysis of 9 RCTs conducted in overweight and obese patients confirmed that quercetin supplementation could significantly reduce LDL cholesterol levels at doses ≥250 mg per day and at a total dose ≥14,000 mg (i.e., at least 56 days of quercetin administration) [25]. It is assumed that quercetin also interferes in the activity of matrix metalloproteinases (MMPs). In the studies using molecular modeling techniques, cultured endothelial cells, murine macrophage cells, and in hypertensive rats, quercetin downregulated the expression of MMP-1, MMP-2, and MMP-9. This is the effect that translates into the prevention of plaque instability [26, 27, 28]. Quercetin was found to have an antiaggregatory effect on rat platelet-rich plasma depending on the concentration [29]. A synergistic increase in the antiplatelet effect was noted when quercetin was added to aspirin [30]. In addition, isorhamnetin and tamarixetin, two methylated metabolites of quercetin, have been shown to inhibit platelet aggregation and thrombus formation in vitro via effects on activation processes such as integrin activation, granule secretion, and intracellular Ca²⁺ mobilization. Their antithrombotic effect was confirmed in mouse cremaster arterioles with laser-induced thrombi [31]. Quercetin significantly increases cyclic adenosine monophosphate (AMP) levels and inhibits arachidonic acid and adenosine diphosphate (ADP)-induced platelet aggregation, in human platelets [32].

4. The effect of quercetin on hypertension

The most common cardiovascular disease present in 1.28 billion adults worldwide is hypertension. Hypertension is a recognized risk factor for the development of atherosclerosis and other cardiovascular diseases. It is estimated that almost 50% of adults with hypertension are not aware of the elevated blood pressure. There are only 20–30% of treated people for hypertension that are under the control [33]. Bioflavonoids, especially quercetin, one of the most important of these, can find their place in the prevention and treatment of hypertension due to their anti-inflammatory potential, as recent findings suggest [34]. There are many mechanisms of hypertension. All of them result in endothelial dysfunction. In addition, oxidative stress accompanied by ROS contributes to this dysfunction. Consequently, this dysfunction disconnects the endothelial nitric oxide synthase (eNOS) which leads to a reduction of the bioavailability of nitric oxide (NO). NO is an endogenous relaxing factor that regulates vascular tone as well as vascular and cardiac remodelation. Decreased NO levels are associated with hypoxia and the progression of cardiovascular diseases in patients with pre-existing vascular dysfunction [35]. The contribution to vasodilatation of healthy individuals is ambiguous. It is assumed that the protective effect of quercetin on endothelial dysfunction is related to its antihypertensive effect. The scavenging activity of quercetin against ROS helps this effect and reduces endoplasmic stress. In vitro study from Lin et al. demonstrated that 20 μmol of quercetin reduced intracellular ROS levels in endothelial cells of mesenteric arteries isolated from hypertensive and normotensive animals [36]. Quercetin can improve vascular function via the activated protein kinase (AMPK) pathway inducing activation of eNOS and, thus, NO production, as ex vivo endothelial function studies have shown [37]. Both in vitro studies conducted by Pereira et al. [38] and Lin et al. [36] confirmed the involvement of quercetin-induced autophagy, which leads to improved endothelial cell quality and increased NO production. Long-term administration of quercetin in an animal study induced progressive reduction of SBP (systolic blood pressure) in spontaneously hypertensive rats (SHR). This effect reached statistical significance after the first week of treatment, while in a group of Wistar Kyoto rats, no changes were observed. After 5 weeks of treatment, direct measurements of blood pressure in conscious rats showed that quercetin treatment on SHR induced a significant reduction in systolic (−18%), diastolic (−23%), and mean (−21%) arterial blood pressure. Quercetin also significantly reduced the heart rate (−12%) in these rats [39]. Besides that, administration of quercetin appears to correlate with a reduction in oxidative stress in the aortas of 2K1C rats. However, its effect on systolic blood pressure (SBP) values in 2K1C rats is controversial. A dose-dependent decrease in SHR was observed, with a high dose of quercetin (>7 mg/kg) required to achieve a significant decrease (p < 0.05) in both systolic (SBP) and diastolic blood pressure (DBP) [38]. The results of another animal study, where rats were fed a high-salt content diet (0.8% NaCl) during 12 weeks, showed, as expected, an increase in systolic, diastolic, pulse, and mean arterial blood pressure. Chronic salt overload also led to an increase in lipid peroxidation and a decrease in the activity of antioxidant enzymes. Treatment with rutin and quercetin for almost 2 weeks resulted in a remarkable reversal of these indicators when compared with animals that continued only on a high-salt diet (no treatment group). A high-salt content diet also led to a significant increase in concentrations of urea, creatinine, glucose, triacylglycerols, total cholesterol, and low-density lipoproteins. The effect of a high-salt diet on the observed parameters was partially reduced by the administration of rutin or quercetin, while the reference drug nitrendipine showed a smaller effect than these two flavonoids. The results of this study confirm the role of rutin and quercetin as relatively potent antihypertensives and antioxidants [40]. In several in vitro and in vivo studies, quercetin has been shown to inhibit angiotensin-converting enzyme (ACE) by binding a zinc molecule to the active site of the ACE. Blocking the active site of the enzyme slows down the conversion of angiotensin I to angiotensin II. This effect is probably related to the chemical structure of flavonoids, mainly the presence of a 30–40 catechol group on the B ring and a double bond and a ketone group on the C ring [41, 42].

On the other hand, the study by Carlstrom et al. did not demonstrate the effect of a diet supplemented with quercetin on the development of arterial hypertension and its complications (e.g., vascular dysfunction and remodeling, hypertrophy of the left ventricular myocardium) in spontaneously hypertensive rats. However, they attributed this discrepancy to the route of administration [43].

Egert et al. found that quercetin in humans led to a significant reduction in systolic blood pressure in all obese and hypertensive participants [44]. On the other hand, Edwards et al. reported that quercetin had no significant effect on blood pressure in prehypertensive patients. Significant reduction in systolic and diastolic blood pressure was shown only in case of patients with stage 1 hypertension [45]. A meta-analysis of data from nine treatment arms of RCTs showed a significant reduction in SBP and DBP after quercetin supplementation. The effect of quercetin probably also depends on the length of its administration. A decrease in both SBD and DBP at the borderline of statistical significance was demonstrated in studies lasting ≥8 weeks, while no significant effect on blood pressure was found in studies in which quercetin was administered for less than 8 weeks. When the studies were categorized by dose of quercetin, there were significant reductions in systolic BP in RCTs with doses ≥500 mg/day and lack of significant effect at doses <500 mg/day. Adjusted indirect comparison did not suggest any significant difference between either of the doses [46].

5. Quercetin and dyslipidemia

Quercetin supplementation significantly reduced levels of plasmatic triglycerides at doses above 50 mg/day, as pointed out in the recent meta-analysis by Sahebkar et al. [47]. However, the available evidence from the 5 RCTs included in this meta-analysis showed a non-significant relationship between quercetin supplementation and other lipid metabolism parameters (total cholesterol, LDL, HDL) [47]. Another systematic review of 9 RCTs described by Guo et al. showed no statistically significant changes in plasma lipids with quercetin supplementation, with the exception of the administration of higher doses of quercetin (more than 250 mg/day) to overweight and obese subjects, in whom it might lower LDL cholesterol [25]. Some other researchers supported the beneficial effects of quercetin in patients with dyslipidemia and metabolic syndrome, when used as add-on therapy. Mazza et al. demonstrated improved plasmatic levels of triglycerides and LDL in hypertensive and dyslipidemic patients with statin intolerance when receiving quercetin in combination with ezetimibe [48]. Quercetin supplementation significantly reduced plasma levels of total cholesterol, LDL, and CRP in patients with metabolic syndrome, as a recent meta-analysis of 16 RCTs has shown [24]. In animal studies, serum triglycerides and total cholesterol levels decreased after quercetin consumption, but this effect was observed only in animals with higher blood lipid concentrations. Quercetin had a beneficial effect on plasma lipid profile in db/db mice [49]. In a study in Western diet-fed mice, Kobori et al. found that quercetin reduced the expression of peroxisome proliferator-activated receptor-α (PPAR-α) and sterol regulatory element-binding protein-1c (SREBP-1c) in the liver, leading to a decrease in triacylglycerol synthesis [50]. Quercetin appears to reduce acetyl-CoA carboxylase (ACC) activity and de novo synthesis of fatty acids and triglycerides in rat hepatocytes. This mechanism could explain the documented effect of quercetin on reducing the concentration of triacylglycerols. Thus, quercetin may improve dyslipidemia through multiple mechanisms, particularly by regulating the expression of PPAR-α, SREBP-1c, and ACC [51].

In addition, quercetin showed a protective effect against high-cholesterol diet-induced cardiac diastolic dysfunction in hyperglycemic rats. This effect is probably caused by the hindrance of cholesterol accumulation and the reduction of ATP, which prevents the change in the expression of PGC-1a, UCP2, and PPARγ receptors [52]. In vitro study by Sun et al. in human THP-1-derived macrophage cells showed that quercetin causes cholesterol efflux, reducing foam cell formation. This potentially slows down the development and progression of atherosclerosis. This effect of quercetin appears to be mediated by up-regulation of the cholesterol transporter ABCA1 and the transcription factor PPARγ [53]. Cui et al. reported the same findings after an 8-week-long treatment of apolipoprotein E-deficient atherosclerotic mice with quercetin [54]. Several studies have shown that quercetin can prevent the overexpression of genes for ICAM-1 and MCP-1 and thereby inhibit cell migration in atherosclerotic plaques, reducing the risk of stroke [55]. Liang et al. underlined the importance of developing new delivery systems that are able to increase the solubility of quercetin in their studies in cell lines in vitro and in an animal model in vivo [56].

6. Quercetin and dysrhythmias

The energy requirements for sustained electrical and contractile activity of the heart muscle are from more than 90% saturated with cellular adenosine triphosphate (ATP), which is produced by mitochondrial oxidative phosphorylation. Reactive oxygen species are widely present in human cells and, among other things, act as active factors in information transfer and cell apoptosis. As already mentioned, ROS are mainly produced in the mitochondrial electron transport chain (ETC), xanthine oxidase, NADPH oxidase (NOX), and nitric oxide synthase (NOS) [57]. Their excess, which can have a harmful effect, is then eliminated by enzymes such as superoxide dismutase (SOD), catalase, etc. An excess of ROS causes mitochondrial oxidative stress, which negatively affects cardiac excitability, mainly by worsening the function of sodium, potassium, calcium channels, and transporters. This potentially leads to structural and electrical remodeling of the heart with the possible occurrence of various types of arrhythmias [58, 59]. In response to various types of damage, the heart responds adaptively by cardiac remodeling, which is characterized by compensatory maladaptive cardiomyocyte hypertrophy and collagen production with fibrosis formation. Accumulation of the extracellular matrix (EMC) in the myocardium increases the stiffness of the ventricles and impairs relaxation and contraction of the heart. This process, known as cardiac fibrosis, is known to be the underlying pathological basis of various heart diseases. The three main components of arrhythmogenesis and arrhythmia maintenance are:

• substrates,

• triggers,

• and facilitators.

There is ample evidence that fibrosis is one of the main substrates for the development and maintenance of arrhythmias. It is proven that fibrosis can contribute to the development and maintenance of arrhythmias by several mechanisms, primarily through direct electrophysiological mechanisms, as well as indirect cellular mechanisms [60, 61].

Fibrosis can be divided into four different patterns: compact, interstitial, patchy, and diffuse. Of these four types, patchy and interstitial fibrosis in particular can disrupt the electrical connections between cardiomyocytes, causing discontinuous or “zig-zag” conduction that induces arrhythmias. In addition to discontinuous “zig-zag” conduction, cardiac fibrosis may induce other electrophysiological abnormalities through the heterocellular electrical coupling of myofibroblasts and cardiomyocytes, contributing to the development of arrhythmias [62]. Quercetin can positively influence arrhythmias mainly through its effect on cardiac ion channels, improving calcium homeostasis, affecting gap junctions and mitochondrial channels, inhibiting mitochondrial oxidative stress and suppressing cardiac fibrosis, inflammation, modulation of autophagy and apoptosis, as well as improving ischemia/reperfusion injury and gut microbiota [63]. Quercetin also regulates or even directly inhibits critical signaling pathways and key molecules involved in the pathomechanism of arrhythmias, such as TGF-β/Smad, NF-κB and PI3K/AKT and others [64]. In summary, it appears that quercetin can prevent and treat arrhythmias by affecting multiple targets, directions, and pathways in arrhythmogenesis. This may have great potential and clinical application value in the future. Nevertheless, there are some objective limitations of the current research and many questions remain to be resolved.

7. Quercetin in diabetes mellitus

Diabetes mellitus is best defined as a group of endocrine diseases characterized by hyperglycemia as a result of defective insulin secretion or insulin resistance. Insulin signaling has been well defined at the molecular level, but the exact reason for insulin resistance in tissues (especially skeletal muscle), adipose tissue, or liver has not yet been precisely elucidated. Imbalance between ROS and antioxidant defense systems leading to oxidative stress is evident in T2DM pathogenesis [65]. In addition, ROS directly damages mitochondrial DNA, lipids, and proteins and stimulates mitophagy [66]. Mitochondrial dysfunction reduces the catabolism of metabolic substrates, leading to the accumulation of lipid metabolites that contribute to the development of insulin resistance in skeletal muscles, adipocytes, and liver [67]. Hyperglycemia has a harmful effect on the mitochondrial oxygen consumption rate in pancreatic beta cells. That worsens glucose-responsive insulin secretion and stimulates apoptosis. Mitochondrial-targeted ROS-scavenging antioxidants have been shown to reduce lipid peroxidation and improve disease status in animal models of several diseases, including neurodegenerative diseases, diabetic kidney damage, hypertension, Parkinson’s disease, and cardiovascular diseases [68]. Excessive accumulation of lipid metabolites inside cells also activates the serine kinase pathway, leading to reduced insulin stimulation and decreased hepatic glucose uptake. Reduced quantity and activity of insulin receptors, serine/threonine hyperphosphorylation of the insulin receptor substrate IRS-1, reduced activity of PI3K, Akt kinase, and PTP1B, and defective expression of GLUT4 have been reported among patients with T2DM [69].

Numerous in vitro and prospective animal and clinical studies provide significant evidence that bioflavonoids can be considered as potential agents for the prevention and treatment of diabetes and its complications. Studies conducted on streptozotocin (STZ) induced diabetes rats and type 2 diabetic rats revealed that quercetin can lower blood glucose levels and improve glucose tolerance [70, 71]. Quercetin has also been shown to activate adenosine monophosphate-activated protein kinase (AMPK) in rat liver, which reduces glucose synthesis primarily through the downregulation of glycogen isoenzymes such as phosphoenolpyruvate carboxylase (PEPCK) and glucose-6-phosphatase (G6Pase) [72]. By promoting GLUT4 translocation to cell membranes in mouse skeletal muscle cells, quercetin increases glucose re-uptake. These findings suggest that quercetin may be involved in the regulation of glucose metabolism, increasing glycolysis, and decreasing gluconeogenesis [73].

8. Conclusion

Quercetin is one of the most potent and widespread biologically active flavonoids found in fruits and vegetables. Flavonoids are special chemicals in plants called phytonutrients and have a wide range of health benefits. Diet plays a vital role in reducing the risk of cardiovascular diseases such as heart disease and stroke. Because fruits and vegetables contain flavonoids, eating more of them can reduce the risk of these diseases. As mentioned above, quercetin can improve a wide range of cardiovascular diseases and many risk factors for their development.

In doses commonly found in food, quercetin is unlikely to interact with drugs used for various diseases. The question is whether it affects the effect of other drugs in supranormal doses when supplemented. As mentioned above, quercetin has vasodilating effects. Although this effect may be beneficial in some cases, it may also potentiate the effects of antihypertensive drugs, potentially leading to unwanted hypotension. Quercetin can thus interact with various antihypertensives, such as ACE inhibitors, calcium channel blockers, and beta blockers. Quercetin is found in foods such as onions, apples, and tea and has mild diuretic properties. Thus, when combined with diuretics, the diuretic effects of quercetin may be additive, leading to an increased risk of dehydration or electrolyte imbalance [74, 75]. Therefore, monitoring blood pressure and some biochemical parameters is important when administering quercetin preparations and antihypertensives simultaneously. In addition, some studies suggest that quercetin can inhibit enzymes of the cytochrome P450 system, which, among other things, are involved in drug metabolism. This inhibition could potentially affect the metabolism and clearance of some drugs and thus lead to changes in the levels of these drugs in the body [76, 77].

However, regardless of its mechanism of action, we still need to confirm the cardiovascular risk-reducing effect of quercetin in humans and its potential pharmacological interactions in larger randomized clinical trials.